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Current Urology Reports

, 20:80 | Cite as

Variant Histology in Bladder Cancer—Current Understanding of Pathologic Subtypes

  • Manju AronEmail author
Urothelial Cancer (S Daneshmand, Section Editor)
  • 58 Downloads
Part of the following topical collections:
  1. Topical Collection on Urothelial Cancer

Abstract

Purpose of Review

Urothelial carcinomas (UC) are characterized by variant morphologies. However, the diagnosis of these variants can be challenging, in part due to their evolving diagnostic criteria. This review discusses the diagnostic criteria, molecular features, and prognostic implications of the UC variants. Evolving subtypes of UC are also briefly discussed.

Recent Findings

The WHO 2016 classification of tumors of the urinary system has refined the morphologic criteria for the diagnosis of UC variants. Many of these follow a more aggressive clinical course, but conclusive data on their effect on survival are lacking. The molecular alterations characteristic of some of these variants may be amenable to targeted therapies.

Summary

Accurate identification of variant histology in UC has important implications for patient management. Despite identification of distinct molecular alterations in some of these variants, current molecular classifiers of invasive UC have not been significantly analyzed in these subtypes, opening up areas of future research.

Keywords

Bladder carcinoma Urothelial carcinoma variants Variant histology Divergent differentiation 

Notes

Compliance with Ethical Standards

Conflict of Interest

Manju Aron declares no potential conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Kirkali Z, Chan T, Manoharan M, Algaba F, Busch C, Cheng L, et al. Bladder cancer: epidemiology, staging and grading, and diagnosis. Urology. 2005;66((6) Suppl 1):4–34.  https://doi.org/10.1016/j.urology.2005.07.062.CrossRefPubMedGoogle Scholar
  2. 2.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9–29.  https://doi.org/10.3322/caac.21208.CrossRefPubMedGoogle Scholar
  3. 3.
    Linder BJ, Boorjian SA, Cheville JC, Sukov WR, Thapa P, Tarrell RF, et al. The impact of histologic reclassification during pathology re-review: evidence of a Will Rogers effect in bladder cancer. J Urol. 2013;190(5):1692–6.  https://doi.org/10.1016/j.juro.2013.05.040.CrossRefPubMedGoogle Scholar
  4. 4.
    •• Luchey AM, Manimala NJ, Dickinson S, Dhillon J, Agarwal G, Lockhart JL, et al. Change in management based on pathologic second opinion among bladder cancer patients presenting to a comprehensive cancer center: implications for clinical practice. Urology. 2016;93:130–4.  https://doi.org/10.1016/j.urology.2016.01.048 This study shows that on secondary review of a large cohort of 1161 bladder resections by genitourinary pathologists 17% of cases showed the presence of variant or non urothelial histologies. There was an agreement with the outside pathologist in only 46% of cases with variant histology, with only 5% of micropapillary and none of the cases of nested and plasmacytoid morphologies, being identified correctly by the outside pathologists. This study underscores the big problem of under-recognition and underreporting of UC variants in general pathology practices. CrossRefPubMedGoogle Scholar
  5. 5.
    •• Moch H, Humphrey PA, Ulbright TM, Reuter V. WHO classification of tumours of the urinary system and male genital organs. Lyon: International Agency for Research on Cancer; 2016. The WHO 2016 classification has updated the diagnostic criteria, prognostic features and molecular data on the histologic variants of UC. Some of the changes include recognition of the large nested variant of urothelial carcinoma and the signet ring morphology as histological subtypes of the nested variant and plasmacytoid urothelial carcinoma, respectively. A new category of poorly differentiated urothelial carcinoma has also been included. Google Scholar
  6. 6.
    Lopez-Beltran A, Cheng L. Histologic variants of urothelial carcinoma: differential diagnosis and clinical implications. Hum Pathol. 2006;37:1371–88.  https://doi.org/10.1016/j.humpath.2006.05.009.CrossRefGoogle Scholar
  7. 7.
    Wasco MJ, Daignault S, Zhang Y, Kunju LP, Kinnaman M, Braun T, et al. Urothelial carcinoma with divergent histologic differentiation (mixed histologic features) predicts the presence of locally advanced bladder cancer when detected at transurethral resection. Urology. 2007;70:69–74.  https://doi.org/10.1016/j.juro.2007.03.033. CrossRefPubMedGoogle Scholar
  8. 8.
    Lopez-Beltran A, Cheng L, Raspollini MR, et al. Variants of bladder cancer: the pathologist’s point of view. Eur Urol Suppl. 2017;16:210–22.CrossRefGoogle Scholar
  9. 9.
    Shanks JH, Iczkowski KA. Divergent differentiation in urothelial carcinoma and other bladder cancer subtypes with selected mimics. Histopathology. 2009;54:885–900.  https://doi.org/10.1111/j.1365-2559.2008.03167.CrossRefPubMedGoogle Scholar
  10. 10.
    Solomon JP, Lowenthal BM, Kader AK, Parsons JK, Flaig TW, Siefker-Radtke AO, et al. Challenges in the diagnosis of urothelial carcinoma variants: can emerging molecular data complement pathology review? Urology. 2017;102:7–16.  https://doi.org/10.1016/j.urology.2016.10.014.CrossRefPubMedGoogle Scholar
  11. 11.
    Amin MB. Histologic variants of urothelial carcinoma: diagnostic, therapeutic and prognostic implications. Mod Pathol. 2009;22:S96–S118.  https://doi.org/10.1038/modpathol.2009.26.CrossRefGoogle Scholar
  12. 12.
    • Liu Y, Bui MM, Xu B. Urothelial carcinoma with squamous differentiation is associated with high tumor stage and pelvic lymph-node metastasis. Cancer Control. 2017;24:78–82.  https://doi.org/10.1177/107327481702400113 This single institution retrospective study of 47 cases of UC with squamous differentiation, shows that these tumors present with higher stage when compared to pure UC (72.3% vs 43.1%; P< 0.01) and tumors with greater than 20% squamous differentiation had significantly higher nodal metastases compared to pure UC (46.2% vs 27%; P= 0.4), which may be contributing factors for the unfavorable outcomes seen in patents with UC with squamous differentiation.CrossRefGoogle Scholar
  13. 13.
    • Gofrit ON, Yutkin V, Shapiro A, Pizov G, Zorn KC, Hidas G, et al. The response of variant histology bladder cancer to intravesical immunotherapy compared to conventional cancer. Front Oncol. 2016;15:43.  https://doi.org/10.3389/fonc.2016.00043 This study involves 41 patients with Ta or T1 UC with variant histology who were treated with BCG. Patients with variant tumors had a significantly worse prognosis compared to patients with conventional high-grade UC, including 5-year recurrence-free survival (63.5 Vs. 71.5%, p = 0.05), 5-year progression (≥T2)-free survival (60 Vs. 82.5%, p = 0.002), 5-year disease-specific survival (73 Vs. 92.5%, p = 0.0004), and overall survival (66 Vs. 89.5%, 0.05). A patient with variant bladder cancer treated with intravesical immunotherapy has a 27% chance of dying from this disease within 5 years compared to 7.5% chance for a patient with conventional high-grade UC, indicating a poor response to BCG therapy.CrossRefGoogle Scholar
  14. 14.
    Li G, Hu J, Niu Y. Squamous differentiation in pT1 bladder urothelial carcinoma predicts poor response for intravesical chemotherapy. Oncotarget. 2017;9:217–23.  https://doi.org/10.18632/oncotarget.18563.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    • Krasnow RE, Drumm M, Roberts HJ, Niemierko A, Wu CL, Wu S, et al. Clinical outcomes of patients with histologic variants of urothelial cancer treated with trimodality bladder-sparing therapy. Eur Urol. 2017;72:54–60.  https://doi.org/10.1016/j.eururo.2016.12.002 The response of histologic variants of bladder cancer to bladder-sparing chemoradiation has not been extensively studied. In this retrospective single institution study the authors compared the outcomes of histologic variants of urothelial cancer (VUC) (66 cases) to pure urothelial cancer (PUC) (237 cases) with trimodality bladder-sparing treatment (TMT). Complete response rate after induction TMT was 83% in PUC and 82% in VUC (p=0.9). The 5-yr and 10-yr disease-specific survival (DSS) was 75% and 67% in PUC versus 64% and 64% in VUC. The 5-yr and 10-yr overall survival (OS) was 61% and 42% in PUC versus 52% and 42% in VUC. On multivariable analysis VUC was not associated with DSS (hazard ratio: 1.3, 95% confidence interval: 0.8-2.2, p=0.3) or OS (hazard ratio: 1.2, 95% confidence interval: 0.8-1.7, p=0.4). Salvage cystectomy rates were similar (log-rank p=0.3). They found that variant histology did not significantly influence outcomes and that these patients should not be excluded from receiving TMT.CrossRefPubMedGoogle Scholar
  16. 16.
    Scosyrev E, Ely BW, Messing EM, Speights VO, Grossman HB, Wood DP, et al. Do mixed histological features affect survival benefit from neoadjuvant platinum- based combination chemotherapy in patients with locally advanced bladder cancer? A secondary analysis of Southwest Oncology Group- Directed Intergroup Study (S8710). BJU Int. 2011;108:693–9.  https://doi.org/10.1111/j.1464-410X.2010.09900. CrossRefPubMedGoogle Scholar
  17. 17.
    Zargar-Shoshtari K, Sverrisson EF, Sharma P, Gupta S, Poch MA, Pow-Sang JM, et al. Clinical outcomes after neoadjuvant chemotherapy and radical cystectomy in the presence of urothelial carcinoma of the bladder with squamous or glandular differentiation. Clin Genitourin Cancer. 2016;14:82–8.  https://doi.org/10.1016/j.clgc.2015.08.006.CrossRefPubMedGoogle Scholar
  18. 18.
    Lin J, Whalen M, Holder D, Hruby G, Decastro GJ, McKiernan J. Neoadjuvant chemotherapy in the treatment of muscle invasive bladder cancer with mixed histology. Can J Urol. 2013;20:6690–5.PubMedGoogle Scholar
  19. 19.
    Pokuri VK, Syed JR, Yang Z, Field EP, Cyriac S, Pili R, et al. Predictors of complete pathologic response (pT0) to neoadjuvant chemotherapy in muscle-invasive bladder carcinoma. Clin Genitourin Cancer. 2016;14:e59–65.  https://doi.org/10.1016/j.clgc.2015.09.013.CrossRefPubMedGoogle Scholar
  20. 20.
    Li G, Yu J, Song H, Zhu S, Sun L, Shang Z, et al. Squamous differentiation in patients with bladder urothelial carcinoma is assosciated with high risk of recurrence and poor survival. BMC Cancer. 2017;17:530.  https://doi.org/10.1186/s12885-017-3520-1.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Alexander RE, Hu YC, Kum JB, Montironi R, Lopez-Beltran A, Maclennan GT, et al. p16 expression is not associated with human papillomavirus in urinary bladder squamous cell carcinoma. Mod Pathol. 2012;25:1526–33.  https://doi.org/10.1038/modpathol.2012.103.CrossRefPubMedGoogle Scholar
  22. 22.
    Oliva E, Amin MB, Jimenez R, Young RH. Clear cell carcinoma of the urinary bladder: a report and comparison of four tumors of mullerian origin and nine of probable urothelial origin with discussion of histogenesis and diagnostic problems. Am J Surg Pathol. 2002;26:190–7.CrossRefGoogle Scholar
  23. 23.
    Vail E, Zheng X, Zhou M, Yang X, Fallon JT, Epstein JI, et al. Telomerase reverse transcriptase promoter mutations in glandular lesions of the urinary bladder. Ann Diagn Pathol. 2015;19:301–5.  https://doi.org/10.1016/j.anndiagpath.2015.06.007.CrossRefPubMedGoogle Scholar
  24. 24.
    Lim M, Adsay NV, Grignon D, Osunkoya AO. Urothelial carcinoma with villoglandular differentiation: a study of 14 cases. Mod Pathol. 2009;22:1280–6.  https://doi.org/10.1038/modpathol.2009.97.CrossRefPubMedGoogle Scholar
  25. 25.
    Yang Z, Epstein JI. Urothelial carcinoma in situ of the bladder with glandular differentiation: report of 92 cases. Am J Surg Pathol. 2018;42:971–6.  https://doi.org/10.1097/PAS.0000000000001073.CrossRefPubMedGoogle Scholar
  26. 26.
    Lopez-Beltran A, Henriques V, Monironi R, Cimadamore A, Raspollini MR, Cheng L. Variants and new entities of bladder cancer. Histopathology. 2019;74:77–96.  https://doi.org/10.1111/his.13752.CrossRefPubMedGoogle Scholar
  27. 27.
    Zhong M, Gersbach E, Rohan SM, Yang XJ. Primary adenocarcinoma of the urinary bladder: differential diagnosis and clinical relevance. Arch Pathol Lab Med. 2013;137:371–81.  https://doi.org/10.5858/arpa.2012-0076-RA.CrossRefGoogle Scholar
  28. 28.
    • Giannico GA, Gowan AM, Epstein JI, Revetta F, Bishop JA. Role of SATB2 in distinguishing the site of origin in glandular lesions of the bladder/urinary tract. Hum Pathol. 2017;67:152–9.  https://doi.org/10.1016/j.humpath.2017.07.002 This study highlights the challenges that arise in the diagnosis of glandular lesions of the bladder, because of the morphological and immunohistochemical overlap among these tumors. The authors investigated the role of SATB2, which is expressed in colorectal and appendiceal neoplasms. The study included 43 primary adenocarcinomas of the bladder/urinary tract, 20 urothelial carcinomas with glandular differentiation, 26 adenocarcinomas of the uterine cervix, and 22 colorectal adenocarcinomas involving the bladder. Positive SATB2 immunostaining was observed in 49% of primary bladder/urinary tract adenocarcinomas, in 77% colorectal adenocarcinomas, and in the glandular component of 22% of urothelial carcinomas with glandular differentiation. SATB2 was negative in 25 of 26 endocervical adenocarcinomas. SATB2 immunohistochemistry was not useful in supporting urothelial versus gastrointestinal or endocervical origin in the differential diagnosis of glandular lesions of the bladder/urinary tract. CrossRefPubMedGoogle Scholar
  29. 29.
    Kim SP, Frank I, Cheville JC, Thompson RH, Weight CJ, Thapa P, et al. The impact of squamous and glandular differentiation on survival after radical cystec- tomy for urothelial carcinoma. J Urol. 2012;188:405–9.  https://doi.org/10.1016/j.juro.2012.04.020.CrossRefPubMedGoogle Scholar
  30. 30.
    Grammatico D, Grignon DJ, Eberwein P, Shepherd RR, Hearn SA, Walton JC. Transitional cell carcinoma of the renal pelvis with choriocarcinomatous differentiation: immunohistochemical and immunoelectron microscopic assessment of human chorionic gonadotropin production by transitional cell carcinoma of the urinary bladder. Cancer. 1993;71:835–1841.CrossRefGoogle Scholar
  31. 31.
    Monn MF, Jaqua KR, Bihrle R, Cheng L. Primary choriocarcinoma of the bladder: a case report and review of literature. Clin Genitourin Cancer. 2017;15:188–91.  https://doi.org/10.1016/j.clgc.2016.08.027.CrossRefPubMedGoogle Scholar
  32. 32.
    Douglas J, Sharp A, Chau C, Head J, Drake T, Wheater M, et al. Serum total HCG beta level is an independent prognostic factor in transitional cell carcinoma of the urothelial tract. Br J Cancer. 2014;110:1759–66.  https://doi.org/10.1038/bjc.2014.89.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Martin JE, Jenkins BJ, Zuk RJ, et al. Human chorionic gonadotrophin expression and histological findings as predictors of response to radiotherapy in carcinoma of the bladder. Virchows Arch A Pathol Anat Histopathol. 1989;414:273–7.CrossRefGoogle Scholar
  34. 34.
    Monn MF, Kaimakliotis HZ, Pedrosa JA, et al. Contemporary bladder cancer: variant histology may be a significant driver of disease. Urol Oncol. 2015;33:18.e15–20.  https://doi.org/10.1016/j.urolonc.2014.10.001.CrossRefGoogle Scholar
  35. 35.
    Black PC, Brown GA, Dinney CP. The impact of variant histology on the outcome of bladder cancer treated with curative intent. Urol Oncol. 2009;27:3–7.  https://doi.org/10.1016/j.urolonc.2007.07.010. CrossRefGoogle Scholar
  36. 36.
    •• Priemer DS, Wang M, Zhang S, Lopez-Beltran A, Kouba E, Monitroni R, et al. Small-cell carcinomas of the urinary bladder and prostate: TERT promoter mutation status differentiates sites of malignancy and provides evidence of common clonality between small-cell carcinoma of the urinary bladder and urothelial carcinoma. Eur Urol Focus. 2018;4:880–8.  https://doi.org/10.1016/j.euf.2017.03.007 In this study TERT promoter mutation status of small cell carcinoma (SCC) of the bladder was compared to TERT promoter mutation status in prostate SCC. Mutations were detected in 29/53 (55%) cases of urinary bladder and 0/26 (0%) cases of prostate SCC. Of 25 cases with concurrent urinary bladder SCC and non-small-cell components, all cases harbored identical TERT promoter mutation status in both phenotypes indicating a clonal evolution.CrossRefPubMedGoogle Scholar
  37. 37.
    Al-Ahmadie H, Iyer G. Updates on the genetics and molecular subtypes of urothelial carcinoma and select variants. Surg Pathol Clin. 2018;11(4):713–23.  https://doi.org/10.1016/j.path.2018.07.011.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Zheng X, Zhuge J, Bezerra SM, Faraj SF, Munari E, Fallon JT 3rd, et al. High frequency of TERT promoter mutation in small cell carcinoma of the bladder, but not in small cell carcinoma of other origins. J Hematol Oncol. 2014;7:47.  https://doi.org/10.1186/s13045-014-0047-7.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    •• Wang G, Xiao L, Zhang M, Kamat AM, Siefker-Radtke A, Dinney CP, et al. Small cell carcinoma of the urinary bladder: a clinicopathologic and immunohistochemical analysis of 81 cases. Hum Pathol. 2018;79:57–65.  https://doi.org/10.1016/j.humpath.2018.05.005 In this retrospective comprehensive analysis of clinicopathologic and immunohistochemical features of 81 cases of small cell carcinoma (SCC) including 25 pure SCC, 95% presented at advanced stage with muscularis propria invasion. Neuroendocrine markers were expressed in the majority of the cases, with loss of RB1 staining in 21/23 cases. Most SCC did not express luminal or basal markers but a few showed positivity for CK5/6 which may suggest evolution from a basal phenotype, and better response to cisplatinum based chemotherapy.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Lopez Beltran A, Cheng L, Montironi R, Bianca A, Leva M, Roupret M, et al. Clinicopathological characteristics and outcome of nested carcinoma of the urinary bladder. Virchows Arch. 2014;465:199–205.  https://doi.org/10.1007/s00428-014-1601-y.CrossRefGoogle Scholar
  41. 41.
    •• Comperat E, McKenney JK, Hartmann A, Hes O, Bertz S, Varinot J, et al. Large nested variant of urothelial carcinoma: a clinicopathological study of 36 cases. Histopathology 2017: 71: 703–710. Doi: 10.1111/his.13280. The largest study to date of large nested variant of UC, that describes the clinical, pathologic and immunohistochemical profile of these tumors. Tumors with pure large nested variant have similar immunohistochemical profile to conventional UC and nested variant of UC, but had a lower rate of advanced disease compared to cases with mixed histologies. CrossRefGoogle Scholar
  42. 42.
    Drew PA, Furman J, Civantos F, Murphy WM. The nested variant of transitional cell carcinoma: an aggressive neoplasm with innocuous histology. Mod Pathol. 1996;9:989–94.PubMedGoogle Scholar
  43. 43.
    Young RH, Oliva E. Transitional cell carcinomas of the urinary bladder that may be underdiagnosed. A report of four invasive cases exemplifying the homology between neoplastic and non-neoplastic transitional cell lesions. Am J Surg Pathol. 1996;20:1448–54.CrossRefGoogle Scholar
  44. 44.
    Murphy WM, Deanna DG. The nested variant of transitional cell carcinoma: a neoplasm resembling proliferation of Brunn’s nests. Mod Pathol. 1992;5:240–3.PubMedGoogle Scholar
  45. 45.
    Volmar KE, Chan TY, De Marzo AM, Epstein JI. Florid von Brunn nests mimicking urothelial carcinoma: a morphologic and immunohistochemical comparison to the nested variant of urothelial carcinoma. Am J Surg Pathol. 2003;27:1243–52.CrossRefGoogle Scholar
  46. 46.
    Brimo F, Dauphin-Pierre S, Aprikian A, Kassouf W, Tanguay S, Ajise O, et al. Inverted urothelial carcinoma: a series of 12 cases with a wide morphologic spectrum overlapping with the large nested variant. Hum Pathol. 2015;46:1506–13.  https://doi.org/10.1016/j.humpath.2015.06.010.CrossRefPubMedGoogle Scholar
  47. 47.
    Mally AD, Tin AL, Lee JK, Satasivam P, Chae EK, Donat SM, et al. Clinical outcomes of patients with T1 nested variant of urothelial carcinoma compared to pure urothelial carcinoma of the bladder. Clin Genitourin Cancer. 2017.  https://doi.org/10.1016/j.clgc.2017.07.002.CrossRefGoogle Scholar
  48. 48.
    Zhong M, Tian W, Zhuge J, Zheng X, Huang T, Cai D, et al. Distinguishing nested variants of urothelial carcinoma from benign mimickers by TERT promoter mutation. Am J Surg Pathol. 2015;39:127–31.  https://doi.org/10.1097/PAS.0000000000000305.CrossRefPubMedGoogle Scholar
  49. 49.
    Warrick JI, Kaag M, Raman JD, Chan W, Tran T, Kunchala S, et al. FOXA1 and CK 14 as markers of luminal and basal subtypes in histologic variants of bladder cancer and their conventional urothelial carcinoma. Virchows Arch. 2017;471:337–45.  https://doi.org/10.1007/s00428-017-2190-3.CrossRefPubMedGoogle Scholar
  50. 50.
    •• Weyerer V, Weisser R, Moksalev EA, Haller F, Stoehr R, Eckstein M, et al. Distinct genetic alterations and luminal molecular subtype in nested variant of urothelial carcinoma. Histopathology. 2019.  https://doi.org/10.1111/his.13958 This study describes the molecular analysis of the largest cohort of nested variant of UC (60 cases) using SNaPshot analysis for TERT mutation anlaysis and target sequencing of 48 cancer related genes by Next Generation Sequencing (NGS) in 26 patients. Immunohistochemical analysis was performed in all cases to elucidate the molecular subtype of these tumors (luminal versus basal). 62.5% of cases showed TERT promoter mutations, with immunohistochemistry revealing a luminal molecular subtype. TP53, JAK3 and CTNNB1 were amongst the most frequently mutated genes by NGS.CrossRefGoogle Scholar
  51. 51.
    Lopez-Beltran A, Montironi R, Cheng L. Microcystic urothelial carcinoma: morphology, immunohistochemistry and clinical behavior. Histopathology. 2014;64:872–9.  https://doi.org/10.1111/his.12345.CrossRefPubMedGoogle Scholar
  52. 52.
    Paner GP, Annaiah C, Gulmann C, Rao P, Ro JY, Hansel DE, et al. Immunohistochemical evaluation of novel and traditional markers associated with urothelial differentiation in a spectrum of variants of urothelial carcinoma of the urinary bladder. Hum Pathol. 2014;45:1473–82.  https://doi.org/10.1016/j.humpath.2014.02.024.CrossRefGoogle Scholar
  53. 53.
    Venyo AK. Microcystic variant of urothelial carcinoma. Ther Adv Urol. 2013;2013:654751.  https://doi.org/10.1155/2013/654751.CrossRefGoogle Scholar
  54. 54.
    Lopez-Beltran A, Montironi R, Blanca A, Cheng L. Invasive micropapillary urothelial carcinoma of the bladder. Hum Pathol. 2010;4:1159–64.  https://doi.org/10.1016/j.humpath.2009.CrossRefGoogle Scholar
  55. 55.
    Wang JK, Boorjian SA, Cheville JC, Kim SP, Tarrell RF, Thapa K, et al. Outcomes following radical cystectomy for micropapillary bladder cancer versus pure urothelial carcinoma: a matched cohort analysis. World J Urol. 2012;30:801–6.  https://doi.org/10.1007/s00345-012-0976-0.CrossRefPubMedGoogle Scholar
  56. 56.
    Amin MB, Ro JY, el-Sharkawy T, Lee KM, Troncoso P, Silva EG, et al. Micropapillary variant of transitional-cell carcinoma of the urinary bladder: histologic pattern resembling ovarian papillary serous carcinoma. Am J Surg Pathol. 1994;18:1224–32.CrossRefGoogle Scholar
  57. 57.
    Kamat AM, Gee JR, Dinney CP, Grossman HB, Swanson DA, Millikan RE, et al. The case of early cystectomy in the treatment of non-muscle invasive micropapillary bladder carcinoma. J Urol. 2006;175:881–5.  https://doi.org/10.1016/S0022-5347(05)00423-4.CrossRefGoogle Scholar
  58. 58.
    Alkibay T, Sozen S, Gurocak S, Isik Gonul I, Poyraz A, Ure I. Micropapillary pattern in urothelial carcinoma: a clinicopathological analysis. Urol Int. 2009;83:300–5.  https://doi.org/10.1159/000241672.CrossRefPubMedGoogle Scholar
  59. 59.
    Sangoi AR, Beck AH, Amin MB, Cheng L, Epstein JI, Hansel DE, et al. Interobserver reproducibility in the diagnosis of invasive micropapillary carcinoma of the urinary tract among urologic pathologists. Am J Surg Pathol. 2010;34:1367–76.  https://doi.org/10.1097/PAS.0b013e3181ec86b3.CrossRefPubMedGoogle Scholar
  60. 60.
    Nassar H, Pansare V, Zhang H, Che M, Sakr W, Ali-Fehmi R, et al. Pathogenesis of invasive micropapillary carcinoma: role of MUC1 glycoprotein. Mod Pathol. 2004;17:1045–50.  https://doi.org/10.1038/modpathol.3800166. CrossRefPubMedGoogle Scholar
  61. 61.
    Comperat E, Roupret M, Yaxley J, Reynolds J, Varinot J, Ouzaid I, et al. Micropapillary urothelial carcinoma of the urinary bladder: a clinicopathological analysis of 72 cases. Pathology. 2010;42:650–4.  https://doi.org/10.3109/00313025.2010.522173.CrossRefPubMedGoogle Scholar
  62. 62.
    Samaratunga H, Khoo K. Micropapillary variant of urothelial carcinoma of the urinary bladder; a clinicopathological and immunohistochemical study. Histopathology. 2004;45:55–64.  https://doi.org/10.1111/j.1365-2559.2004.01895.CrossRefPubMedGoogle Scholar
  63. 63.
    •• Zinall U, Weyerer V, Comperat E, Camparo P, Gaisa TN, Knuechel-Clarke R, et al. Micropapillary urothelial carcinoma: evaluation of HER2 status and immunohistochemical characterization of the molecular subtype. Hum Pathol. 2018;80:55–64.  https://doi.org/10.1016/j.humpath.2018.05.022 This study is the largest study to date of 94 cases of micropapillary urothelial carcinoma (MPUC, evaluated for HER2 status using immunohistochemistry, CISH and mutational analysis. HER2 overexpression and/amplification were seen in 30% of the cases while HER 2 mutations using Sanger sequencing for exons 4 and 8 were seen in a very small fraction of cases. Luminal markers were overexpressed in the majority of cases allowing for the subclassification of this variant into the luminal subtype. This finding has implications for targeted therapy in MPUC.CrossRefGoogle Scholar
  64. 64.
    Nguyen D, Taheri D, Springer S, Cowan M, Guner G, Mendoza Rodriguez MA, et al. High prevalence of TERT promoter mutations in micropapillary urothelial carcinoma. Virchows Arch. 2016;469:427–34.  https://doi.org/10.1007/s00428-016-2001. CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Schneider SA, Sukov WR, Frank I, Boorjian SA, Costello BA, Tarrell RF, et al. Outcome of patients with micro- papillary urothelial carcinoma following radical cystectomy: ERBB2 (HER2) amplification identifies patients with poor outcome. Mod Pathol. 2014;27:758–64.  https://doi.org/10.1038/modpathol.2013.201.CrossRefPubMedGoogle Scholar
  66. 66.
    Figueroa JD, Ye Y, Siddiq A, Garcia-Closas M, Chatterjee N, Prokunina-Olsson L, et al. Genome-wide association study identifies multiple loci associated with bladder cancer risk. Hum Mol Genet. 2014;23:1387–98.  https://doi.org/10.1093/hmg/ddt519. CrossRefPubMedGoogle Scholar
  67. 67.
    Willis DL, Flaig TW, Hansel DE, Milowsky MI, Grubb RL, Al-Ahmadie HA, et al. Micropapillary bladder cancer: current treatment patterns and review of the literature. Urol Oncol. 2014;32:826–32.  https://doi.org/10.1016/j.urolonc.2014.01.020.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Willis DL, Fernandez MI, Dickstein RJ, Parikh S, Shah JB, Pisters LL, et al. Clinical outcomes of cT1 micropapillary bladder cancer. J Urol. 2015;193:1129–34.  https://doi.org/10.1016/j.juro.2014.09.092.CrossRefPubMedGoogle Scholar
  69. 69.
    Spaliviero M, Dalbagni G, Bochner BH, Poon BY, Huang H, Al-Ahmadie HA, et al. Clinical outcome of patients with T1 micropapillary urothelial carcinoma of the bladder. J Urol. 2014;192:702–7.  https://doi.org/10.1016/j.juro.2014.02.2565.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Siefker-Radtke AO, Dinney CP, Shen Y, Williams DL, Kamat AM, Grossman HB, et al. A phase 2 clinical trial of sequential neoadjuvant chemotherapy with ifosfamide, doxo- rubicin, and gemcitabine followed by cisplatin, gemcitabine, and ifosfamide in locally advanced urothelial cancer: final results. Cancer. 2013;119:540–7.  https://doi.org/10.1002/cncr.27751.CrossRefPubMedGoogle Scholar
  71. 71.
    •• Vetterlein MW, Wankowicz SAM, Seisen T, Lander R, Loppenberg B, Chun FK. Neoadjuvant chemotherapy prior to radical cystectomy for muscle-invasive bladder cancer with variant histology. Cancer. 2017;15(123):4346–55.  https://doi.org/10.1002/cncr.30907 2018 cases with histological variants were retrieved from the National Cancer Database. Logistic regression models estimated the odds of non-organ-confined disease at the time of RC for each histological variant, stratified by the receipt of neoadjuvant chemotherapy (NAC). Cox regression models were used to examine the effect of NAC on overall mortality in each variant subgroup. This study found that variant histology including neuroendocrine tumors, micropapillary UC and sarcomatoid urothelial carcinomas were less likely to have non organ-confined disease after neoadjuvant chemotherapy, but only patients with neuroendocrine tumors had an overall survival benefit because of the NAC.CrossRefGoogle Scholar
  72. 72.
    Gulley ML, Amin MB, Nicholls JM, Banks PM, Ayala AG, Srigley JR, et al. Epstein-Barr virus is detected in undifferentiated nasopharyngeal carcinoma but not in lymphoepithelioma-like carcinoma of the urinary bladder. Hum Pathol. 1995;26:1207–14.CrossRefGoogle Scholar
  73. 73.
    Lopez-Beltran A, Luque RJ, Vicioso L, Anglada F, Requena MJ, Quintero A, et al. Lymphoepithelioma- like carcinoma of the urinary bladder: a clinicopathologic study of 13 cases. Virchows Arch. 2001;438:552–7.CrossRefGoogle Scholar
  74. 74.
    Williamson SR, Zhang S, Lopez-Beltran A, Shah RB, Montironi R, Tan P-H, et al. Lymphoepithelioma-like carcinoma of the urinary bladder: clinicopathologic, immunohistochemical and molecular features. Am J Surg Pathol. 2011;35:474–83.  https://doi.org/10.1097/PAS.0b013e31820f709e.CrossRefPubMedGoogle Scholar
  75. 75.
    Tamas EF, Nielsen ME, Schoenberg MP, Epstein JI. Lymphoepithelioma-like carcinoma of the urinary tract: a clinicopathological study of 30 pure and mixed cases. Mod Pathol. 2007;20:828–34.  https://doi.org/10.1038/modpathol.3800823.CrossRefPubMedGoogle Scholar
  76. 76.
    Ricardo-Gonzalez RR, Nguyen M, Gokden N, Sangoi AR, Presti JC Jr, McKenney JK, et al. Plasmacytoid carcinoma of the bladder: a urothelial carci- noma variant with a predilection for intraperitoneal spread. J Urol. 2012;187:852–5.  https://doi.org/10.1016/j.juro.2011.10.145.CrossRefPubMedGoogle Scholar
  77. 77.
    Kaimakliotis HZ, Monn MF, Cary KC, Pedrosa JA, Rice K, Materson TA, et al. Plasmacytoid variant urothelial bladder cancer: is it time to update the treatment paradigm? Urol Oncol. 2014;32:833–8.  https://doi.org/10.1016/j.urolonc.2014.03.008.CrossRefPubMedGoogle Scholar
  78. 78.
    • Fox MD, Xiao L, Zhang M, Kamat AM, Siefker-Radtke A, Zhang L, et al. Plasmacytoid urothelial carcinoma of the urinary bladder. A clinicopathologic and immunohistochemical analysis of 49 cases. Am J Clin Pathol. 2017;147:500–6.  https://doi.org/10.1093/ajcp/aqx029 This study is a comprehensive clinicopathologic and immunohistochemical analysis of a large cohort of plasmacytoid urothelial carcinoma (PUC). All cases showed diffuse infiltration of the muscle wall, with 57% dying from the disease at a mean of 23 months. Majority of the cases showed lack of immunoreactivity for RB1 protein (12/32) and E-cadherin (8/30). The lack of E-cadherin in PUC may contribute to the discohesion of the tumor cells and to the aggressive nature of this variant.CrossRefGoogle Scholar
  79. 79.
    •• Li Q, Assel M, Benfante NE, Pietzak JE, Herr HW, Donat M, et al. The impact of plasmacytoid variant histology on the survival of patients with urothelial carcinoma of bladder after radical cystectomy. Eur Urol Focus. 2019;5(1):104–8.  https://doi.org/10.1016/j.euf.2017.06.013 One of the largest retrospective study of patients with plasmacytoid urothelial carcinoma (PCV) (98 patients) who underwent radical cystectomy compared to a large cohort (1312 patients ) with pure UC. The study found that patients with PCV UC were more likely to have advanced tumor stage (p=0.001), positive lymph nodes (p=0.038), and receive neoadjuvant chemotherapy than those with pure UC (46% vs 22%, p<0.0001). The rate of positive soft tissue surgical margins was over five times greater in the PCV UC group compared with the pure UC group, with median OS for pure UC being 8yr versus PCV patients of 3.8 yr. On multivariable analysis the association between PCV and OS was not significant. The authors conclude that patients with PCV features have a higher disease burden at RC compared with those with pure UC. However, PCV was not an independent predictor of survival after RC on multivariable analysis, suggesting that PCV histology should not be used as an independent prognostic factor.CrossRefGoogle Scholar
  80. 80.
    Lopez-Beltran A, Requena MJ, Montironi R, Blanca A, Cheng L. Plasmacytoid urothelial carcinoma of the bladder. Hum Pathol. 2009;40:1023–8.  https://doi.org/10.1016/j.humpath.2009.01.001.CrossRefPubMedGoogle Scholar
  81. 81.
    Nigwekar P, Tamboli P, Amin MB, Osunkoya AO, Ben-Dor D, Amin MB. Plasmacytoid urothelial carcinoma: detailed analysis of morphology with clinicopathological correlation in 17 cases. Am J Surg Pathol. 2009;33:417–24.  https://doi.org/10.1097/PAS.0b013e318186c45e.CrossRefPubMedGoogle Scholar
  82. 82.
    • Perrino CM, Eble J, Kao C, Whaley RD, Cheng L, Idrees M, et al. Plasmacytoid/diffuse urothelial carcinoma: a single-institution immunohistochemical and molecular study of 69 patients. Hum Pathol. 2019;90:27–36.  https://doi.org/10.1016/j.humpath.2019.04.012 Study of a large cohort of plasmacytoid urothelial carcinoma (PUC), with the identification of 3 distinct morphological subtypes of PUC: classic, desmoplastic and pleomorphic. This study reaffirms the previous studies regarding the immunohistochemistochemical profile of these tumors with a frequent loss of E-cadherin. They reported worst clinical behavior for tumors in the desmoplastic subgroup. This study also raises the issue of whether some tumors classified as UC with rhabdoid morphology may actually fall into the pleomorphic subtype of PUC. However, more studies are required to validate this finding. CrossRefPubMedGoogle Scholar
  83. 83.
    •• Al-Ahmadie HA, Iyer G, Lee BH, Scott SN, Mehra R, Bagrodia A, et al. Frequent somatic CDH1 loss-of-function mutations in plasmacytoid variant bladder cancer. Nat Genet. 2016;48:356–8.  https://doi.org/10.1038/ng.3503 This study documents CDH1 alterations as pathognomonic of plasmacytoid UC (PUC). In a study of 31 cases of PUC, 97% showed alterations in the CDH1 gene. 84% showed truncating somatic mutations in CDH1 gene with all cases showing loss of protein expression of E-cadherin by immunohistochemistry. Also using two urothelial cell lines with CRISPR/Cas9-mediated knockout of CDH1, the authors were able to demonstrate increased tumor cell migration, which helps explain the invasive properties characteristic of plasmacytoid urothelial carcinoma. These alterations were not seen in non plasmacytoid urothelial carcinoma. In addition the similarities in the pattern of co-altered genes within the plasmacytoid and non plasmacytoid UC suggest a common cell of origin.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507:315–22.  https://doi.org/10.1038/nature12965.CrossRefGoogle Scholar
  85. 85.
    Keck B, Wach S, Kunath F, Bertz S, Taubert H, Lehmann J, et al. Nuclear E-cadherin expression is associated with the loss of membranous E-cadherin, plasmacytoid differentiation and reduced overall survival in urothelial carcinoma of the bladder. Ann Surg Oncol. 2013;20:2440–5.  https://doi.org/10.1245/s10434-013-3075-6.CrossRefPubMedGoogle Scholar
  86. 86.
    • Borhan WM, Cimino-Mathews AM, Montgomery EA, Epstein JI. Immunohistochemical differentiation of plasmacytoid urothelial carcinoma from secondary carcinoma involvement of the bladder. Am J Surg Pathol. 2017;41:1570–5.  https://doi.org/10.1097/PAS.0000000000000922 Comparative immunohistochemistry study using a large cohort of plasmacytoid urothelial carcinoma (PUC), to distinguish from lobular breast carcinoma and signet ring adenocarcinomas of the stomach, which are close morphological differentials of PUC. The authors recommend a panel of mammaglobin, ER and uroplakin II to exclude lobular breast carcinoma, and the use of GATA-3 and uroplakin II to rule out gastric primary. CrossRefGoogle Scholar
  87. 87.
    • Samaratunga H, Delahunt B, Egevad L, Adamson M, Hussey D, Malone G, et al. Pleomorphic giant cell carcinoma of the urinary bladder: an extreme form of tumour dedifferentiation. Histopathology. 2016;68:533–40.  https://doi.org/10.1111/his.12785 The largest study to date of this variant of UC, consisting of the clinical, morphological and immunohistochemical profile of 13 cases. 50% of patients with available follow up died within 1 year of diagnosis. The authors documented the presence of admixed conventional UC in 62% of their cases, with similar immunohistochemical profile as the conventional UC. They suggest that this variant represents an extreme form of de-differentiation of UC.CrossRefPubMedGoogle Scholar
  88. 88.
    Samaratunga H, Delahunt B. Recently described and unusual variants of urothelial carcinoma of the urinary bladder. Pathology. 2012;44:407–18.  https://doi.org/10.1097/PAT.0b013e3283560172.CrossRefPubMedGoogle Scholar
  89. 89.
    Lopez-Beltran A, Amin MB, Oliveira PS, Montironi R, Algaba F, McKenney JK, et al. Urothelial carcinoma of the bladder, lipid cell variant: clinicopathologic findings and LOH analysis. Am J Surg Pathol. 2010;34(3):371–6.  https://doi.org/10.1097/PAS.0b013e3181cd385b.CrossRefPubMedGoogle Scholar
  90. 90.
    Knez VM, Barrow W, Lucia MS, Wilson S, La Rosa FG. Clear cell urothelial carcinoma of the urinary bladder: a case report and review of the literature. J Med Case Rep. 2014;8:275.  https://doi.org/10.1186/1752-1947-8-275.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Lopez-Beltran A, Pacelli A, Rothenberg HJ, Wollan PC, Zincke H, Blute ML, et al. Carcinosarcoma and sarcomatoid carcinoma of the bladder: clinicopathological study of 41 cases. J Urol. 1998;159:1497–503.  https://doi.org/10.1097/00005392-199805000-00023.CrossRefPubMedGoogle Scholar
  92. 92.
    Wright JL, Black PC, Brown GA, Porter MP, Kamat AM, Dinney CP, et al. Differences in survival among patients with sarcomatoid carcinoma, carcinosarcoma and urothelial carcinoma of the bladder. J Urol. 2007;178:2302–6.  https://doi.org/10.1016/j.uro.2007.08.038.CrossRefPubMedGoogle Scholar
  93. 93.
    Sanfrancesco J, McKenney JK, Leivo MZ, Gupta S, Elson P, Hansel DE. Sarcomatoid urothelial carcinoma of the bladder: analysis of 28 cases with emphasis on clinicopathologic features and markers of epithelial-to-mesenchymal transition. Arch Pathol Lab Med. 2016;140:543–51.  https://doi.org/10.5858/arpa.2015-0085-OA.CrossRefPubMedGoogle Scholar
  94. 94.
    •• Guo CC, Majewski T, Zhang L, Yao H, Bondaruk J, Wang Y, et al. Dysregulation of EMT drives the progression to clinically aggressive sarcomatoid bladder cancer. Cell Rep. 2019;27(6):1781–93.  https://doi.org/10.1016/j.celrep.2019.04.048 The authors report a comprehensive genomic analysis of 28 cases of SARC and 84 cases of conventional urothelial carcinoma (UC), with the TCGA cohort of 408 muscle-invasive bladder cancers serving as the reference. SARCs showed a distinct mutational landscape, with enrichment of TP53, RB1, and PIK3CA mutations. They are related to the basal molecular subtype of conventional UCs and could be divided into epithelial-basal and more clinically aggressive mesenchymal subsets on the basis of TP63 and its target gene expression levels. Other analyses revealed that SARCs are driven by downregulation of homotypic adherence genes and dysregulation of the EMT network, and nearly half exhibit a heavily infiltrated immune phenotype. These findings have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    •• Priore SF, Schwartz LE, Epstein JI. An expanded immunohistochemical profile of osteoclast-rich undifferentiated carcinomas of the urinary tract. Mod Pathol. 2018;31:984–8.  https://doi.org/10.1038/s41379-018-0012-z This is the largest study to date of osteoclast-rich undifferentiated carcinomas of the urinary tract (ORUCUT), which investigates the immunohistochemical profile of these tumors with respect to more specific urothelial markers. This study identified 21 cases of ORUCUT and performed immunohistochemistry for GATA3, uroplakin II, and thrombomodulin along with pancytokeratin (AE1/3) on all cases. Mononuclear cells stained positive in 20 cases (95%) for GATA3 and 19 cases (90%) for thrombomodulin. None of the mononuclear cells were positive for uroplakin II and only three cases showed focal positivity for AE1/3. The osteoclast-like giant cells were negative for GATA3, uroplakin II, thrombomodulin, and AE1/3, providing additional support to a reactive origin for these cells. Additionally, 15 cases (71%) were associated with either in situ or invasive urothelial carcinoma. The findings support a urothelial origin for this tumor.CrossRefPubMedGoogle Scholar
  96. 96.
    Paner GP, Cox RM, Richards K, Akki A, Gokden N, Lopez-Beltran A, et al. Pseudoangiosarcomatous urothelial carcinoma of the urinary bladder. Am J Surg Pathol. 2014;38:1251–9.  https://doi.org/10.1097/PAS.0000000000000241.CrossRefPubMedGoogle Scholar
  97. 97.
    Yildiz P, Behzatoglu K, Hacihasanoglu E, Okcu O, Durak H, Yucetas U. Histological, immunohistochemical features and pathogenesis of pseudoan giosarcomatous urothelial carcinoma. Ann Diagn Pathol. 2017;30:17–20.  https://doi.org/10.1016/j.anndiagpath.2017.05.007.CrossRefPubMedGoogle Scholar
  98. 98.
    Cox RM, Schneider AG, Sangoi AR, Clingan WJ, Gokden N, McKenney JK. Invasive urothelial carcinoma with chordoid features. A report of 12 distinct cases characterized by prominent myxoid stroma and cordlike epithelial architecture. Am J Surg Pathol. 2009;33:1213–9.  https://doi.org/10.1097/PAS.0b013e3181a8ffbe.CrossRefPubMedGoogle Scholar
  99. 99.
    Parwani AV, Herawi M, Volmar K, Tsay SH, Epstein JI. Urothelial carcinoma with rhabdoid features: report of 6 cases. Hum Pathol. 2006;37:168–72.  https://doi.org/10.1016/j.humpath.2005.10.002.CrossRefPubMedGoogle Scholar
  100. 100.
    • Agaimy A, Bertz S, Cheng L, Hes O, Junker K, Keck B, et al. Loss of expression of the SWI/SNF complex is a frequent event undifferentiated/dedif- ferentiated urothelial carcinoma of the urinary tract. Virchows Arch. 2016;469:321–30.  https://doi.org/10.1007/s00428-016-1977-y This is the first study exploring SWI/SNF expression in undifferentiated UC of the urinary tract. In this study, the authors analyzed by immunohistochemistry 14 undifferentiated UCs (11 from bladder and 3 from renal pelvis) with a nondescript anaplastic or rhabdoid morphology, using commercially available antibodies against the SWI/SNF components SMARCB1 (INI1), SMARCA2, SMARCA4, SMARCC1, SMARCC2, and ARID1A. All tumors were muscle-invasive (9 were T3-4). A conventional UC component was seen in 57% of the cases. The undifferentiated component expressed pan-cytokeratin AE1/AE3 (13/14), vimentin (8/14) and GATA3 (9/14). Complete loss of at least one SWI/SNF subunit was detected in 10/14 cases (71 %) in the undifferentiated component. SMARCA2 was most frequently lost followed by ARID1A. Their results are similar to studies in other epithelial tumors where the SWI/SNF complex has been implicated in the dedifferentiation process and association with aggressive clinical course.CrossRefPubMedGoogle Scholar
  101. 101.
    Sjödahl G, Lövgren K, Lauss M, Patschan O, Gudjonsson S, Chebil G. Toward a molecular pathologic classification of urothelial carcinoma. Am J Pathol. 2013;183(3):681–91.  https://doi.org/10.1016/j.ajpath.2013.05.013.CrossRefPubMedGoogle Scholar
  102. 102.
    •• Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD, et al. Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell. 2017;171(3):540–56.  https://doi.org/10.1016/j.cell.2018.07.036 This study reports a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. The study found fifty-eight genes to be significantly mutated, with the overall mutational load to be associated with APOBEC-signature mutagenesis. mRNA expression clustering also identified a poor-survival "neuronal" subtype which is not characterized by small cell or neuroendocrine morphology. Clustering by mRNA, long non-coding RNA (lncRNA), and miRNA expression identified subsets with differential epithelial-mesenchymal transition status, histologic features, and survival. This study identified 5 expression subtypes that have a lot of promise to stratify response to different treatments.CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.University of Southern CaliforniaLos AngelesUSA

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