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Year : 2017  |  Volume : 60  |  Issue : 4  |  Page : 462-463
Immunohistochemical and molecular markers in urothelial carcinoma

Department of Pathology, Rohilkhand Medical College Hospital, Bareilly, Uttar Pradesh, India

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Date of Web Publication12-Jan-2018

How to cite this article:
Agrawal R. Immunohistochemical and molecular markers in urothelial carcinoma. Indian J Pathol Microbiol 2017;60:462-3

How to cite this URL:
Agrawal R. Immunohistochemical and molecular markers in urothelial carcinoma. Indian J Pathol Microbiol [serial online] 2017 [cited 2022 Aug 11];60:462-3. Available from: https://www.ijpmonline.org/text.asp?2017/60/4/462/222981

Urothelial carcinomas (UCs) are the second most common cancer of the genitourinary tract preceded by prostate carcinoma. It ranks fourth among men and eighth among women. They can present in an advanced stage invading the detrusor muscle or maybe superficial or nonmuscle invasive being confined to the mucosa or lamina propria. About 80% UCs are superficial and 70% recur after resection.[1] Multifocality is common leading to recurrence. Carcinomas “in situ” although nonmuscle invasive are more aggressive requiring excessive monitoring.

Since 2004, the WHO/ISUP 1998 classification has been used for the grading of bladder neoplasms. The newly described noninvasive urothelial lesions include urothelial dysplasia and urothelial proliferation of uncertain malignant potential (UPUMP). UPUMP is noticed in patients a lateral extension, i.e., “shoulder lesion” of papillary neoplasm as termed.[2],[3] Noninvasive tumors can be divided into two categories: papillary or flat. Flat ones include a wide spectrum ranging from reactive to preneoplastic to frankly malignant lesions. Papillary tumors include reactive proliferations, papilloma, and papillary urothelial proliferation of low malignant potential (PUNLMP) and low (LGPUC) and high grade (HGPUC) papillary carcinomas.

Histological grade has great significance in noninvasive lesions, especially the papillary types. Recurrence and progression are influenced by the pattern of growth, grade, dimension, multifocality, time of recurrence, and any prior bladder therapy. Grading can be subjective and so immunohistochemistry or molecular tests play a great role. Immunohistochemical markers serve as additional criteria in risk stratification of patients with noninvasive UC. Early lesions are associated with recurrence only when there is involvement of the lamina propria.[1] It is required that invasive UC should mention the percentage and types of divergent morphology in the histopathology report.[2],[4]

For urinary neoplasias, currently, the most frequent problem relates to the classification of noninvasive lesions, especially separating PUNLMP from LGPUC.[5] The only criteria available for differentiating these tumors are the degree of anaplasia or dysplasia. This distinction carries importance for the urologists in terms of tumor recurrence and progression. Clinical and morphological parameters, namely, size, grade, multifocality, and carcinoma “in situ” in the adjacent mucosa carry different clinical management. Some markers to correlate with the histologic grade, progression, clinical staging, and recurrence of UC include p53, Ki-67, and cytokeratin (CK20). p53 has been associated with recurrence, tumor progression, and metastasis-free interval. Mutation in p53 has a major role in the pathogenesis of urothelial tumors but is not the only step in carcinogenesis. It, however, has a role in the progression of PUNLMP to LGPUC.[5],[6] The expression of Ki-67 in the normal urothelium is low and restricted to the basal layers only. It, however, varies with the histologic grade, clinical stage, and is associated with recurrence. Aberrant expression of CK20 distinguishes between PUNLMP and LGPUC besides predicting recurrence. p63 immunoreactivity does not express any difference between LGPUC and HGPUC or noninvasive papillary UC. On the contrary, highly significant relationship has been reported for pT1 and pT2 in terms of percentage of p53 staining. Studies on the role of p53 and p63 immune reactions in the differential diagnosis and prognosis of UC according to the pathological stage and histological grade of UC are still underway. When PUNLMP and LGPUC cannot be differentiated by morphology alone or in high-grade lesions, cytoplasmic and basal (aberrant) expression pattern of MUC1 is helpful. MUC1 is expressed in a normal pattern in areas of the urinary bladder not involved by neoplasia or even in areas of PUNLMP but displays aberrant expression in areas of LGPUC and HGPUC. MUC1 sends a signal to p53, thus inhibiting cell death.[5]

Bladder tumors have diverse biological behaviors so should be stratified at a molecular level with a purpose to segregate those with poor prognosis and to formulate treatment plans for superficial tumors diagnosed by morphology alone. Increasing tumor grade and stage expresses copy number abnormalities, increased genomic instability, and loss of heterozygosity. Numerous oncogenes and tumor suppressor genes have been identified in invasive UC including TP53, RB1, PIK3CA, and HRAS. TERT mutations may not predict the clinical outcome but carry significant diagnostic importance.[7] Micropapillary variant (MPV) is more aggressive and carries a poor prognosis than the conventional UC. Conventional UC has a high Ki-67 index, but MPV displays more venous and lymphatic tumor emboli, nodal metastasis, and overall poorer prognosis. Tenascin-C, fibronectin, and point mutations of KRAS exon are more expressed in MPV than in UC, especially at the epithelial-mesenchymal interface. Aurora-A related to mitosis and centrosome maturation is implicated in UC. MIB-1 is also a predictive marker of relapse and progression, especially in superficial bladder cancers. Aurora-A is a more sensitive marker than MIB-1 to predict relapse in pTa bladder neoplasias. When combined together, both markers give better prediction of recurrence.[8]

   References Top

Ogata DC, Marcondes CA, Tuon FF, Busato WF Jr., Cavalli G, Czeczko LE. Superficial papillary urothelial neoplasms of the bladder (PTA E PT 1): Correlation of expression of P53, Ki-67 and CK 20 with histologic grade, recurrence and tumor progression. Rev Col Bras Cir 2012;39:394-400.  Back to cited text no. 1
Humphrey PA, Moch H, Cubilla AL, Ulbright TM, Reuter VE. The 2016 WHO classification of tumours of the urinary system and male genital organs-part B: Prostate and bladder tumours. Eur Urol 2016;70:106-19.  Back to cited text no. 2
Readal N, Epstein JI. Papillary urothelial hyperplasia: Relationship to urothelial neoplasms. Pathology 2010;42:360-3.  Back to cited text no. 3
Montironi R, Lopez-Beltran A, Scrapelli M, Mazzucchelli R, Cheng L. 2004 World Health Organization classification of the noninvasive urothelial neoplasms: Inherent problems and clinical reflections. Eur Urol 2009;8:453-7.  Back to cited text no. 4
Kaymaz E, Ozer E, Unverdi H, Hucumenoglu S. Evaluation of Muc1 and p53 expressions in non-invasive papillary. Urothelial neoplasms of the bladder, their relationship with tumor grade and their role in the differential diagnosis. Ind J Pathol Microbiol 2017;60:509-13.  Back to cited text no. 5
Koyuncuer A. Immunohistochemical expression of p63, p53 in urinary bladder carcinoma. Indian J Pathol Microbiol 2013;56:10-5.  Back to cited text no. 6
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Allory Y, Beukers W, Sagrera A, Flández M, Marqués M, Márquez M, et al. Telomerase reverse transcriptase promoter mutations in bladder cancer: High frequency across stages, detection in urine, and lack of association with outcome. Eur Urol 2014;65:360-6.  Back to cited text no. 7
Ishii S, Ohbu M, Toomine Y, Nishimura Y, Hattori M, Yokoyama M, et al. Immunohistochemical, molecular, and clinicopathological analyses of urothelial carcinoma, micropapillary variant. Pathol Int 2011;61:723-30.  Back to cited text no. 8

Correspondence Address:
Ranjan Agrawal
Department of Pathology, Rohilkhand Medical College Hospital, Bareilly, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_474_17

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