1Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
2Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
3Department of Pathology, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea
Copyright © 2024 by the Korean Cancer Association
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Case 1 | Case 2 | Case 3 | Case 4 | Case 5 | |
---|---|---|---|---|---|
Clinical feature | |||||
Age (yr) | 53 | 74 | 66 | 62 | 54 |
Sex | Female | Female | Female | Female | Female |
Site | Proximal urethra | Proximal urethra | Proximal urethra | Urethra | Urethra |
Size (cm) | 5×2×1.3 | 4×2.5×2.5 | 1.8×1.5×1 | 3×2×1.1 | N/A |
Treatment | Pelvic exenteration and adjuvant chemotherapy | Radical cystectomy with vaginectomy | Neoadjuvant chemotherapy and radical cystectomy, adjuvant chemotherapy | Radical cystectomy, urethrectomy and vaginectomy | TUR with pelvic lymph node dissection and palliative chemoradiation therapy |
Outcome (F/U time) | PD, metastasis to lung (6 mo) | PD, metastasis to lung (37 mo) | PD, local recurrence with neck and mediastinal LN metastasis (9 mo) | PD, metastasis to lung, peritoneal seeding (23 mo) | PD, metastasis to lung (4 mo) |
Death (36 mo) | Death (11 mo) | ||||
Pathologic feature | |||||
Tumor architecture | Tubulocystic | Papillary and tubulocystic | Tubulocystic | Papillary, solid and tubulocystic | Solid and tubulocystic |
Cell morphology | Clear and eosinophilic cells | Hobnail and eosinophilic cells | Hobnail and eosinophilic cells | Clear and hobnail cells | Clear and hobnail cells |
Nuclear pleomorphism | Moderate | Marked | Mild | Marked | Moderate |
Mitosis (per 10 HPFs) | 3 | 12 | 1 | 9 | 4 |
Urethral diverticulum | Present | Present | Present | Present | Absent |
Tumor extension | Bladder neck | Bladder neck and vagina | Bladder neck and vagina | Bladder neck and vagina | N/A |
LVI | Lymphatic | None | None | None | N/A |
Lymph node metastasis | Present (4/6) | N/A | Present (23/53) | Absent (0/36) | Present (5/5) |
Other malignancy | No | No | No | Yes, breast cancer | Yes, breast cancer |
Case | PAX-8 | CK7 | GATA3 | AMACR | HNF1β | Napsin A | Ki-67 (%) |
---|---|---|---|---|---|---|---|
1 | P | P | N | P | N | P | 10 |
2 | P | P | N | FP | P | N | 1 |
3 | P | P | N | P | P | P | 5 |
4 | P | FP | N | FP | P | N | 25 |
5 | P | P | N | FP | P | N | 70 |
Case | Gene | Driver | Role | Effect | Type | Reference | Alternate | Chr. | cDNA change | Protein change | VAF (%) |
---|---|---|---|---|---|---|---|---|---|---|---|
1 | WBSCR27 | - | - | Splice site | Indel | CTGTG | C | 7 | c.389-5_389-2delCACA | 30.76 | |
2 | APC2 | - | - | Nonsense variant | SNV | C | A | 19 | c.2855C>A | p.Ser952* | 42.85 |
CSMD3 | - | TSG | Missense variant | SNV | C | T | 16 | c.2972G>A | p.Arg991His | 14.28 | |
LAMC2 | - | - | Missense variant | SNV | C | T | 1 | c.301C>T | p.Arg101Trp | 12.5 | |
3 | ZNF219 | - | - | In-frame deletion | Indel | GGAGGCT | G | 14 | c.698_703delAGCCTC | p.Gln233_Pro234del | 46.34 |
KRAS | + | OG | Missense variant | SNV | C | A | 12 | c.35G>T | p.Gly12Val | 11.79 | |
4 | KEAP1 | - | TSG | Missense variant | SNV | C | T | 19 | c.1085G>A | p.Arg362Gln | 37.5 |
SMARCA4 | - | TSG | Missense variant | SNV | T | C | 19 | c.3461T>C | p.Leu1154Pro | 25.45 | |
CACNA1D | - | OG | Missense variant | SNV | C | G | 3 | c.4780C>G | p.Arg1594Gly | 24.17 | |
AMER1 | + | TSG | Missense variant | SNV | C | T | X | c.2254G>A | p.Glu752Lys | 24.07 | |
PIK3R1 | + | TSG | Missense variant | SNV | G | A | 5 | c.1670G>A | p.Arg557Gln | 19.17 | |
TNK2 | - | - | Missense variant | SNV | G | T | 3 | c.1700C>A | p.Ser567Tyr | 17.97 | |
5 | PBRM1 | + | TSG | Frameshift variant | Indel | AC | A | 3 | c.3245delG | p.Gly1082fs | 31.75 |
ARID1A | + | TSG | Nonsense variant | SNV | G | A | 1 | c.4634G>A | p.Trp1545* | 45.26 | |
NKD1 | - | - | Missense variant | SNV | G | A | 16 | c.92G>A | p.Arg31Gln | 40.35 | |
ACVRL1 | + | - | Missense variant | SNV | C | A | 12 | c.532C>A | p.Leu178Met | 30.76 | |
CAPN2 | - | - | Missense variant | SNV | C | T | 1 | c.1433C>T | p.Pro478Leu | 29.52 | |
CC2D1B | - | - | Missense variant | SNV | C | G | 1 | c.1208G>C | p.Arg403Pro | 28.82 | |
CHD4 | - | OG,TSG | Missense variant | SNV | C | T | 12 | c.4822G>A | p.Val1608Ile | 28.4 | |
KMT2D | + | OG, TSG | Missense variant | SNV | G | T | 12 | c.2312C>A | p.Ser771Tyr | 28 | |
TCF12 | - | TSG | Missense variant | SNV | C | T | 15 | c.280C>T | p.His94Tyr | 26.51 |
Case | Gene | Driver | Role | Pathway | Biologic function | Tumor |
---|---|---|---|---|---|---|
1 | WBSCR27 | - | - | - | Methyltransferase | Colorectal ADC; malignant melanoma |
2 | APC2 | - | - | Wnt/β-catenin pathway | Cell proliferation, apoptosis epithelial-mesenchymal transition, invasion, metastasis | Thyroid PTC, malignant melanoma, colorectal ADC, bladder urothelial carcinoma; HCC |
CSMD3 | - | TSG | - | Tumor mutation burden, tumor-promoting inflammation | Ovarian serous carcinoma; breast IDC; colorectal ADC; uterine endometrial carcinoma | |
LAMC2 | - | - | PI3K/AKT/mTOR pathway | Cell junction organization; increase aggressiveness; focal adhesion; inflammatory response pathway | HCC; malignant melanoma; uterine endometrial carcinoma, lung ADC | |
3 | ZNF219 | - | - | Chromatin remodeling | Transcription factor | Colorectal ADC; thyroid PTC; malignant melanoma; stomach cancer; uterine endometrial carcinoma |
KRAS | + | OG | MAPK signaling pathway; PI3K/AKT/mTOR pathway; RAS signaling pathway | Cell proliferation, differentiation and migration | Lung ADC; pancreas ADC; colorectal ADC; uterine endometrial carcinoma | |
4 | KEAP1 | - | TSG | Keap1-Nrf2 pathway | Detoxification or antioxidation | Lung ADC, SqCC; endometrial carcinoma; uterine carcinomsarcoma; tonsil SqCC; biliary tract ADC |
SMARCA4 | - | TSG | Chromatin remodeling | Gene expression regulation | Lung ADC; colorectal ADC; uterine endometrial carcinoma; bladder urothelial carcinoma; breast IDC | |
CACNA1D | - | OG | MAPK signaling pathway | Cell proliferation, differentiation and migration | Uterine endometrial carcinoma; malignant melanoma; stomach ADC; lung SqCC | |
AMER1 | + | TSG | Wnt/β-catenin pathway | - | Lung cancer; malignant melanoma; uterine endometrial carcinoma; Wilms tumor | |
PIK3R1 | + | TSG | PI3K/AKT/mTOR pathway; JAK/STAT pathway; RAS signaling pathway; Cell cycle pathway | Cell proliferation; apoptosis; protein synthesis; metabolism; cell cycle; apoptosis | Uterine endometrial carcinoma; colorectal ADC; breast IDC; glioblastoma; lung ADC | |
TNK2 | - | . | ACK1 signaling | Cell proliferation; apoptosis | Prostate cancer, breast IDC, pancreas ADC | |
5 | PBRM1 | + | TSG | Chromatin remodeling | - | Renal cell carcinoma, clear cell type; lung ADC; colorectal ADC; breast IDC |
ARID1A | + | TSG | Chromatin remodeling | Cell cycle progression; invasiveness; stemness; differentiation | Uterine endometrial carcinoma; lung ADC; colorectal ADC; bladder urothelial carcinoma; breast IDC | |
NKD1 | - | - | Wnt/β-catenin pathway | Cell proliferation; cell adhesion and motility; cell cycle progression; invasiveness | HCC; head and neck SqCC | |
ACVRL1 | + | - | TGF-beta receptor signaling pathway; PI3K/AKT/mTOR pathway; MAPK pathway | Angiogenesis; invasion; migration; cell proliferation and growth; cell-cell interaction and differentiation; epithelial-mesenchymal transition; invasion; dissemination to distant organ sites | Breast IDC | |
CAPN2 | - | - | Integrin-mediated cell adhesion pathway | Cellular shape; mobility; cell cycle regulation | Breast IDC, uterine endometrial carcinoma; HCC | |
CC2D1B | - | - | EGFR signaling; TLR4 signaling | Transcription factor; cell proliferation | Uterine endometrial carcinoma | |
CHD4 | - | OG, TSG | Chromatin remodeling | Genome instability and mutations | Uterine endometrial cancer; brain diffuse glioma; lung ADC; colorectal ADC | |
KMT2D | + | OG, TSG | Chromatin remodeling | - | Lung adenocarcinoma; colorectal ADC; bladder urothelial carcinoma; breast IDC; uterine endometrial carcinoma | |
TCF12 | - | TSG | Transcriptional regulation; MAPK pathway | - | Extraskeletal myxoid chondrosarcoma; hepatocellular carcinoma |
Case | p53 | ATMa) | Smad4a) | Phospho-mTOR | β -catenin | Phospho-p44/42 MAPK | ARID1Aa) | CHD4 | PBRM1a) | PD-L1 SP142 | PD-L1 22C3 |
---|---|---|---|---|---|---|---|---|---|---|---|
1 | WT | N | P | N | M | N | N | N | N | N | N |
2 | WT | P | P | N | M | N | N | N | P | N | N |
3 | WT | P | P | WP | C | P | P | P | P | N | N |
4 | WT | N | FP | N | C | WP | P | N | P | N | N |
5 | MT | P | P | P | M | P | N | P | Strong P | N | N |
CCA, clear cell adenocarcinoma; F/U, follow-up; HPF, high power field; LN, lymph node; LVI, lymphovascular invasion; N/A, not available; PD, progressive disease; TUR, transurethral resection.
FP, focal positive; N, negative; P, positive.
Chr., chromosome; Indel, insertion and deletion; OG, oncogene, SNV, single nucleotide variation; TSG, tumor suppressor gene, VAF, variant allele frequency.
ACK1, activated Cdc42-associated tyrosine kinase 1; ADC, adenocarcinoma; EGFR, epidermal growth factor receptors; HCC, hepatocellular carcinoma; IDC, invasive ductal carcinoma; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; OG, oncogene; PI3K, phosphatidylinositol-3-kinase; PTC, papillary thyroid carcinoma; SqCC, squamous cell carcinoma; STAT, signal transducer and activator of transcription; TGF, transforming growth factor; TRL4, Toll-like receptor 4; TSG, tumor suppressor gene.
C, cytoplasmic staining (in the markers with a)P: retained expression, N: loss of expression); FP, focal positive; M, membranous staining; MT, mutant type; N, negative; P, positive; WP, weak positive; WT, wild type.