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. Author manuscript; available in PMC: 2026 Aug 20.
Published in final edited form as: Hum Pathol. 2025 May 20;159:105812. doi: 10.1016/j.humpath.2025.105812

Molecular Profile of Micropapillary Urothelial Carcinoma of the Urinary Bladder: An Analysis of 99 Cases by Next-Generation Sequencing

Yuan Shen a, Lan Zheng a, Jianping Zhao a, Yishan Wang b, Hui Chen a, Sinchita Roy-Chowdhuri a, Ashish M Kamat c, Omar Alhalabi d, Jianjun Gao d, Arlene Siefker-Radtke d, Peng Wei b, Donna E Hansel a, Bogdan Czerniak a, Charles C Guo a
PMCID: PMC13489496  NIHMSID: NIHMS2198926  PMID: 40403852

Abstract

Micropapillary urothelial carcinoma (MPUC) is an aggressive neoplasm with distinct histology. We examined the molecular profile of MPUC and its relationship to patients’ clinicopathologic features in 99 patients who underwent next-generation sequencing from 2010 to 2020 at a single institution. The patients included 77 men and 22 women with a mean age of 68 years (range, 24–91 years). Next-generation sequencing was performed on primary (n=74) and metastatic (n=25) tumor specimens. Somatic gene mutations were detected in 98 tumors, and the most common mutations were TP53 (n=71), TERT (n=49), ARID1A (n=28), ERBB2 (n=24), and RB1 (n=22). Copy number variations were detected in 22 tumors, including ERBB2 (n=8), CDK12 (n=3), CCND1 (n=3), and other genes (n=8). No gene fusions or microsatellite instability was detected. Human epidermal growth factor receptor 2 (HER2) overexpression was detected more frequently in MPUCs with ERBB2 amplifications than those with ERBB2 mutations. Individual gene mutations did not significantly affect the overall survival, but patients with ERBB2 amplifications had a significantly shorter overall survival than those with ERBB2 mutations (p=0.043). MPUC demonstrated distinct gene alterations in oncogenes and tumor suppressor genes that may be involved in MPUC’s oncogenesis. ERBB2 gene amplifications were associated with HER2 overexpression in MPUC, which may contribute to MPUC’s aggressive behavior.

Keywords: micropapillary urothelial carcinoma, bladder cancer, next-generation sequencing, gene mutations, ERBB2

1. Introduction

Bladder cancer is a heterogeneous disease that develops along two distinct oncogenic pathways, referred to as papillary and non-papillary, leading to various morphology and clinical behavior [1–3]. Most bladder cancers are noninvasive papillary urothelial carcinomas (UCs), which frequently recur after local treatment. The remaining bladder cancers are non-papillary UCs, which exhibit a high propensity for invasive growth and metastatic spread resulting in significant mortality [4]. Invasive UC often demonstrates various histologic features that are distinct from the conventional UC, including a number of histological subtypes [5, 6]. The UC “subtypes” were previously considered “variants”, but the term “variant” is no longer preferred in the current World Health Organization classification, because it is more commonly used to signify genomic alterations [7].

Micropapillary UC (MPUC), a distinct UC subtype, is characterized by small nests of tumor cells surrounded by empty space [8]. The tumor nests invade the bladder wall, mimicking lymphovascular invasion, but the empty space is not lined by endothelial cells and likely caused by retraction artifacts during tissue fixation and processing [9]. Micropapillary-like structures characterized by slender, delicate, filiform processes without fibrovascular cores may be present in papillary UC, but such structures are not considered MPUC if they are noninvasive and lack invasive micropapillary morphology [10]. MPUC is an aggressive disease that often presents at an advanced stage associated with a high propensity for metastasis. Studies have demonstrated that MPUC may respond favorably to a more aggressive treatment than those used for conventional UC [11, 12]. Therefore, it is important to recognize MPUC, as it is an important part of the risk stratification in bladder cancer that informs prognosis and treatment decision.

Several comprehensive genomic analyses have revealed that bladder UC can be classified into distinct molecular subtypes, which are associated with different clinical behaviors and may have implications for targeted therapy [13–16]. Although these studies propose different names and numbers of molecular subtypes, there is a remarkable intrinsic association with the top hierarchical level of separation between the luminal and basal categories, which express the signature genes characteristic of the luminal and basal layers of the normal urothelium, respectively [2, 17]. A recent genomic mRNA expression analysis of MPUC revealed that this subtype is primarily luminal and is characterized by the enrichment of active peroxisome proliferator-activated receptor γ and suppression of p63-targeted genes [18]. These tumors also consistently exhibit a higher rate of ERBB2 (also known as HER2) gene amplifications than conventional UC and other UC subtypes [19–21]. Nevertheless, there have been limited studies on the relationship between gene mutations and patients’ clinicopathologic features in MPUC. We aimed to investigate the molecular profile of MPUC and its relationship with patients’ clinicopathologic features in a large cohort of patients from a single institution.

2. Materials and methods

2.1. Patient selection and clinicopathologic data collection

After the study was approved by the institutional review board of The University of Texas MD Anderson Cancer Center (Houston, TX), we conducted a retrospective search of our pathology files, which identified 99 patients with MPUC of the urinary bladder who underwent next-generation sequencing (NGS) from 2010 to 2020. Patients’ hematoxylin and eosin–stained slides were reviewed for pathologic analysis. Clinicopathologic data were collected from patients’ medical records, including patient age, sex, tumor grade, TNM stage, micropapillary subtype amount, other histologic features, and clinical outcome. Overall survival was recorded from the date of initial MPUC diagnosis to the date of death or last follow-up.

2.2. Next-generation sequencing

Formalin-fixed, paraffin-embedded primary (n=74) and metastatic (n=25) tumor specimens were used for NGS analysis. We used the following panels to identify clinically relevant gene mutations, copy number variations, gene fusions, and microsatellite DNA loci: a 50-Gene Somatic Mutation Analysis Panel (Ion AmpliSeq Hotspot Panel, version 2) (n=34); a 134-Gene Solid Tumor Genomics Assay, V1 (or Comprehensive Oncomine Assay, version 1) (n=18); a 146-Gene Solid Tumor Genomics Assay, V2 (or Comprehensive Oncomine Assay, version 2) (n=46); and a 610-Gene Mutation Analysis Precision Panel (n=1) (Thermo Fisher Scientific, Waltham, MA) (Supplemental Tables 1–7). These gene alterations could be used as targets for existing anticancer drugs or have previously been required for inclusion in mechanism-driven clinical trials [22]. Our analysis was focused on the 50 genes in the 50-Gene Somatic Mutation Analysis Panel, which are known to have predictive or actionable value and were also included in all other test panels.

2.3. Immunohistochemistry and fluorescence in situ hybridization

To measure the expression of human epidermal growth factor receptor 2 (HER2), immunohistochemistry (IHC) was performed in a subset of patients using a rabbit monoclonal anti-HER2/neu(4B5) antibody (Roche Diagnostics, Indianapolis, IN). IHC score was used to evaluate the HER2 overexpression according to the recommendations of HER2 testing in breast cancer by College of American Pathologists and American Society of Clinical Oncology [23]. Positive cases were those with intense circumferential membrane staining in >10% of tumor cells (Score 3+). Negative cases included those with no observable staining or weak and incomplete membrane staining in ≤10% of tumor cells (Score 0) as well as weak and incomplete membrane staining in >10% of tumor cells (Score 1+). Equivocal or indeterminate cases were those with moderate complete membrane staining in >10% of tumor cells or intense circumferential membrane staining ≤10% of tumor cells (Score 2+). For equivocal cases, ERBB2 gene amplification was analyzed by fluorescence in situ hybridization (FISH) using a dual-color PathVysion HER-2 DNA Probe kit (Abbott Molecular, Des Plaines, IL). Standard laboratory procedures were conducted according to the manufacturer’s recommendation.

2.4. Statistical analysis

Statistical analysis was performed using IBM SPSS for Windows, version 24. Overall survival was estimated using the Kaplan–Meier method, and the differences between survival curves were analyzed using the log-rank test. The chi-square (χ2) test was used to evaluate potential associations between categorical groups. A p value less than 0.05 was considered statistically significant.

3. Results

3.1. Clinicopathologic features

The cohort of patients with MPUC comprised 77 men and 22 women, with an average age of 68 years (range, 24–91 years). In all patients, MPUC coexisted with conventional UC, and MPUC accounted for a mean of 20% of the tumor (range, 5%–90%). MPUC was characterized by small nests of tumor cells that were surrounded by empty space (Fig. 1A). The tumor cells showed high-grade cytologic atypia with large and irregular nuclei and a high nuclear-cytoplasmic ratio. The most characteristic feature was the presence of multiple small tumor nests within the same lacunar space (Fig. 1B). Most MPUCs were at an advanced stage, including pT2 (n=12), pT3 (n=48), and pT4 (n=34), and only 5 tumors were at pT1. Other UC subtypes and divergent differentiation were observed in 15 cases, including squamous differentiation (n=5), glandular differentiation (n=5), sarcomatoid (n=3), and small cell carcinoma (n=2) features. Overall, 84 patients developed metastases, and the common metastatic sites included lymph nodes (n=77), lungs (n=10), peritoneal cavity (n=7), liver (n=4), bone (n=4), and adrenal glands (n=3).

Fig. 1.

Fig. 1.

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Morphologic features of micropapillary urothelial carcinoma. (A) Small nests of tumor cells are surrounded by empty space. (B) Multiple small tumor nests located within the same lacunar space.

3.2. Molecular features

NGS was conducted on primary tumors (n=74) and metastatic tumors (n=25). Somatic gene mutations were identified in 98 f 99 patients (Fig. 2A). The most prevalent mutations occurred in TP53 (n=71), TERT (n=49), ARID1A (n=28), ERBB2 (n=24), and RB1 (n=22). The canonical pathway analysis revealed that the mutated genes were involved in the cell-cycle, RTK-RAS-PI3K, and epigenetic pathways (Fig. 2B). Copy number variations were detected in 22 tumors, occurring in ERBB2 (n=8), CDK12 (n=3), CCND1 (n=3), and other genes (n=8). However, no gene fusion or microsatellite instability was detected in any MPUC.

Fig. 2.

Fig. 2.

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Gene mutations in micropapillary urothelial carcinoma (MPUC). (A) Next-generation sequencing showed various gene mutations in MPUC. (B) Oncogenic pathways associated with identified gene mutations. PI3K, phosphatidylinositol 3-kinase, RTK, receptor tyrosine kinase.

ERBB2 gene alterations were detected in 24 cases, including amplifications (n=7), missense mutations (n=16), and a combined amplification and missense mutation (n=1). Six distinct ERBB2 mutations were identified. The most common ERBB2 mutation was p.S310F (n=12), and the other mutations were p.S310Y (n=2), p.S305F (n=2), p.L313V (n=1), p.S653C (n=1), and p.D769Y (n=1) (Fig. 3A). In 3 cases, the MPUC tumor showed two different ERBB2 mutations. In MPUC cases with ERBB2 amplifications, the most common co-occurring gene mutations were in TP53 (n=7), CDK12 (n=4), and TERT (n=3) genes (Fig. 4A). In MPUC with ERBB2 mutations, the most common co-occurring gene mutations were in TP53 (n=9), TERT (n=8), NF1 (n=5), ATM (n=4), and ARID1A (n=3) genes (Fig. 4B).

Fig. 3.

Fig. 3.

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ERBB2 alterations in micropapillary urothelial carcinoma (MPUC). (A) Different mutations found in ERBB2. (B) Overexpression of human epidermal growth factor receptor 2 (HER2) in MPUC with ERBB2 amplifications or mutations.

Fig. 4.

Fig. 4.

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ERBB2 alterations are associated with other genetic alterations in micropapillary urothelial carcinoma (MPUC). (A) Co-occurring gene mutations in MPUC cases with ERBB2 amplifications. (B) Co-occurring gene mutations in MPUC cases with ERBB2 mutations. For each gene, the percentage of gene mutation is calculated by dividing the number of cases with gene mutation by the total number of cases analyzed.

3.3. Immunohistochemistry and fluorescence in situ hybridization analysis

IHC for HER2 was performed in 54 MPUC cases, and overexpression of HER2 was found in 39 cases (72%) (Fig. 5). These cases were classified as HER2 2+ (n=23) and HER2 3+ (n=16). FISH analysis of ERBB2 amplification was performed in 26 cases, and ERBB2 amplification was identified in 11 cases (42%). The rate of ERBB2 amplification in tumors with HER2 3+ status was higher (78%) than that in tumors with HER2 2+ status (29%). Overall, 20 MPUCs had positive HER2 status, which was defined as HER2 3+ on IHC or HER2 2+ on IHC with HER2 gene amplification by FISH. HER2 positivity was present in 100% of MPUCs harboring ERBB2 amplification (4/4), 38% of MPUCs with ERBB2 mutations (5/13), and 30% of MPUCs with the wild-type ERBB2 (11/37) (Fig. 3B).

Fig. 5.

Fig. 5.

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HER2 expression by immunohistochemistry in micropapillary urothelial carcinoma. (A) No staining in tumor cells (Score 0). (B) Weak membrane staining in >10% of tumor cells (Score 1+). (C) Moderate membrane staining in >10% of tumor cells (Score 2+). (D) Intense circumferential membrane staing in >10% of tumor cells (Score 3+).

3.4. Clinical follow-up

All patients had follow-up information available; the mean follow-up time was 32 months (range, 5–144 months). Fifty-six patients died of disease after a median of 18 months (range, 5–95 months), and 43 patients were still alive after a median of 56 months (range, 34–144 months). Individual gene mutations did not have any significant impact on the clinical outcome, but the analysis was limited because of the small number of cases with specific gene mutations. Although HER2 positivity status did not significantly affect survival, patients with ERBB2 amplifications had a significantly shorter overall survival than those with ERBB2 mutations in an univariant analysis (p=0.043) (Fig. 6). A multivariant analysis including age, sex, cancer grade, stage, variant history, and ERBB2 gene alterations was performed, but the prognostic impact of ERBB2 gene alterations was not significant in the multivariant analysis, probably due to the limited number of cases with ERBB2 amplifications and mutations in our cohort.

Fig. 6.

Fig. 6.

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Kaplan–Meier curves compare overall survival time between patients with ERBB2 amplifications and those with ERBB2 mutations.

4. Discussion

Bladder UC develops into various histological subtypes with unique microscopic features and different clinical behaviors [5, 6]. Genomic analyses have revealed that UC subtypes are likely to evolve from precursor conventional UC along its intrinsic basal and luminal tracks [2, 24], in which lineage plasticity and epithelial–mesenchymal transition (EMT) are the major driving forces [18, 25, 26]. Our previous genomic mRNA expression analysis revealed that MPUC expressed high levels of luminal markers, such as KRT20, GATA3, uroplakins, CD24, and FOXA1; and low levels of basal markers, such as CD44, TP63, KRT5, KRT6, and KRT14 [18]. Subsequent IHC analysis demonstrated strong expressions of luminal markers (GATA3, FOXA1, and CK20) and weak or absent expressions of basal markers (CK5, p63, and CD44) in the vast majority of MPUC cases [27–29]. Furthermore, when conventional UC is adjacent to MPUC in the same tumor, the conventional UC is usually luminal as well, supporting that MPUC is likely to evolve from precursor luminal UC [18].

Our current study identified several clinically relevant gene alterations in MPUC. These genes could be targeted using currently available anticancer drugs or serve as biomarkers for mechanism-driven registered clinical trials [22]. The most prevalent mutations in MPUC were found in TP53, TERT, ERBB2, ARID1A, and RB1, which are not significantly different from those seen in conventional UC [13, 15]. However, compared with conventional UC, our previous genomic mRNA expression analysis revealed that MPUC is characterized by changes in gene expression associated with oncogenic pathways, including cell-cycle regulation (cyclins, G1/S checkpoint), transformation (mechanisms of cancer, glioma, and glioblastoma; RhoA; p53), DNA damage repair (BRCA1), and signal transduction (ephrin signaling) [18, 24]. Similarly, in MPUC, the current study has also found frequent gene mutations involved in similar pathways, such as cell-cycle regulation (TP53, RB1, FBXW7), chromatin modification (ARID1A, CREBBP), and the RTK-RAS-PI3K pathway (PIK3CA, ERBB2, CDK12), supporting the key role of these molecular pathways in the development of MPUC.

Several studies have demonstrated that ERBB2 amplification is present in a small subset of bladder UCs [30–32]. Laé et al. assessed 1005 bladder cancer samples and found that HER2 overexpression was detected by IHC in 93 tumors, including HER2 2+ in 42 tumors and 3+ in 51 tumors [31]. Furthermore, FISH revealed all tumors with a HER2 3+ status also exhibited ERBB2 amplifications, whereas no ERBB2 amplification was found in any tumors with a HER2 2+ status. Compared with conventional UC, MPUC has been found to exhibit more frequent HER2 overexpression on IHC and a higher rate of ERBB2 amplifications on FISH analysis [19, 29]. In the current study, 72% of MPUC cases showed HER2 overexpression on IHC. All tumors with ERBB2 amplification showed HER2 overexpression, but only 38% of tumors with ERBB2 gene mutations showed HER2 overexpression. Furthermore, the rate of ERBB2 amplification in tumors with HER2 3+ status was higher (78%) than that in tumors with HER2 2+ status (29%). Interestingly, 30% tumors with the wild-type ERBB2 gene also showed HER2 overexpression, but this rate is considerably lower than that of cases with ERBB2 amplification or mutations, indicating that other factors may have also contributed to the HER2 overexpression in these cases. The presence of ERBB2 amplification has also been associated with poor cancer-specific survival following radical cystectomy [21, 33]. In our study, patients with ERBB2 amplification experienced a significantly shorter overall survival than those with ERBB2 mutations.

Our study also identified several distinct ERBB2 missense mutation patterns in MPUC, and p.S310F was the most common mutation, accounting for 63% of all the ERBB2 mutations in our cohort. Previous studies have found that S310F and S310Y mutations are the most frequent mutations that affect the extracellular domain of HER2 in bladder cancer; these mutations may facilitate the hyperphosphorylation of HER2 and serve as an alternative mechanism for ERBB2 amplification [22, 34, 35]. Posada et al. identified 219 cases of bladder UC with activating mutations (74% were S310F and 26% were S310Y) that affect the extracellular domain of HER2; 63 (28.8%) of these cases were MPUC [34]. HER2-activating mutations have emerged as oncogenic drivers and therapeutic targets in several human tumors [36]. Altogether, because of the high rate of ERBB2 mutations in MPUC, ERBB2-targeting drugs may have the potential to improve the treatment of MPUC [37]. Indeed, a recent study found that a subgroup of patients with ERBB2 missense mutations in muscle-invasive bladder cancer showed an excellent response to neoadjuvant chemotherapy [38].

Intratumoral heterogeneity of ERBB2 amplification and HER2 overexpression, defined as the coexistence of subpopulations of tumor cells with different HER2 gene or protein expression within a tumor, may be significant in bladder cancers with different histologic subtypes [39, 40]. Isharwal S et al analyzed ERBB2 amplification by FISH and HER2 protein expression by IHC in 35 cases of bladder tumors containing matched micropapillary and conventional (or not otherwise specified) UC components [40]. Only 34 % of bladder tumors showed concordance of ERBB2 amplification in micropapillary and conventional UC components, and 43% of bladder tumors showed discordance of ERBB2 amplification. HER2 protein overexpression was significantly more common in the micropapillary component (69%) compared to the conventional component (34%) within the same tumor. Moreover, the association between HER2 overexpression and ERBB2 amplification is not linear [41, 42]; Moktefi et al. reported HER2 protein overexpression in as many as 60% of micropapillary UC, with only 12% showing HER2 amplification on FISH analysis [41]. In the current study, we retrospectively reviewed the available IHC data in our pathology files, which were performed for the purpose of patient care. As some materials were not available for research study, comparison of HER2 expression across different UC subtypes and conventional UC was not performed.

ERBB2 mutations have been associated with other gene alterations in MPUC [43, 44]. A recent genomic analysis demonstrated that MPUC with ERBB2 mutations also exhibits frequent co-occurring mutations in TERT, TP53, and ARID1A, like those in the conventional UC [34]. However, the same study found that KMT2D, RB1, and MTAP alterations are more common in ERBB2-mutated MPUC than in conventional UC [34]. In the current study of MPUC cases, we assessed which mutations co-occurred with different ERBB2 alterations. In MPUC cases with ERBB2 amplifications, the most common gene mutations were TP53, CDK12, and TERT. In MPUC cases with ERBB2 mutations, common co-occurring mutations included TP53, TERT, NF1, and ATM. Co-occurring genes were similar between cases with ERBB2 amplifications and ERBB2 mutations, suggesting that these alterations are key oncogenic drivers and represent potential molecular targets [36, 45].

Our study has several limitations. First, it is a retrospective study in a relatively small cohort of patients, as MPUC is rare. Particularly, the numbers of patients with specific gene mutations were small, and meaningful statistical analysis could not be performed to evaluate the clinical significance of specific mutations. Second, our NGS panels were not uniform and had different numbers of gene targets. Nonetheless, all the panels contained 50 most clinically relevant genes, which comprised key oncogenes and tumor suppressor genes in bladder cancer. In the current study, we retrospectively reviewed the NGS data that were available in our pathology database, and we did not perform additional tests on other UC subtypes, as some materials were not available for research study. However, our previous genomic analysis of mRNA expressions between matched micropapillary and conventional UC samples demonstrated a similar gene expression profile [18]. Finally, although multiple gene mutations were identified in our study, whether these mutations are driver or passenger mutations remains uncertain. Therefore, additional studies are needed to further elucidate the biological function of mutated genes in MPUC.

5. Conclusion

In summary, our NGS analysis reveals distinct gene mutations and copy number variations in MPUC. The most common mutations occur in TP53, TERT, ARID1A, ERBB2, and RB1, and the most common copy number variations occur in ERBB2, CDK12, and CCND1. Those altered genes are clinically relevant oncogenes and tumor suppressor genes that may contribute to the development of MPUC and serve as potential biomarkers for targeted therapy. MPUC also shares gene alterations with conventional UC, suggesting that MPUC is likely to evolve from precursor conventional UC through the luminal pathway. HER2 overexpression is found to be common in MPUC, particularly in cases with ERBB2 amplifications. Finally, patients with ERBB2 amplifications have a significantly shorter overall survival time than those with ERBB2 mutations, suggesting that ERBB2 amplifications may contribute to the aggressive behavior of a subset of MPUCs.

Supplementary Material

1

Acknowledgments

We thank Madison Semro, Associate Scientific Editor, and Sarah Bronson, Scientific Editor, in the Research Medical Library at The University of Texas MD Anderson Cancer Center for editing this article.

Funding:

This study was supported by the National Institutes of Health/National Cancer Institute under award number P30CA016672.

Footnotes

Declaration of interest: All authors declare they have no conflicts of interest.

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1
NIHMS2198926-supplement-1.pptx (17.3MB, pptx)

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