A case of neuroendocrine carcinoma of the urachal cancer with comprehensive genomic profiling results

Abstract

Urachal cancer is a rare malignancy, and cases with neuroendocrine features are extremely uncommon. We present a man in his 30s with gross hematuria. Imaging revealed a nodular mass in the bladder dome with lung metastases. Histopathology after transurethral and open resection revealed a large cell neuroendocrine carcinoma arising from the urachus. Comprehensive genomic profiling (CGP) identified FGFR2–TACC2 fusion, TP53 mutation, and Rb1 loss. These findings suggest that targeted therapy may be considered in such rare and aggressive variants.

Introduction

The urachus is a tubular structure that exists between bladder and peritoneum during embryonic development, and is often identified as a remnant of the allantois [1]. Urachal cancer occurs in this remnant of the urachus and is a rare malignancy, accounting for 1% of bladder cancers [2]. Among these rare cases of urachal cancer, adenocarcinoma is a major histology; however, as for neuroendocrine carcinoma (NEC), only 11 cases have been reported.

Case report

A man in his 30s visited his family doctor because of gross hematuria. An abdominal ultrasound revealed a mass at the dome of the bladder, and a cystoscopy was performed, which revealed a single nodular mass (Fig. 1). Contrast computed tomography (CT) showed multiple nodules in his lungs. Magnetic resonance imaging (MRI) of the bladder revealed a 2.4 cm mass at the dome of the bladder. The mass mainly resided in the muscle layer, and there was also a suspicion of infiltration into the surrounding fatty tissue (Fig. 2). At this point, urachal cancer was suspected, and classified as Sheldon Stage IVB and Mayo stage IV. We first performed transurethral resection of the bladder tumor. The pathological findings showed atypical epithelial cells proliferating in large and small solid cystic foci, and the patient was diagnosed with a NEC based on the results of immunostaining. Based on the cell’s morphology, final diagnosis was large cell type of neuroendocrine tumor. No other tumors were found in the PET-CT or gastrointestinal endoscopy. We performed an open resection of the urachus tumor together with partial cystectomy and pelvic lymph node dissection. Histological examination revealed a proliferation of nest-like and cord-like cells in the muscularis propria of the bladder dome, with infiltration into the extravesical adipose tissue (Fig. 3a, b). The tumor was located in close proximity to a residual urachal remnant (Fig. 3c), and no malignant findings were observed in the bladder mucosa (Fig. 3d). Immunohistochemically, CD56 was partially positive, and chromogranin A and synaptophysin were positive (Fig. 3e, f). Based on these findings, the patient was diagnosed with neuroendocrine carcinoma (NEC) derived from the urachus. Dissected pelvic lymph nodes and surgical margins were negative. Comprehensive genomic profiling (CGP) of the resected specimen revealed fibroblast growth factor receptor 2–transforming acidic coiled-coil gene families (FGFR2–TACC) gene fusions, TP53 mutations, c.524G > A (p.Arg175His, R175H), was identified with an allele frequency of 81.86% at a sequencing depth of 2260 reads, and Rb1 loss. It was suggested that fucibatinib or pemigatinib, FGFR inhibitors, may be effective in the treatment of metastatic lesions. However, due to insurance coverage issues, treatment with cisplatin and etoposide was initiated first. However, due to insurance coverage issues, treatment with cisplatin and etoposide was initiated first. The regimen consisted of etoposide 100 mg/m² on days 1–3 and cisplatin 80 mg/m² on day 1, administered every 3 weeks. The best overall response was stable disease (SD). At 9 months after surgery, the patient remains alive and is continuing chemotherapy.

Fig. 1.

Cystoscopy image. A non-papillary, stalked tumor was seen in the dome of the bladder. (red arrows) No other tumors were found on the mucosa within the bladder

Fig. 2.

MRI T2-weighted image. The tumor located in the dome of the bladder (red arrows), which seemed to originate in the muscle layer. A cystoscopy revealed a non-papillary nodular lesion in the same location. Chest CT showing multiple small nodules in both lungs (red arrows: representative one), consistent with metastases

Fig. 3.

a Low-magnification view. The tumor was located in the muscularis propria of the bladder dome (black arrow) and infiltrated into the perivesical adipose tissue (*) (scale bar: 5 mm). b High-magnification view. Nest-like and cord-like cell proliferation was observed in the muscularis propria (scale bar: 100 μm). c The tumor was located in close proximity to a residual urachal lumen (▽) (scale bar: 1 mm). d The bladder mucosa showed no malignant changes (scale bar: 100 μm). e, f Immunohistochemical staining. Chromogranin A and synaptophysin were positive, supporting the diagnosis of neuroendocrine carcinoma

Discussion

The urachus is a tubular structure in the fetal stage that connects the fetal bladder to the umbilicus and functions as a passage for urine excretion into the amniotic fluid. After birth, it usually closes and regresses, transforming into a ligament known as the urachus. When this regression is incomplete, it can cause infection as a remnant of the umbilical cord, and sometimes even cause malignant tumors [1]. The prognosis of advanced urachal cancer is poor, the 5-year survival rate for Stage I is about 63%, while for Stage IV, it is about 8% [3].

Diagnosis of urachal carcinoma should follow internationally accepted criteria as defined in the 2022 WHO Classification of Tumors, Urinary and Male Genital Tumors (5th edition). For nonglandular urachal carcinoma, the diagnosis requires (1) tumor located in the bladder dome or anterior wall and/or midline supravesical to the umbilicus, (2) tumor epicenter in the bladder wall (muscularis propria or deeper) with intact or ulcerated urothelium, and (3) no primary tumor of similar morphology elsewhere (except urothelial carcinoma in the genitourinary tract). All of the above criteria must be met, and in addition, at least one of the following: (4) close relationship with urachal remnant structures, (5) if no urachal remnant structure is identifiable, the tumor does not involve the intact bladder surface, or (6) if no urachal remnant structure is identifiable and the tumor involves the bladder surface: for urothelial carcinoma only, cavitary or cystic tumor with intraluminal papillary structures; for all nonglandular urachal carcinomas, presence of a reverse invasive front [4, 5]. In this case, (1) the tumor was localized in the dome of the bladder, (2) the tumor epicenter was within the bladder muscularis propria, (3) no primary tumors were found elsewhere on whole-body CT, PET-CT, or gastrointestinal endoscopy, and (4) the resected specimen showed that the tumor was located in close proximity to a urachal remnant without direct histologic continuity. These findings satisfy the criteria for urachal carcinoma, and the tumor was classified as Sheldon Stage IVB and Mayo stage IV.

Most cases of urachal cancer present as adenocarcinomas, but 4–27% are non-adenocarcinomas [1]. The WHO classification of tumors published in 2022 includes squamous cell carcinoma and NEC in addition to adenocarcinoma of the urachus [4]. (Table 1) However, the number of urachal NEC cases reported is limited. Table 2 shows previous reported cases of urachal cancer with NEC [1, 6–12]. The median age of occurrence of urachal cancer is 52 years, but in the 12 NEC cases, including our case, the median age was 36 years, which is younger than that of common urachal cancer with adenocarcinoma [13]. Although 20% of cases of urachal cancer with adenocarcinoma are Stage IV, however, in cases of NEC, around 54% presented as Stage IV [13], as our case and thus overall survival is dismal. It might be that urachal cancer that presents as NEC has a different metastatic ability and invasiveness to the norm. In the histopathology of urachal cancer, which indicates NEC, many reports have shown a mixture of adenocarcinoma components, but what is particularly noteworthy in this case is that almost all of the tumor components were NEC components.

Table 1.

Histological Classification of Urachal Cancer (WHO 2022)

Adenocarcinoma

Non-cystic

Enteric (intestinal)

Mucinous (colloid)

Signet-ring cell

NOS

Mixed

Cystic

Mucinous cystic tumor of low malignant potential

Mucinous cystadenocarcinoma

Urothelial carcinoma

Squamous cell carcinoma

Neuroendocrine carcinoma

Mixed carcinoma

Table 2.

Summary of previously reported urachal neuroendocrine carcinoma cases and clinical outcomes

Author	Sex	Age	Sheldon Stage	LNM	Metastasis	Surgical resection	Cystectomy	Urethrectomy	PLND	Umbilical fusion resection	RT	Histopathology	CGP	Outcome
Obiedat S [6]	Male	33	Ⅳ	Yes	Lung, Bone, Liver	No	No	No	No	No	Yes	60% ADE and NEC	None	Unknown
Ebara S [7]	Male	32	Ⅲ	No	Lung, Bone, Local	Yes	Partial	No	Yes	Unknown	Yes	ADE and SCC	None	Unknown
Wang G [8]	Male	23	ⅢA	Yes	Lung, Pleura	Yes	Partial	No	Yes	Yes	No	ADE and SCC (70%)	None	Developed widespread metastases at 21 mo
	Female	25	ⅣA	Yes	Brain, Lungs, Liver	Yes	Partial	No	Yes	Yes	Yes	ADE and LCC	None	Died at 31 mo
	Male	34	ⅣA	Yes	Liver, Spine, Local	Yes	Partial	No	Yes	Yes	Yes	ADE and SCC	None	Died at 10 mo
Paner GP [1]	Female	56	ⅣA	Yes	Lungs, Spine, Mediastinum	Yes	Partial	No	Yes	Unknown	No	UC in situ and SCC	None	Died at 18 mo
	Male	64	ⅢA	No	Spine	Yes	Radical	Unknown	Yes	Unknown	Yes	SCC	None	Died at 24 mo
Johnson DE [9]	Female	76	Ⅲ	No	No	Yes	Partial	No	Unknown	Yes	No	ADE and SCC	None	Alive at 72 mo
Munichor M [10]	Male	53	Ⅲ	No	No	Yes	Partial	No	Yes	Yes	No	ADE and SCC	None	Unknown
Abenoza P [11]	Male	55	Ⅳ	Yes	Ureters, Lungs, Brain, Liver, Bone	Yes	Radical	Unknown	Yes	Unknown	No	ADE and LCC	None	Died 30 mo after first examination
Hom JD (12)	Female	31	Unknown	Yes	Liver, Bones	Yes	Partial	No	Yes	Yes	No	ADE and SCC	None	Died 3 mo after surgery
Our case	Male	38	ⅣB	Yes	Lung	Yes	Partial	No	Yes	Yes	No	LCC	Yes	Alive at 9 mo after surgery

LNM lymph node metastasis, PLND pelvic lymph node dissection, RT radiation therapy, CGP comprehensive genomic profiling, ADE adenocarcinoma, NEC neuroendocrine carcinoma, SCC small cell carcinoma, LCC large cell carcinoma, UC urothelial carcinoma, mo months

The mechanism of NEC development in urachal cancer has not yet been defined, but the following theories have been proposed as possible mechanisms of NEC development in urothelial cells: it originates from undifferentiated stem cells, neuroendocrine cells within normal epithelium become malignant, it originates from cells derived from the neural crest [14, 15]. NEC arises from undifferentiated cells should be mixed with other histological cells, such as adenocarcinoma; thus, the origin of the tumor in this case might be one of the latter two.

The patient was found to have a TP53 mutation (allele frequency: 81.86%), RB1 deletion, and FGFR-TACC2 fusion. Changes in TP53 and Rb1 have been shown to contribute to NEC formation in genetically engineered mouse models, and it is possible that these gene mutations are significantly involved in the development of the tumors in this study [16].

FGFR is a transmembrane cell surface receptor with tyrosine kinase activity, ranging from FGFR1-4. FGFR2 is an extracellular ligand-binding domain, intracellular tyrosine kinase domain, is associated with fine-tuning of receptor activity, and is composed of 18 exons [17]. FGFR2 consists of 18 exons and encodes a tyrosine kinase cell surface receptor that acts in cell growth, differentiation, and angiogenesis [18].

The TACC family consists of TACC 1–3, known as centrosome/microtubule interactive proteins, which regulate various functions, such as genome stability, transcription, cytoskeleton organization, and protein transport [19, 20]. TACC2 consists of 23 exons and has been reported to be involved in androgen dependence of prostate cancer as an androgen-regulated gene [21].

In this case, FGFR2–TACC2 gene fusion was observed. This gene fusion has been reported in gastrointestinal stromal tumors, pancreatic cancer, and other cancer types with neuroendocrine tumor components similar to the present case [22–24]. From the results from our CGP, this FGFR2–TACC2 fusion occurred between F17 and T7. This fusion results in a loss of exon 18, which may act as a potent single-driver alteration, further suggesting that FGFR-targeted therapy may be effective [25].

This case reports a ureteral carcinoma with a very rare neuroendocrine tumor and is the first report of FGFR2–TACC2 fusion in a ureteral carcinoma. CGP for ureteral duct carcinoma can be useful in therapeutic strategies.

Conclusion

This is the first case of pure NEC originated from urachus with comprehensive genomic profiling.

Author contributions

All authors contributed to the conception and design of the study, data acquisition, analysis, and drafting of the manuscript. All authors reviewed and approved the final version of the manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Data availability

The data that support the findings of this case report are available from the corresponding author upon reasonable request.

Declarations

Conflict of interest

The authors declare that they have no conflicts of interest to disclose regarding the publication of this case report.

Ethical approval

Not applicable.

Consent to participate

Written informed consent was obtained from the patient for participation in this case report.

Consent to publish

Written informed consent was obtained from the patient for the publication of this case report and accompanying images.