Identical clonal origin of synchronous and metachronous low-grade, noninvasive papillary transitional cell carcinomas of the urinary tract

doi:10.1016/S0046-8177(99)90037-0

Human Pathology

Volume 30, Issue 10, October 1999, Pages 1197-1200

https://doi.org/10.1016/S0046-8177(99)90037-0 Get rights and content

Abstract

One of the most important biological features of papillary transitional cell carcinoma (pTCC) of the urinary tract is its multicentricity and its tendency for recurrences. Two possible mechanisms, field effect and intramucosal seeding/spreading, have been proposed. The former theory hypothesizes that carcinogenic agents cause synchronous or metachronous malignant transformation of multiple urothelial cells (independent clonal origin), and the latter speculates that synchronous and metachronous tumors are derived from implantation or direct spreading of tumor cells (identical clonal origin). We tested these hypotheses by analyzing the methylation patterns of the androgen receptor gene (HUMARA) located at the X-chromosome. Thirty-five metachronous and synchronous, low-grade (grade 1 or 2), noninvasive pTCCs of the urinary tract from 10 heterozygous female patients were successfully analyzed using formalin-fixed, paraffin-embedded tissue. These included 16 recurrent bladder tumors from 4 patients, 10 metachronous bladder and ureter/renal pelvis tumors from 4 patients, and 9 multifocal tumors from 2 patients. All tumors are monoclonal as indicated by unbalanced methylation of HUMARA. Furthermore, same methylated allele was detected in multiple recurrent or multifocal tumors from any given patient, indicating their identical clonal origin. We conclude that low-grade, noninvasive pTCCs are monoclonal in nature. Synchronous or metachronous pTCCs have an identical clonal origin, strongly supporting the intramucosal seeding/spreading hypothesis.

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Carcinoma of the urinary bladder is the fourth most common malignancy in men, accounting for an estimated 60,490 new cases and 12,240 cancer deaths in the United States in 2018. Significant progress has been made in the diagnosis and treatment of bladder cancer. Bladder cancer is morphologically heterogeneous; more than 90% of bladder cancer cases are urothelial (transitional cell) carcinoma, whereas primary squamous cell carcinoma, adenocarcinoma, small cell carcinoma, and other tumors are less common. The classification system of urinary bladder neoplasia used in this chapter has been modified according to the 2016 World Health Organization (WHO) classification of tumors of the urinary system.
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However, there is currently no consensus concerning whether multifocal urothelial carcinoma is of monoclonal or oligoclonal origin. Many studies have suggested a monoclonal origin for multifocal TCC [229-240], but other studies have shown an independent origin for some multicentric urothelial tumors using similar methods [231,234,238,239,241-247]. A recent study suggests that both field cancerization and monoclonal tumor spread may coexist in the same patient [216].
Transitional cell (urothelial) carcinoma of the bladder is the second most common urologic malignancy and is one of the best understood neoplasms, with relatively well-defined pathogenetic pathways, natural history, and tumor biology. Conventional clinical and pathologic parameters are widely used to grade and stage tumors and to predict clinical outcome of transitional cell carcinoma; but the predictive ability of these parameters is limited, and there is a lack of indices that could allow prospective assessment of risk for individual patients. In the last decade, a wide range of candidate biomarkers representing key pathways in carcinogenesis have been reported to be clinically relevant and potentially useful as diagnostic and prognostic molecular markers, and as potential therapeutic targets. The use of molecular markers has facilitated the development of novel and more accurate diagnostic, prognostic, and therapeutic strategies. FGFR3 and TP53 mutations have been recognized as key genetic pathways in the carcinogenesis of transitional cell carcinoma. FGFR3 appears to be the most frequently mutated oncogene in transitional cell carcinoma; its mutation is strongly associated with low tumor grade, early stage, and low recurrence rate, which confer a better overall prognosis. In contrast, TP53 mutations are associated with higher tumor grade, more advanced stage, and more frequent tumor recurrences. These molecular markers offer the potential to characterize individual urothelial neoplasms more completely than is possible by histologic evaluation alone. Areas in which molecular markers may prove valuable include prediction of tumor recurrence, molecular staging of transitional cell carcinoma, detection of lymph node metastasis and circulating cancer cells, identification of therapeutic targets, and prediction of response to therapy. With accumulating molecular knowledge of transitional cell carcinoma, we are closer to the goal of bridging the gap between molecular findings and clinical outcomes. Assessment of key genetic pathways and expression profiles could ultimately establish a set of molecular markers to predict the biological nature of tumors and to establish new standards for molecular tumor grading, classification, and prognostication. The main focus of this review is to discuss clinically relevant biomarkers that might be useful in the management of transitional cell carcinoma and to provide approaches in the analysis of molecular pathways that influence the clinical course of bladder cancer.
p16<sup>ink4</sup> immunoreactivity is a reliable marker for urothelial carcinoma in situ
2008, Human Pathology
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2) P16INK4 mutation may not play a role in the field effect of carcinogenic agents on urothelium. The field effect is speculated when urinary carcinogenic agents cause genetic alterations and carcinogenic progression in multiple urothelial cells, leading to multiple synchronous or metachronous tumors [36]. The current study showed the lack of immunohistochemical p16INK4 expression in the normal-appearing urothelium adjacent to the high-grade lesions.
Morphological discrimination of urothelial carcinoma (UC) in situ, a precursor of high-grade invasive carcinoma, from severe reactive atypia is essential, but can be challenging at times. Mutations of the cell cycle regulatory gene INK4a (located at 9p21) that encodes p16^INK4 are one of the critical early events in carcinogenesis of UC. The purpose of this study was to investigate p16^INK4 expression in different urothelial lesions and assess its possible utility in distinguishing reactive versus neoplastic changes. Immunoreactivity of p16^INK4 was investigated using paraffin sections from 8 different sample groups (n = 80), including organ donor bladders with normal and/or reactive urothelium; bladder biopsies with reactive atypia; isolated carcinoma in situ; high-grade UC with concurrent carcinoma in situ; low-grade papillary urothelial neoplasms; high-grade stage T1 UC; and high-grade stage T2-T4 UC without concomitant carcinoma in situ. A composite staining score was calculated (Σ% positive cells × intensity) for each case. Fluorescence in situ hybridization analysis was performed in selected cases. A uniform and weak cytoplasmic p16^INK4 expression was observed in normal urothelium and urothelium with reactive atypia from organ donors. Bladder biopsies with reactive atypia showed lower scores and loss of p16^INK4 expression in 38% of cases. Strong p16^INK4 staining was found in 100% of carcinoma in situ with no loss of p16^INK4 expression. The strong p16^INK4 immunoreactivity in foci of carcinoma in situ clearly demarcated the neoplastic cells from adjacent nonneoplastic cells, which showed either normal or focal loss of p16^INK4 staining. Fluorescence in situ hybridization study revealed abundant deletion of chromosome 9p21 or polysomy of chromosome 9 in malignant cells of carcinoma in situ. Increased p16^INK4 expression was also seen in most high-grade invasive UC with concurrent carcinoma in situ, but the intensity of p16^INK4 staining did not correlate with the cancer grade or stage. We conclude that the 16^INK4 immunoreactivity seems to be most useful in distinguishing carcinoma in situ from severe reactive atypia. Alterations of 9p21/chromosome 9 detected by fluorescence in situ hybridization can also be used for diagnostic confirmation and prognostic prediction.
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In each case the tumors showed X-inactivating patterns consistent with a monoclonal origin. Li et al. [20] studied 10 patients with both synchronous and metachronous Ta/T1 tumors by X-chromosome inactivation analyses. Tumors from the same patient showed the same X-inactivation pattern indicating a monoclonal origin in all investigated cases.
The processes of intraepithelial migration, intraluminal seeding, and field cancerization as models for initiation, spread, and recurrences of urothelial cell carcinoma (UCC) are reviewed in light of recent molecular investigations. The accumulated molecular data on synchronous and metachronous tumors indicate that the majority of recurrent and multiple tumors are monoclonal. Molecular data has also shown the presence of chromosomal and genetic changes in precursor lesions as well as in normal urothelial cells. Genetic-histological mapping of cystectomized bladders has shown that overt tumors occur as local events in areas of genetically altered urothelium. A model is put forward in which the tumor process is initiated by genetically altered but histologically normal cells that produce fields of altered cells by intraepithelial displacement. By the accumulation of further genetic changes the fields of altered urothelium reaches a state of criticality, which locally may produce frank tumors.
On the Origin of Syn- and Metachronous Urothelial Carcinomas
2007, European Urology
Citation Excerpt :
Thus if tumors A, B, and C in Fig. 1 show inactivation of the same X chromosome as indicated, they are likely to be clonal even though they do not share all late genetic changes. Sidransky et al [4] and Li et al [5] used X-inactivation studies to establish the clonal relationship among syn- and metachronous tumors from a total of 23 patients. In each case tumors from the same patient did show X-inactivating patterns consistent with a monoclonal origin.
To evaluate existing models for the origin of meta- and synchronous urothelial carcinomas in light of the accumulated genetic data.
Published studies on the clonal origin and genetic relationships of syn- and metachronous tumors, genetic aberrations in normal and premalignant urothelial lesions, as well as histologic and genetic mapping studies of cystectomized bladder samples are reviewed.
The most common models for the origin of syn- and metachronous tumors are found to conform less well to the accumulated genetic data. A new model is proposed, the field-first-tumor-later model, in which aberrant cells with a stem cell, or stem cell-like, origin spread in the urothelium by cellular displacement, creating fields of premalignant cells. Tumor growth is suggested to be initiated by critical genetic events occurring in individual cells in such fields. Hence, recurring tumors are proposed to originate from a shared field of premalignant cells and not from previous overt tumors.
The proposed model can better account for the existing genetic and histological data on syn- and metachronous urothelial carcinomas.

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^☆: Presented in part at the 87th Annual Meeting of United States and Canadian Academy of Pathology, Boston, MA, February 28, 1998.

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Original contributionIdentical clonal origin of synchronous and metachronous low-grade, noninvasive papillary transitional cell carcinomas of the urinary tract☆

Abstract

J Urol

J Urol

J Urol

J Urol

Hum Pathol

J Urol

Lancet

Hum Pathol

Urology

Urology

Lancet

Lancet

J Urol

Urinary bladder cancer: Mechanisms of development and progression

Lab Invest

Ta and T1 bladder cancer: Location, recurrence and progression

Br J Urol

Non-invasive papillary carcinoma of the bladder associated with carcinoma in situ

J Urol

Bladder cancer as seen in giant histological sections

Cancer

Original contribution
Identical clonal origin of synchronous and metachronous low-grade, noninvasive papillary transitional cell carcinomas of the urinary tract☆