Unusual Variants of Bladder Cancer Cristina Magi-Galluzzi, MD, PhD
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1 Unusual Variants of Bladder Cancer Cristina Magi-Galluzzi, MD, PhD Director of Genitourinary Pathology, Professor of Pathology, Lerner College of Medicine Cleveland Clinic
2 Objectives Update on variants of urothelial carcinoma (UC) associated with aggressive behavior Review recently described variants of urothelial carcinoma and uncommon variants
3 Recently Described Variant of Urothelial Carcinoma and Variants Associated with Aggressive Behavior Large nested variant UC Invasive micropapillary UC Plasmacytoid UC
4 Case Presentation TURBT from a 71 year-old female with large bladder tumor
5 Large Nested Variant of UC
6 Large Nested Variant of UC Necrosis Inflammatory reaction
7 Large Nested Variant of UC LP invasion MP invasion
8 Fibrous reaction Large Nested Variant of UC
9 Large Nested Variant of UC Bland cytology Perivesical adipose tissue invasion
10 Diagnosis Large nested variant urothelial carcinoma
11 Large Nested Variant UC Rare pattern of invasion with large, regularirregular nests, with bland cytology 23 patients; 86% 20 cases invaded MP, 2 LP, 1 indeterminate between MP/LP Necrosis: focal (4 cases) and extensive (3 cases) Surface component was present in 19/23 (lowgrade in 16 cases) Follow-up available in 17/23 cases: - 3 developed metastatic disease (2 DOD) - 1 DOD Cox & Epstein AJSP 2011
12 UC, Large Nested Variant, superficial component
13 Case Presentation 72 year-old man with gross hematuria CT urogram demonstrate 3.2 cm left lateral wall mass Underwent a transurethral resection of bladder tumor
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19 Diagnosis Invasive urothelial carcinoma with micropapillary features
20 Invasive Micropapillary UC Micropapillary UC has received much attention for: Refined criteria for increased diagnostic reproducibility Clinical implications: controversy over role for early cystectomy Distinctive molecular features: ERBB2 mutation and amplification
21 Invasive Micropapillary Urothelial Carcinoma % of UC M:F=3:1 Refined diagnostic criteria: - Multiple small nests, without vascular cores, in same lacunar space (mimicking vascular invasion) - Intracytoplasmic vacuoles with distortion of nuclear contour ( ring forms ) - Peripherally oriented nuclei with high-grade atypia % of micropapillary component influences outcome; estimate its proportion (no specific threshold) Sangoi et al. AJSP 2010
22 Invasive Micropapillary UC Multiple nests in the same lacuna Epithelial ring forms
23 Invasive Micropapillary UC
24 Retraction artifact in Urothelial Carcinoma
25 Clinical significance of prominent retraction clefts in invasive urothelial carcinoma Prominent retraction clefts were associated with LN metastasis but not pt stage or other oncologic parameters Shah TS et al. Hum Pathol 2017
26 Invasive Micropapillary Urothelial Carcinoma Prognosis Lymphovascular invasion (LVI) is frequent CIS is present in >50% of cases Any % of micropapillary component should be reported (no specific threshold) Propensity for lymph node metastasis presentation Associated with increased risk of mortality Pathological stage is significant predictor of disease specific survival
27 Invasive Micropapillary Urothelial Carcinoma Management Controversy over role of early cystectomy (rather than intravesical therapy) in nonmuscle invasive disease (pt1) Controversy over role of neoadjuvant therapy in muscle invasive disease (pt2) Lack of consensus regarding most appropriate management (institutiondependent) Kamat et al. J Urol 2006; Gaya et al. Can J Urol 2010; Ghoneim et al. Urology 2011; Spaliviero et al. J Urol 2014
28 Micropapillary Urothelial Carcinoma High prevalence of HER2 overexpression/amplification compared to conventional UC Potential therapeutic target HER2
29 Non-Invasive Micropapillary Urothelial Carcinoma Reminiscent of papillary ovarian serous tumors Slender, delicate, filiform processes, rarely with a fibrovascular core Critical to differentiate from invasive micropapillary UC Not necessarily associated with adverse outcome
30 Non-Invasive Micropapillary Urothelial Carcinoma It should not be classified as "micropapillary" carcinoma!
31 Case Presentation 49 year-old male with microhematuria CT shows irregular R bladder wall thickening with perivesical fat stranding concerning for tumor extension
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34 Rare variant composed of cells resembling plasma cells Presentation: gross hematuria > ; age Plasmacytoid Urothelial Carcinoma Mass-like lesion or thickening of bladder wall
35 Plasmacytoid Urothelial Carcinoma
36 Plasmacytoid UC
37 Plasmacytoid Urothelial Carcinoma Dyscohesive oval/round cells in a loose myxoid stroma Abundant eosinophilic, rarely vacuolated cytoplasm Eccentric nuclei displaying inconspicuous nucleoli Striking plasmacytoid features
38 Signet ring cell carcinoma with NO extracellular mucin is classified as plasmacytoid carcinoma
39 Plasmacytoid Urothelial Carcinoma Immunohistochemistry Panel including CK, LCA, T- and B-cell markers, S-100 may be necessary CK+ confirms diagnosis of carcinoma CK7, CK20, GATA3, 34βE12 + Vimentin, LCA, synaptophysin, chromogranin p63 may be lost Diagnostic pitfall: often CD138+ (MUM1 ) AE1/3 39 CD138
40 Plasmacytoid Urothelial Carcinoma Immunohistochemistry CCND1 and SNAI1 loss is common; could contribute to aggressive behavior Loss of membranous and increased nuclear E- cadherin expression increases risk of death 2 fold E-cadherin #Keck et al. Urol Oncol. 2014; *Keck et al. Ann Surg Oncol 2013
41 Plasmacytoid Urothelial Carcinoma GATA3
42 Plasmacytoid Urothelial Carcinoma Differential Diagnosis Plasmacytoid histology may be seen in: lymphomas plasmacytomas melanoma metastatic carcinoma (i.e. lobular and gastric cancer) paraganglioma rhabdomyosarcoma neuroendocrine carcinoma B-cell lymphoma Metastatic breast carcinoma 42
43 Plasmacytoid Urothelial Carcinoma Prognosis is uniformly poor with advanced stage at presentation and metastatic disease progression High incidence of positive parivesical surgical margins 43
44 Plasmacytoid Urothelial Carcinoma Unique pattern of spread along ureter and fascial sheath Unusual disease spread - Peritoneal (33%) - Bowel serosa and mesentery - Ovary - Peritoneal carcinomatosis - Malignant pleural effusions Fallopian tube Ricardo-Gonzalez et al. J Urol 2012; Dayyani et al. J Urol 2013
45 Plasmacytoid UC in Peri-Ureteral Tissue 45
46 Contemporary bladder cancer: Variant histology may be a significant driver of disease Monn et al. Urologic Oncology 2015 log-rank test P <0.001 Plasmacytoid UC Micropapillary UC
47 Variant histology: role in management and prognosis of nonmuscle invasive bladder cancer Porten et al. Current Opinion in Urology 2014 Sarcomatoid Plasmacytoid Micropapillary + adjuvant platinum-based chemotherapy Small cell 2
48 Plasmacytoid UC in Lymph Node AE1/3 AE1/3 48
49 Plasmacytoid variant UC Intranodal Histiocytes
50 Plasmacytoid Urothelial Carcinoma Correct diagnosis may not be difficult if adequate tissue is available Small biopsies occasionally show plasmacytoid pattern closely mimicking a plasmacytoma or lymphoma or may be interpreted as inflammatory When plasmacytoid carcinoma is not associated with UC, diffuse growth pattern may suggest a plasmacytoma
51 Undifferentiated carcinoma with rhabdoid features Rare tumor, muscle invasive (18 cases reported) Conventional UC component frequently present Diffuse dyscohesive or pseudoalveolar growth of variably sized cells with frequent rhabdoid features Agaimy et al, Virchows Arch 2016
52 Undifferentiated carcinoma with rhabdoid features Discohesive appearance Sheets of cells with high-grade features, eccentrically located vesicular nuclei and eosinophilic cytoplasmic
53 Undifferentiated carcinoma with rhabdoid features
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55 Undifferentiated carcinoma with rhabdoid features Undifferentiated component: - AE1/AE3 (13/14) + - vimentin (8/14) + - GATA3 (9/14) + Loss of at least one of SWI/SNF subunit in 71% (associated with aggressive clinical course) Included in WHO poorly differentiated carcinomas (sarcomatoid, pleomorphic giant cell, and undifferentiated)
56 Undifferentiated carcinoma with rhabdoid features Differential Diagnosis Extrarenal malignant rhabdoid tumor Metastatic melanoma Aggressive lymphoma High-grade clear cell RCC with rhabdoid features Rhabdoid cell-rich renal medullary carcinoma and collecting duct carcinoma Undifferentiated carcinomas Neuroendocrine carcinomas Stromal sarcomas with rhabdoid features
57 UC with chordoid features UC with unique chordoid morphology; - Cellular cording - Myxoid stromal matrix Reminiscent of chordoma, extraskeletal myxoid chondrosarcoma, YST, myoepithelioma/mixed tumor of soft tissue Conventional UC seen in all cases % of chordoid: variable Cox et al. AJSP 2009; Wei et al. Int J Clin Exp Pathol. 2015
58 UC with chordoid features
59 UC with chordoid features NO sarcomatous differentiation NO intracytoplasmic mucin NO glandular formation C, Magi-Galluzzi
60 UC with chordoid features
61 UC with chordoid features P63, HMWCK, CK20 + Calponin, GFAP, S-100 Glypican-3 Brachyury High stage: extension into fat or adjacent organs Lymph node metastases in 3/4 of cases 2/10 patients died of disease Cox et al. AJSP 2009; Wei et al. Int J Clin Exp Pathol. 2015
62 UC with chordoid features Differential Diagnosis Primary myxoid mesenchymal neoplasm (leiomyosarcoma) - rare Carcinoma with significant extracellular myxoid or mucinous component (prostate, ureter) UC with abundant myxoid stroma (no chordoid pattern) Sarcomatoid carcinoma with myxoid changes (cellular atypia and mitotic figures) Fibromyxoid nephrogenic adenoma (PAX-2, PAX-8+) Inflammatory myofibroblastic tumor
63 Take home message UC variants that can lead to diagnostic difficulties: Large nested variant UC: rare pattern of invasion with large nests and bland cytology Refined diagnostic criteria for increased reproducibility of micropapillary UC Unique pattern of spread along ureter and fascial sheath for plasmacytoid UC Undifferentiated carcinoma with rhabdoid features and frequent loss of SWI/SNF UC with unique chordoid morphology
64 Thank you!
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