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Clinicopathological characteristics of transcription factor-defined subtypes in bladder small cell carcinoma

BMC Cancer volume 25, Article number: 766 (2025) Cite this article

Abstract

Background

Small cell carcinoma (SmCC) of the bladder is a rare and aggressive malignancy. Characterizing transcription factor (TF)-defined subtypes may provide insights into its biology and inform targeted therapies. This study investigates lineage-specific TF expression in bladder SmCC, its association with clinicopathological features, and comparisons with prostate SmCC.

Methods

A retrospective analysis was conducted on 9 cases of bladder SmCC and 6 cases of prostate SmCC diagnosed at a single cancer hospital in Japan. Immunohistochemistry was performed for lineage-specific TFs (ASCL1, NEUROD1, POU2F3, and YAP1) and neuroendocrine and other markers. Statistical comparisons were made using Fisher’s exact test and independent samples t-tests.

Results

Combined SmCC morphology, including urothelial carcinoma (UC) (5 cases) and adenocarcinoma (2 cases), was more frequent in bladder SmCC than in prostate SmCC (78% [7 of 9 cases] vs. 17% [1 of 6 cases], p = 0.041). NEUROD1 was more frequently expressed in bladder SmCC than in prostate SmCC (67% [6 of 9 cases] vs. 0% [0 of 6 cases]; p = 0.028). NEUROD1 expression was more frequent in combined SmCC and UC bladder tumors than in other bladder SmCC tumors (100% [5 of 5 cases] vs. 25% [1 of 4 cases], p = 0.048). Conversely, HNF4A expression was absent in all combined SmCC and UC bladder tumors (0 of 5) but present in 75% (3 of 4) of other bladder SmCC tumors (p = 0.048). In 2 cases of bladder SmCC, NEUROD1 and POU2F3 were expressed in a mutually exclusive manner, with neuroendocrine markers expressed only in the NEUROD1-expressing component.

Conclusions

NEUROD1 is characteristically expressed in bladder SmCC, especially in SmCC combined with UC, suggesting a distinct phenotype from prostate SmCC. These findings highlight the potential for TF-based classification to improve diagnostic accuracy and inform therapeutic strategies.

Peer Review reports

Introduction

Small cell carcinoma (SmCC) is a rare histological variant of bladder cancer [1,2,3,4,5,6]. Bladder SmCC occurs predominantly in men and is associated with a history of smoking [6]. Combined SmCC morphology is more common than pure SmCC morphology and generally includes a urothelial carcinoma (UC) component [4,5,6,7,8]; however, the clinicopathological differences between combined and pure SmCC tumors remain unclear [4, 7].

Emerging evidence indicates that lung SmCC can be subclassified into subtypes based on the immunohistochemical expression of 4 lineage-specific transcription factors (TFs), ASCL1, NEUROD1, POU2F3, and YAP1 [9]. Both ASCL1- and NEUROD1-dominant lung SmCC tumors frequently express high levels of neuroendocrine markers, such as chromogranin A, synaptophysin, and CD56. Conversely, POU2F3-dominant SmCC tumors, which are thought to originate from tuft cells [10], do not express ASCL1 or NEUROD1 and less frequently express neuroendocrine markers [9]. Recent studies suggest that YAP1 expression in lung SmCC is either absent or present at only a low level, indicating that YAP1 expression alone cannot be used to define a lung SmCC subgroup [11,12,13,14].

Recent efforts have attempted to characterize TF-defined subtypes in bladder SmCC [15,16,17,18]. However, little is known about the clinicopathological characteristics of each TF-defined subtype, intratumoral heterogeneity of TF expression in a single bladder SmCC tumor, and relationships between TF-defined subtypes and clinicopathological characteristics, including histological features (e.g., pure SmCC or combined SmCC and non-SmCC histology). This study aimed to describe the clinicopathological characteristics of each TF-defined subtype of bladder SmCC; the intratumoral heterogeneity of TF expression within a single bladder SmCC tumor; and the relationships between TF-defined subtypes and clinicopathological characteristics, using a consecutive series of 9 cases of bladder SmCC. Additionally, to investigate organ-specific characteristics of bladder SmCC, we compared the 9 cases of bladder SmCC with a consecutive series of 6 cases of prostate SmCC as a secondary analysis.

Materials and methods

Patient data

We retrospectively analyzed data from consecutive patients diagnosed with SmCC of the urinary bladder or prostate at The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan, between January 1, 2006, and September 31, 2022. Clinical data including age, sex, history of smoking, medical history, date of initial diagnosis, pathological diagnosis, treatment received (e.g., surgery, hormone therapy, chemotherapy, and radiotherapy), and survival status at the last follow-up, were retrieved from medical records. The tumor location was defined as ‘wide spread’ if the tumor extended beyond a single area within the bladder, involving multiple regions (e.g., from the anterior wall to the lateral wall). For prostate SmCC, both de novo and treatment-related SmCC tumors were included. The study protocol was approved by the Institutional Review Board of the JFCR (approval number: 2018 − 1177). The requirement for informed consent was waived owing to the retrospective study design.

Pathological evaluation

The bladder SmCC cohort included 9 primary SmCC cases, with 5 specimens obtained through transurethral resection (TUR) and 4 through cystectomy. The prostate SmCC cohort comprised 5 primary SmCC cases and 1 metastatic SmCC case in the adrenal gland, with 5 specimens obtained through needle biopsy and 1 through TUR. The histology slides from all cases including all the available previous specimens were retrieved and independently evaluated in a blinded manner by 2 pathologists (K.K. and K.I.). The diagnosis of SmCC was determined based on the criteria detailed in the 5th edition of the World Health Organization classification of urinary and male tumors [8]. Both the SmCC components and the non-SmCC components, including UC, adenocarcinoma, squamous cell carcinoma, and other tumor types, were evaluated. In tumors containing UC components, the histological variants, divergent histological differentiation, and UC in situ components were evaluated. Divergent histological differentiation was noted even if present in minimal amounts. The morphology of the adenocarcinoma components was evaluated. Pathological and clinical stages were based on the 8th American Joint Cancer Committee TNM staging system [19]. For bladder SmCC tumors removed by cystectomy, the pathological stage was determined, whereas for other bladder SmCC tumors and prostate SmCC tumors, the clinical stage was determined based on the clinical and radiographic findings. In cases in which the 2 pathologists disagreed on the pathological evaluation, consensus was reached through discussion and joint review of the specimens. If the pathologists did not reach consensus, the case was excluded from the study.

Immunohistochemical analysis

Tissue sections were selected from representative regions with sufficient SmCC and non-SmCC components, if present. Consecutive 4-µm-thick whole tissue sections were cut from formalin-fixed paraffin-embedded blocks. The bladder SmCC tissue sections were stained for 20 markers (ASCL1, NEUROD1, POU2F3, YAP1, chromogranin A, synaptophysin, CD56, INSM1, HNF4A, DLL3, TTF1, BCL2, RB1, TP53, CK5/6, CK20, GATA3, p40, NKX3.1, and Ki-67), whereas the prostate SmCC tissue sections were stained for 16 markers (ASCL1, NEUROD1, POU2F3, YAP1, chromogranin A, synaptophysin, CD56, INSM1, DLL3, TTF1, BCL2, RB1, TP53, p40, NKX3.1, and Ki-67). The immunohistochemistry protocols are summarized in Supplementary Table 1. Neuroendocrine markers (chromogranin A, synaptophysin, and CD56), INSM1, ASCL1, NEUROD1, POU2F3, YAP1, HNF4A and DLL3 were evaluated using the H score (on a scale of 0 to 300) calculated based on the staining intensity (0: absent, 1: weak, 2: medium, 3: strong) multiplied by the percentage of positive cells (0 to 100%) [14, 20]. H scores < 10 and ≥ 10 were regarded as negative and positive, respectively, for chromogranin A, synaptophysin, CD56, INSM1, ASCL1, NEUROD1, POU2F3, YAP1, HNF4A and DLL3, following thresholds used in previous studies [12, 20, 21]. For combined SmCC tumors, only the SmCC component was assessed and scored. When multiple lineage-specific TFs were expressed, the predominant subtype was assigned based on the marker with the highest H score.

Statistical analysis

All statistical analyses were performed using EZR software version 1.61 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [22]. Groups were compared using Fisher’s exact test for categorical variables and independent samples t-tests for continuous variables. All statistical tests were two-sided, with statistical significance defined as p < 0.05.

Results

Patient characteristics

The 9 patients with bladder SmCC comprised 5 men and 4 women, with a mean age at diagnosis of 68.9 years (range: 54 to 87 years). Five patients reported a history of smoking. The initial stage was stage II in 3 patients (33%), stage III in 4 patients (44%) and stage IV in 2 patients (22%). Most of the tumors were widespread (6 cases), while the others were located in the dome (2 cases) and on the trigone (1 case). The surgical procedures were TUR in 5 patients (56%), cystectomy in 3 patients (33%), and partial cystectomy in 1 patient (11%). Except for 1 patient (Case 5) who underwent TUR, all patients received either pre- or post-treatment chemotherapy or radiotherapy. Four patients died within 1 year, and 2 of the 3 survivors experienced recurrence within 6 months after treatment. The median follow-up period was 377 days (range: 76 to 1963 days). The clinical features of patients with bladder SmCC are shown in Supplementary Table 2.

Among the 6 patients with prostate SmCC, the mean age at diagnosis was 69.2 years (range: 61 to 82 years). Four patients reported a history of smoking. All cases presented at an initial stage of IV. One patient was initially diagnosed at another hospital with prostate adenocarcinoma (Gleason group 5) and later found to have combined SmCC with a sarcomatoid component, suggesting treatment-related endocrine prostate carcinoma. The other 5 patients were diagnosed with SmCC at the initial diagnosis and considered to be de novo SmCC. All the patients underwent chemotherapy, radiotherapy, hormone therapy, or nuclear medicine therapy after the current diagnosis. The median follow-up period was 571 days (range: 108 to 1702 days). The clinical features of patients with prostate SmCC are shown in Supplementary Table 3.

Pathological morphology

Of the 9 cases of bladder SmCC, 2 (22%) had pure SmCC morphology, and 7 (78%) had combined SmCC morphology. The coexisting histology of the combined SmCC tumors included UC in 5 cases and adenocarcinoma in 2 cases. The UC components consist of invasive UC (IUC) in 1 case, IUC with UC in situ in 3 cases and UC in situ in 1 case. Additionally, glandular differentiation was observed in one case of IUC and one case of UC in situ. All 2 cases of combined SmCC and adenocarcinoma tumors were considered urachal carcinomas owing to their localization in the dome and their morphology showing an adenocarcinoma component comprising tall columnar cells. The 6 cases of prostate SmCC comprised 5 cases of pure SmCC (83%) and 1 case of SmCC (17%) combined with a sarcomatoid component. Combined SmCC morphology was more frequent in the bladder SmCC tumors (7 of 9 cases, 78%) than in the prostate SmCC tumors (1 of 6 cases, 17%; p = 0.041).

Immunohistochemical assay

The immunohistochemical findings of the cases of bladder and prostate SmCC are summarized in Fig. 1. In all the cases of bladder and prostate SmCC, the expression of neuroendocrine markers (chromogranin A, synaptophysin, and CD56), ASCL1, NEUROD1, and POU2F3, was confined to the SmCC components. YAP1 was not expressed in any of the SmCC components, but in all the combined bladder SmCC tumors, YAP1 was expressed in non-SmCC components, including the UC and adenocarcinoma components. YAP1 was also expressed in the sarcomatoid component of the prostate combined SmCC case. The morphology of the SmCC components did not differ according to the expression of ASCL1, NEUROD1, POU2F3, or neuroendocrine markers in any of the bladder or prostate SmCC tumors studied. Among the SmCC component of the bladder SmCC tumors, chromogranin A, synaptophysin, CD56, and INSM1 were immunohistochemically positive in 56% (5 of 9), 100% (9 of 9), 100% (9 of 9), and 100% (9 of 9) of the cases, respectively (Fig. 1). ASCL1, NEUROD1, POU2F3, and YAP1 were immunohistochemically positive in 33% (3 of 9), 67% (6 of 9), 22% (2 of 9), and 0% (0 of 9), respectively, and all 4 TF markers were negative in 22% (2 of 9) of the cases. A single TF marker was positive in 33% (3 of 9) of the cases, whereas 2 TF markers were positive in 44% (4 of 9) of the cases. Two of the 4 double-positive tumors predominantly expressed NEUROD1 with co-expression of ASCL1, and the double-positive components had high expression levels of neuroendocrine markers. The other 2 double-positive tumors predominantly expressed NEUROD1 with co-expression of POU2F3 in a mutually exclusive manner, with positivity for neuroendocrine markers being present only in the NEUROD1-expressing component. According to the expression of TF markers, bladder SmCC tumors were categorized as NEUROD1-dominant in 6 (67%), ASCL1-dominant in 1 (11%), and quadruple-negative in 2 (22%) of the 9 cases. HNF4A was expressed in 3 of the 9 cases (33%). DLL3 was expressed in 6 of the 9 cases (67%). TTF1 was expressed in 3 of the 9 cases (33%), with 2 cases (Case 1 and 2) showing diffuse positivity, and 1 case (Case 4) showing positivity only in regions expressing NEUROD1, synaptophysin, CD56 and INSM1. BCL2 was positive in all cases (100%). In 1 case (Case 5), BCL2 was absent in regions positive for NEUROD1 and NE markers but was expressed in the POU2F3-expressing area. RB1 protein expression was absent in 6 of the 9 cases (67%). Nuclear TP53 accumulation was observed in all 9 cases, whereas none of the cases expressed p40, GATA3, CK5/6, CK20, or NKX3.1. The Ki-67 labeling index was at least 50% in the SmCC components of all 9 cases.

Fig. 1
figure 1

Clinicopathological features and immunohistochemical expression of bladder small cell carcinoma. SmCC, small cell carcinoma; UC, urothelial carcinoma

Full size image

In prostate SmCC tumors, chromogranin A, synaptophysin, CD56, and INSM1 were expressed in 83% (5 of 6), 100% (6 of 6), 67% (4 of 6), and 100% (6 of 6) of the cases, respectively (Fig. 1). ASCL1 was positive in 50% (3 of 6) prostate SmCC tumors, whereas NEUROD1, POU2F3, and YAP1 expression was absent in all of the prostate SmCC tumors. NEUROD1 was more frequently expressed in bladder SmCC than in prostate SmCC (67% [6 of 9 cases] vs. 0% [0 of 6 cases]; p = 0.028). In prostate SmCC tumors, DLL3 and TTF1 were each expressed in 50% (3 of 6), while BCL2 was expressed in 67% (4 of 6). RB1 protein expression was absent in 33% (2 of 6); nuclear TP53 accumulation was present in 67% (4 of 6); and p40 expression was absent in all cases. NKX3.1 was expressed in all cases examined, and the Ki-67 labeling index was at least 50% in each case.

Relationship between morphology and immunohistochemistry

All 5 cases of combined SmCC and UC bladder tumors were NEUROD1-dominant. Among them, 2 expressed NEUROD1 and ASCL1, 2 expressed NEUROD1 and POU2F3, and 1 expressed only NEUROD1 (Fig. 1). ASCL1 and NEUROD1 were co-expressed with other neuroendocrine markers (Fig. 2). TTF1 was expressed in only 3 tumors: 2 co-expressed ASCL1 and NEUROD1, while 1 co-expressed only NEUROD1. In contrast, NEUROD1 and POU2F3 showed mutually exclusive expression patterns, with the NEUROD1-positive components showing increased expression of neuroendocrine markers compared with the POU2F3-positive components (Fig. 3). NEUROD1 expression was more frequent in combined SmCC and UC bladder tumors than in other bladder SmCC tumors (100% [5 of 5 cases] vs. 25% [1 of 4 cases], p = 0.048). Conversely, HNF4A expression was absent in all combined SmCC and UC bladder tumors (0 of 5) but present in 75% (3 of 4) of other bladder SmCC tumors (p = 0.048).

Fig. 2
figure 2

Co-expression of ASCL1, NEUROD1, and synaptophysin in combined bladder small cell carcinoma. (A) H&E, low magnification; (B) ASCL1, low magnification; (C) NEUROD1, low magnification; (D) synaptophysin, low magnification; (E) H&E, high magnification; (F) ASCL1, high magnification; (G) NEUROD1, high magnification; (H) synaptophysin, high magnification. H&E, hematoxylin and eosin. These slides illustrate the co-expression of ASCL1, NEUROD1, and synaptophysin. H&E, hematoxylin and eosin

Full size image
Fig. 3
figure 3

Differential expression of NEUROD1, POU2F3, and synaptophysin in combined bladder small cell carcinoma. (A) H&E, low magnification; (B) NEUROD1, low magnification; (C) POU2F3, low magnification; (D) synaptophysin, low magnification; (E) H&E, high magnification; (F) NEUROD1, high magnification; (G) POU2F3, high magnification; (H) synaptophysin, high magnification. H&E, hematoxylin and eosin. These slides illustrate the mutually exclusive expression patterns of NEUROD1 with synaptophysin or POU2F3 alone. H&E, hematoxylin and eosin

Full size image

Discussion

This study demonstrates the unique clinicopathological characteristics of bladder SmCC, distinguishing it from prostate and lung SmCC. Combined SmCC morphology was present in most of bladder SmCC cases but absent in most of prostate SmCC cases. Notably, the predominance of the NEUROD1 subtype in bladder SmCC, particularly in conjunction with UC, indicates a distinct divergence of the molecular pathology from that of prostate and lung SmCC. These findings enhance our understanding of the landscape of bladder SmCC on a pathological and molecular level and provide a basis for the development of targeted therapies designed for the unique profile of bladder SmCC.

Bladder SmCC exhibits overlapping characteristics with SmCC tumors from other organs. As with lung SmCC, this study showed that TP53 alterations are ubiquitous whereas most cases are RB1 deficient. The differential expression of neuroendocrine markers, highly expressed in the ASCL1- or NEUROD1-expressing SmCC components, with limited expression in the POU2F3-expressing SmCC component, indicates a differential expression profile associated with specific TFs, consistent with previous reports [9, 14, 18].

Our study highlights the predominance of the NEUROD1-dominant subtype and the frequent occurrence of combined SmCC morphology in bladder SmCC. These characteristics contrast with those of prostate and lung SmCCs, which predominantly exhibit the ASCL1-dominant subtype [9, 14, 20] and a pure SmCC morphology [23,24,25]. A recent study assessing TF markers expression in bladder SmCC found ASCL1 to be slightly more prevalent than NEUROD1 [18]. However, because this study used tissue microarrays, it may have been limited in evaluating TF markers expression across the entire tumor. Studies of extrapulmonary neuroendocrine carcinomas in multiple organs have shown that the expression patterns of TF markers vary depending on the organ system [26]. In particular, combined SmCC morphology is also associated with NEUROD1 expression in SmCC of the lung [27] and uterine cervix [28], which is consistent with our findings in combined SmCC of bladder.

Notably, all combined SmCC and UC bladder tumors were NEUROD1-dominant. Furthermore, NEUROD1 was more frequently expressed in combined SmCC and UC tumors than in other bladder SmCC tumors, suggesting a potential association between UC morphology and NEUROD1 expression. The underlying mechanisms driving this predominance remain unclear. One possibility is that NEUROD1 expression reflects temporal changes in TF dynamics during tumor progression. In a lung SmCC mouse model, tumors were shown to transition from an ASCL1-dominant to a NEUROD1-dominant phenotype over time, with MYC activation playing a key role in this shift [29]. In human lung SmCC, NEUROD1 expression has also been associated with advanced disease stages and metastatic tumors [12, 30], further supporting the idea that NEUROD1 may emerge as a late-stage phenotype. Whether a similar temporal evolution of TF expression occurs in bladder SmCC is not yet known. Importantly, bladder SmCC is thought to arise from a urothelial lineage [31, 32], and the presence of coexisting UC suggests a shared cellular origin. Thus, future studies should investigate whether changes in molecular signaling pathways in the UC component influence the emergence of specific TF subtypes, particularly NEUROD1, in associated SmCC components. Understanding this potential temporal and lineage-driven relationship may provide insight into the biology of bladder SmCC and inform subtype-specific therapeutic approaches

Furthermore, MYC and NOTCH signal pathways are also involved in intratumoral heterogeneity in lung SmCC [29]. Our whole-slide immunohistochemical analysis revealed significant intratumoral heterogeneity in TF expression in combined SmCC and UC tumors. In 22% of cases, NEUROD1-positive and POU2F3-positive SmCC components coexisted within the same tumor but were mutually exclusive. This specific pattern was not observed in a study of lung SmCC using tissue microarrays [20] and was extremely rare in whole-slide analysis of lung SmCC surgical specimens [33]. The ASCL1-dominant subtype is predominant in lung SmCC and is accompanied by expression of the other 3 TFs (NEUROD1, POU2F3, and YAP1); however, the coexistence of NEUROD1 and POU2F3 is uncommon in lung SmCC [33]. Additionally, a recent tissue microarray-based study of bladder SmCC observed a moderate negative correlation between the expression of NEUROD1 and ASCL1 and that of POU2F3 [18]. However, their whole-slide immunohistochemical analysis revealed mutually exclusive staining of ASCL1 and POU2F3 within the same tumor in 12% of cases [18]. These findings, along with our results, suggest that tissue microarrays may not fully capture the intratumoral heterogeneity of bladder SmCC. Moreover, the coexistence of ASCL1/NEUROD1- and POU2F3-expressing components within the same tumor may not be uncommon and could represent a distinct feature of bladder SmCC. Because differences in TF expression are not discernible on H&E staining, whole-slide immunohistochemical evaluation is essential to accurately characterize the intratumoral heterogeneity of bladder SmCC.

The standard treatment for lung SmCC typically involves systemic chemotherapy with platinum-based agents and topoisomerase inhibitors, often combined with immune checkpoint inhibitors and radiotherapy [34]. In contrast, no standardized treatment protocols have been established for bladder SmCC, although neoadjuvant platinum-based chemotherapy followed by radical cystectomy has shown potential survival benefits [35]. Recently, molecular subclassification of lung SmCC based on TF expression has led to efforts in developing TF subtype-specific targeted therapies, for example, DLL3 inhibitors for ASCL1-positive tumors, AURK or mTOR inhibitors for NEUROD1-positive tumors, and IGF1R inhibitors for POU2F3-positive tumors [23]. A recent large-scale analysis of bladder SmCC reported an association between POU2F3 positivity and poor prognosis [18]. In our study, two cases showed predominant NEUROD1 expression with focal POU2F3 positivity and poor clinical outcomes, raising the possibility that even minor POU2F3-positive components may have prognostic significance. These findings suggest that TF-based subtyping, if validated in larger studies, may inform treatment selection in bladder SmCC, as has been proposed for other organ systems.

This study has some limitations. The major limitation is the small sample size, which reflects the low incidence of bladder SmCC. Due to the rarity of bladder SmCC, it is difficult to obtain statistically robust results within a single institution, and multi-institutional collaboration will be essential to validate our findings and draw more generalizable conclusions. Second, the immunohistochemical analysis was confined to representative sections of the surgical and TUR specimens, and the analysis may not reflect the heterogeneity of the entire tumor. Third, in a few cases, TF expression was analyzed using post-chemotherapy cystectomy specimens, and the possibility that chemotherapy might have altered the histological features or TF expression cannot be excluded.

Finally, as the study was conducted at a single institution, the patient population, diagnostic criteria, and treatment approaches may not be representative of broader clinical practice. This might limit the generalizability of our results.

In conclusion, this study sheds light on the unique characteristics of bladder SmCC, highlighting the prevalence of NEUROD1 dominance and the coexistence of NEUROD1 and POU2F3, particularly in combined bladder SmCC and UC tumors. These findings need to be confirmed by conducting multicenter studies with a larger sample size. Further research is needed to identify the underlying mechanisms and clinical implications of these findings.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

H&E:

Hematoxylin and eosin

IUC:

Invasive urothelial carcinoma

JFCR:

Japanese Foundation for Cancer Research

SmCC:

Small cell carcinoma

TF:

Transcription factor

TUR:

Transurethral resection

UC:

Urothelial carcinoma

References

  1. Kouba EJ, Cheng L. Understanding the genetic landscape of small cell carcinoma of the urinary bladder and implications for diagnosis, prognosis, and treatment: A review. JAMA Oncol. 2017;3(11):1570–8.

    Article  PubMed  Google Scholar 

  2. Jung K, Ghatalia P, Litwin S, Horwitz EM, Uzzo RG, Greenberg RE, Viterbo R, Geynisman DM, Kutikov A, Plimack ER, et al. Small-Cell carcinoma of the bladder: 20-Year Single-Institution retrospective review. Clin Genitourin Cancer. 2017;15(3):e337–43.

    Article  PubMed  Google Scholar 

  3. Teo MY, Guercio BJ, Arora A, Hao X, Regazzi AM, Donahue T, Herr HW, Goh AC, Cha EK, Pietzak E, et al. Long-term outcomes of local and metastatic small cell carcinoma of the urinary bladder and genomic analysis of patients treated with neoadjuvant chemotherapy. Clin Genitourin Cancer. 2022;20(5):431–41.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Wang G, Xiao L, Zhang M, Kamat AM, Siefker-Radtke A, Dinney CP, Czerniak B, Guo CC. Small cell carcinoma of the urinary bladder: a clinicopathological and immunohistochemical analysis of 81 cases. Hum Pathol. 2018;79:57–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cheng L, Pan CX, Yang XJ, Lopez-Beltran A, MacLennan GT, Lin H, Kuzel TM, Papavero V, Tretiakova M, Nigro K, et al. Small cell carcinoma of the urinary bladder: a clinicopathologic analysis of 64 patients. Cancer. 2004;101(5):957–62.

    Article  PubMed  Google Scholar 

  6. Abrahams NA, Moran C, Reyes AO, Siefker-Radtke A, Ayala AG. Small cell carcinoma of the bladder: a contemporary clinicopathological study of 51 cases. Histopathology. 2005;46(1):57–63.

    Article  CAS  PubMed  Google Scholar 

  7. Parimi V, Choi W, Feng M, Fong M, Hoffman-Censits J, Kates M, Lombardo KA, Comperat E, McConkey DJ, Hahn NM, et al. Comparison of clinicopathological characteristics, gene expression profiles, mutational analysis, and clinical outcomes of pure and mixed small-cell carcinoma of the bladder. Histopathology. 2023;82(7):991–1002.

    Article  PubMed  Google Scholar 

  8. Compérat EM, Netto GJ, Tsuzuki T, editors:. WHO classification of tumours: urinary and male genital tumours. 5th ed. Lyon (France): International Agency for Research on Cancer; 2022.

    Google Scholar 

  9. Rudin CM, Poirier JT, Byers LA, Dive C, Dowlati A, George J, Heymach JV, Johnson JE, Lehman JM, MacPherson D, et al. Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. Nat Rev Cancer. 2019;19(5):289–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gerbe F, Sidot E, Smyth DJ, Ohmoto M, Matsumoto I, Dardalhon V, Cesses P, Garnier L, Pouzolles M, Brulin B, et al. Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature. 2016;529(7585):226–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Matsuoka R, Kawai H, Ito T, Matsubara D. Determining whether YAP1 and POU2F3 are antineuroendocrine factors. J Thorac Oncol. 2022;17(9):1070–3.

    Article  CAS  PubMed  Google Scholar 

  12. Denize T, Meador CB, Rider AB, Ganci ML, Barth JL, Kem M, Mino-Kenudson M, Hung YP. Concordance of ASCL1, NEUROD1 and POU2F3 transcription factor-based subtype assignment in paired tumour samples from small cell lung carcinoma. Histopathology. 2023;83(6):912–24.

    Article  PubMed  Google Scholar 

  13. Ito T, Matsubara D, Tanaka I, Makiya K, Tanei ZI, Kumagai Y, Shiu SJ, Nakaoka HJ, Ishikawa S, Isagawa T, et al. Loss of YAP1 defines neuroendocrine differentiation of lung tumors. Cancer Sci. 2016;107(10):1527–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Baine MK, Hsieh MS, Lai WV, Egger JV, Jungbluth AA, Daneshbod Y, Beras A, Spencer R, Lopardo J, Bodd F, et al. SCLC subtypes defined by ASCL1, NEUROD1, POU2F3, and YAP1: A comprehensive immunohistochemical and histopathologic characterization. J Thorac Oncol. 2020;15(12):1823–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Feng M, Matoso A, Epstein G, Fong M, Park YH, Gabrielson A, Patel S, Czerniak B, Comperat E, Hoffman-Censits J et al. Identification of Lineage-specific transcriptional Factor-defined molecular subtypes in small cell bladder Cancer. Eur Urol 2023:523–6.

  16. Cai Z, Cheng X, Liao S, Zou W, Li L, Liu F, Huang W. POU2F3-positive small cell carcinoma of the bladder: A clinicopathologic analysis of 4 cases and literature review. Pathol Res Pract. 2024;257:155296.

    Article  CAS  PubMed  Google Scholar 

  17. Galea LA, Batrouney A, Flynn M, Christie M. POU2F3-expressing intraepithelial small-cell carcinoma with mixed small-cell carcinoma and conventional-type urothelial carcinoma of the urinary bladder. Virchows Arch. 2024;485(5):947–52.

    Article  CAS  PubMed  Google Scholar 

  18. Akbulut D, Whiting K, Teo MY, Tallman JE, Gokturk Ozcan G, Basar M, Jia L, Chen JF, Sarungbam J, Chen YB, et al. Differential NEUROD1, ASCL1, and POU2F3 expression defines molecular subsets of bladder small cell/neuroendocrine carcinoma with prognostic implications. Mod Pathol. 2024;37:100557.

    Article  CAS  PubMed  Google Scholar 

  19. Amin MBES, Greene FL, Schilsky RL, Gaspar LE, Washington M. AJCC cancer staging manual. New York: NY:Springer; 2017.

    Google Scholar 

  20. Qu S, Fetsch P, Thomas A, Pommier Y, Schrump DS, Miettinen MM, Chen H. Molecular subtypes of primary SCLC tumors and their associations with neuroendocrine and therapeutic markers. J Thorac Oncol. 2022;17(1):141–53.

    Article  CAS  PubMed  Google Scholar 

  21. Baine MK, Febres-Aldana CA, Chang JC, Jungbluth AA, Sethi S, Antonescu CR, Travis WD, Hsieh MS, Roh MS, Homer RJ, et al. POU2F3 in SCLC: clinicopathologic and genomic analysis with a focus on its diagnostic utility in Neuroendocrine-Low SCLC. J Thorac Oncol. 2022;17(9):1109–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transpl. 2013;48(3):452–8.

    Article  CAS  Google Scholar 

  23. Wang WZ, Shulman A, Amann JM, Carbone DP, Tsichlis PN. Small cell lung cancer: subtypes and therapeutic implications. Semin Cancer Biol. 2022;86:543–54.

    Article  CAS  PubMed  Google Scholar 

  24. Nicholson SA, Beasley MB, Brambilla E, Hasleton PS, Colby TV, Sheppard MN, Falk R, Travis WD. Small cell lung carcinoma (SCLC): a clinicopathologic study of 100 cases with surgical specimens. Am J Surg Pathol. 2002;26(9):1184–97.

    Article  PubMed  Google Scholar 

  25. Wang W, Epstein JI. Small cell carcinoma of the prostate. A morphologic and immunohistochemical study of 95 cases. Am J Surg Pathol. 2008;32(1):65–71.

    Article  PubMed  Google Scholar 

  26. Koh J, Kim H, Moon KC, Lee C, Lee K, Ryu HS, Jung KC, Jeon YK. Molecular classification of extrapulmonary neuroendocrine carcinomas with emphasis on POU2F3-positive tuft cell carcinoma. Am J Surg Pathol. 2023;47(2):183–93.

    Article  PubMed  Google Scholar 

  27. Hwang S, Hong TH, Kim HK, Choi YS, Zo JI, Shim YM, Han J, Chan Ahn Y, Pyo H, Noh JM, et al. Whole-Section landscape analysis of molecular subtypes in curatively resected small cell lung cancer: clinicopathologic features and prognostic significance. Mod Pathol. 2023;36(7):100184.

    Article  CAS  PubMed  Google Scholar 

  28. Kim G, Kim M, Nam EJ, Lee JY, Park E. Application of small cell lung Cancer molecular subtyping markers to small cell neuroendocrine carcinoma of the cervix: NEUROD1 as a poor prognostic factor. Am J Surg Pathol. 2024;48(3):364–72.

    Article  PubMed  Google Scholar 

  29. Ireland AS, Micinski AM, Kastner DW, Guo B, Wait SJ, Spainhower KB, Conley CC, Chen OS, Guthrie MR, Soltero D, et al. MYC drives Temporal evolution of small cell lung Cancer subtypes by reprogramming neuroendocrine fate. Cancer Cell. 2020;38(1):60–78. e12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ikematsu Y, Tanaka K, Toyokawa G, Ijichi K, Ando N, Yoneshima Y, Iwama E, Inoue H, Tagawa T, Nakanishi Y, et al. NEUROD1 is highly expressed in extensive-disease small cell lung cancer and promotes tumor cell migration. Lung Cancer. 2020;146:97–104.

    Article  PubMed  Google Scholar 

  31. Cheng L, Jones TD, McCarthy RP, Eble JN, Wang M, MacLennan GT, Lopez-Beltran A, Yang XJ, Koch MO, Zhang S, et al. Molecular genetic evidence for a common clonal origin of urinary bladder small cell carcinoma and coexisting urothelial carcinoma. Am J Pathol. 2005;166(5):1533–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chang MT, Penson A, Desai NB, Socci ND, Shen R, Seshan VE, Kundra R, Abeshouse A, Viale A, Cha EK, et al. Small-Cell carcinomas of the bladder and lung are characterized by a convergent but distinct pathogenesis. Clin Cancer Res. 2018;24(8):1965–73.

    Article  CAS  PubMed  Google Scholar 

  33. Qi J, Zhang J, Liu N, Zhao L, Xu B. Prognostic implications of molecular subtypes in primary small cell lung Cancer and their correlation with Cancer immunity. Front Oncol. 2022;12:779276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sen T, Takahashi N, Chakraborty S, Takebe N, Nassar AH, Karim NA, Puri S, Naqash AR. Emerging advances in defining the molecular and therapeutic landscape of small-cell lung cancer. Nat Rev Clin Oncol. 2024;21(8):610–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Siefker-Radtke AO, Kamat AM, Grossman HB, Williams DL, Qiao W, Thall PF, Dinney CP, Millikan RE. Phase II clinical trial of neoadjuvant alternating doublet chemotherapy with Ifosfamide/doxorubicin and Etoposide/cisplatin in small-cell urothelial cancer. J Clin Oncol. 2009;27(16):2592–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank Mr. Motoyoshi Iwakoshi, Ms. Keiko Shiozawa, Dr. Shuhei Ishii, and Ms. Miyuki Kogure for their technical assistance and Ms. Yuki Takano for her secretarial expertise.

Funding

K.I. was financially supported by JSPS KAKENHI (Grant numbers JP22H02930 and JP23K18246), the Takeda Science Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Ichiro Kanehara Foundation, Suzuki Foundation for Urological Medicine, Foundation for Promotion of Cancer Research in Japan, and the Yakult Bio-Science Foundation. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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Authors and Affiliations

  1. Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan

    Keiichiro Kitahama, Yasuyuki Shigematsu, Emiko Sugawara, Gulanbar Amori, Kengo Takeuchi & Kentaro Inamura

  2. Department of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan

    Keiichiro Kitahama, Yasuyuki Shigematsu, Emiko Sugawara, Gulanbar Amori, Kengo Takeuchi & Kentaro Inamura

  3. Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan

    Keiichiro Kitahama

  4. Division of Tumor Pathology, Jichi Medical University, Shimotsuke, Japan

    Mahmut Amori, Gulanbar Amori & Kentaro Inamura

  5. Department of Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan

    Rumiko Saito & Akihiro Ohmoto

  6. Department of Clinical Chemotherapy, The Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan

    Rumiko Saito

  7. Graduate School of Engineering, Chiba Institute of Technology, Chiba, Japan

    Rumiko Saito

  8. Department of Genitourinary Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan

    Junji Yonese

  9. Pathology Project for Molecular Targets, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan

    Kengo Takeuchi

Authors
  1. Keiichiro Kitahama
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  10. Kentaro Inamura
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Contributions

K.K. and K.I. conceived and designed the study. K.K., Y.S., E.S., M.A., G.A., R.S., A.O., J.Y., and K.I. contributed to the acquisition of clinical and tumor tissue data. K.K. performed data analyses. K.K. and K.I. contributed to the interpretation of the findings. K.I. acquired funding. K.T. and K.I. supervised the project. K.K. and K.I. drafted the manuscript. All authors read, modified, and approved the final manuscript. K.I. is responsible for the overall content as a guarantor.

Corresponding author

Correspondence to Kentaro Inamura.

Ethics declarations

Ethics approval and consent to participate

All procedures in this study were performed in accordance with the ethical standards outlined in the Declaration of Helsinki and were approved by the Institutional Review Board of the Japanese Foundation for Cancer Research (protocol code: 2018 − 1177; date of approval: December 21, 2018), which also determined that the requirement for informed consent could be waived owing to the retrospective study design.

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Not applicable.

Competing interests

Yasuyuki Shigematsu is currently employed by LabCorp. The other authors declare no competing interests.

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Kitahama, K., Shigematsu, Y., Sugawara, E. et al. Clinicopathological characteristics of transcription factor-defined subtypes in bladder small cell carcinoma. BMC Cancer 25, 766 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12885-025-14157-1

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Keywords

BMC Cancer

ISSN: 1471-2407

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