Squamous cell carcinoma of the urinary bladder in patients with chronic spinal cord injury: A case series

Abstract

Introduction

Patients with spinal cord injury/disorder (SCI/D) and neurogenic lower urinary tract dysfunction (NLUTD) are on a 16–28 folder higher risk for bladder cancer [1]. Whereas in the general population 90% of bladder tumors are transitional cell carcinoma (TCC) patients with NLUTD have a shift to squamous cell carcinoma with 36,8% and only 46.3% TCC [2]. In addition, there is a significant increase in the bladder cancer-specific death rate in SCI patients (3rd most common) compared to the general population (10th most common) [2]. Chronic inflammation and mechanical irritation by permanent indwelling catheters are discussed as risk factors for developing bladder cancer. Typical symptoms of bladder cancer are often absent in patients with NLUTD and a reliable screening has not been established.

Case presentation

We present a case series of six patients with SCI and with squamous cell carcinoma diagnosed in the last 5 years in our institution. In five patients, bladder management was performed by indwelling suprapubic catheters, one patient used reflex voiding. Three patients were diagnosed during the regular, annual neuro-urological check-up, the remaining due to increasing spasticity and autonomic dysregulation. Subsequently, five patients underwent cystectomy with ileal conduit or uretercutaneostomy, one patient refused further surgical treatment. Four patients died within one year after diagnosis.

Discussion

Squamous cell carcinoma of the bladder is more common in patients with NLUTD. Chronic inflammation and mechanical irritation may be the reasons for carcinoma genesis. A regular check including cystoscopy is strongly recommended to detect tumor development early.

Introduction

Spinal cord injury (SCI) causes an irreversible dysfunction of the lower urinary tract [3, 4]. As a result of impaired central nervous control, various neurogenic dysfunctions of the lower urinary tract (NLUTD) can occur. Besides detrusor overactivity in the storage phase, detrusor-sphincter dyssynergia (DSD) in the voiding phase can lead to incomplete voiding and unphysiological voiding pressure. Problems like urinary tract infections or bladder stones are common. Therefore a life-long therapy, adapted to the pattern of NLUTD and general condition (age, dexterity, completeness, and level lesion) is necessary [5]. With increasing age and duration of SCI/D, the percentage of persons using indwelling catheters is increasing too. These factors lead to chronic irritation and ultimately to changes in the mucous membrane of the bladder, which favor tumor formation in the bladder. The overall incidence of bladder cancer in the general population is rare with an incidence of 9.0 for men to 2.0 for women to 100000 [6]. In contrast, in the population of patients with SCI, bladder cancer is the third leading cause of death [7]. Whereas squamous cell cancer of the bladder (SCCB) in the general population is rare, the incidence in SCI patients is substantially higher. The proportion was between 20% and 47% [2, 8]. Due to the usually delayed diagnosis and the histological peculiarity, the SSCB is limiting lifetime. Due to this fact, it is important to provide early diagnosis in order to initiate a potential curative therapy. Identifying risk factors and patient groups at risk is a challenge and currently no clear recommendation is available. Especially In patients with an indwelling catheter symptoms such as hematuria may be caused by urinary tract infections and are not necessarily associated with a tumor. Although the risk for bladder cancer in this patient population is known, a defined screening method is still missing [9]. Regarding the literature, a screening with annually cystoscopy from a duration of SCI of more than 10 years seems to be sufficient [2]. Furthermore, the combination with urine cytology can improve bladder tumor detection rates [10]. Based on the 6 cases (Table 1), we would like to emphasize that squamous tumors are common in SCI patients, and classic early symptoms are frequently missing or unspecific.

Table 1.

Descriptive summary of the cases.

	Gender	Level of paraplegia	Paraplegia in years	Bladdermanagement in years after developing a neurogenic bladder					Infections requiring antibiosis per year	Essential bacteria in urine	History of bladder-stones	First Sign of tumor	urine cytology	Years with paraplegia until diagnosis of tumor	Stage of tumo	Therapy	Death in months after diagnosis of tumor	Age at death
				Spontaneous	Reflex	CIC/IFK	indwelling catheter	anterior root
Case 1	m	Th11 AIS A	27	18	0	o	9	0	na	na	no	Pelvic abscess	na	26	pT3b pL1 pV1 N1 cM1 R1 G3	Emergency Cx + UCN	3	61
Case 2	m	C7 AIS A	40	0	28	2	0	0	2	na	no	Hematuria	Low grade	39	pT3a N2 L0 R0 G3	Cx + UCN; Nephro left	na	77
Case 3	m	Th8 AIS A	41	0	32	0	9	0	6	na	yes	Hematuria	na	41	pT3b pN1 R0 G3 + PCA Gleason 6	Cpx + Conduit	8	68
Case 4	m	Th4 AIS A	52	0	45	0	7	0	2	Enterococcs faecalis	no	Hematuria	Low grade	49	pT3b N0 L0 R0 G2	Cpx + UCN	na	na
Case 5	m	Th4 AIS A	35	0	na	na	Unknown period	0	10	Enterococcus faecalis	no	Wild tissue at Cystostomy	na	15	pT4b cN+ pL1 pV0 pPn0 cM1(PUL) R1 G3	Nephrostomies + CTx	0.5	36
Case 6	f	Th10 AIS A	35	0	0	9	13	13	3	Pseudomonas aeruginosa	no	Hematuria	Negative	33	pT3b pN0 cM0 L1 V1 R0 G3	Cx + Conduit + Rx + CTx	1	66

m male, f female, na not available, Cx Cystectomy, UCN Uretero-cutaneo-stomy, Rx Radiation, CTx Chemotherapy, the last type of bladder management is elevated by red color.

Case presentation

Case 1

A 61-years-old male patient with complete SCI, lesion level Th 11 (AIS A, according to ASIA/ISCoS International Standards for Neurological Classification of Spinal Cord Injury) as a consequence of a car accident in 1992. In a consequence of incomplete bladder emptying and urinary incontinence due to bladder neck insufficiency, he received a suprapubic catheter in 2010. He refused regular urological and urodynamic controls. In 2018 an extensive perineal abscess was surgically treated, with closure of the urethra due to infiltration. Due to increasing spasticity and fever, a CT scan was conducted. The images revealed a huge abscess in the pelvis with contact to the bladder and intestine. Because of the poor clinical condition, an immediate surgical intervention was performed. An extensive tumor was detected intraoperatively. A cystectomy and ureter-cutaneostomy was conducted. The histology revealed a squamous cell carcinoma (pT3b, pL1, pV1, pN1, cM1 (PUL, HEP), R1, G3) with hepatic and pulmonary metastasis. Due to the tumor progression and reduced general condition with poor prognosis palliative chemotherapy was not given. The patient passed away three months later.

Case 2

A 77-years-old male patient with complete SCI, lesion level C7 (AIS A) since a car accident in 1980. For a period of 28 years, bladder evacuation was performed by reflex voiding. In 2018 due to a urethral stricture and increasing post-void residual urine and autonomic dysreflexia an endoscopy urethrotomy was performed. Due to persistent post-void residual urine, the patient was on intermittent catheterization (IC). With a continuous macrohematuria he presented to the emergency unit. A bladder tumor was identified by cystoscopy (Fig. 1). Urine cytology revealed a low-grade dysplasia. As histology of the transurethral resection of the tumor revealed muscle invasion, secondary a cystectomy and ureter-cutaneostomy was performed. The histological result demonstrated a squamous cell carcinoma (pT3a, N2 (2/14), L0, R0, G3) (Fig. 2). Due to secondary stricture of the left ureter, a percutaneous nephrostomy was placed two months after surgery. During the follow-up, the patient was in stable condition with currently no recurrence of the tumor. Finally, he died for other reason at the age of 77 years.

Fig. 1.

Large and diffuse partly whitish partly papillary changes of the bladder mucosa of a trabeculated bladder with isolated contact hemorrhages.

Fig. 2. Microscopical aspects of a squamous bladder cell carcinoma: pleomorphism, hyperchromasia, and keratinization of the tumor cells invading suburothelial tissue.

(Hematoxylin-Eosin-stain A, B). Tumorcells present a high mitotic activity (Ki67/MIB1, C).

Case 3

A male patient, born in 1951, suffered from a complete paraplegia Th 8 (AIS A) since 1977 after a motor-cycle accident. Initial bladder management was reflex voiding with implantation of an urethra wall-stent and subsequent resection of the bladder neck and recurrent endoscopic urethrotomies. While the fixation of the urinary sheath was difficult and as a result of incomplete voiding a suprapubic catheter was inserted in 2009. In the following years, he suffered from recurrent symptomatic urinary tract infections and subsequently, three bladder stone lithotripsies were necessary. In November 2018 recurrent hematuria occurred, in the diagnostic work up a muscle-invasive bladder tumor was diagnosed by resection (Fig. 3). Based on the histological results, a cystectomy and ileal conduit were conducted. The pathological result revealed a squamous cell carcinoma (pT3b, pR0, N1 (2/15)) and prostate cancer with Gleason score 3 + 3 = 6, R0. In the months after surgery the patient suffered from different complications (abscess formation, stenosis of the ileal conduit, and tumor progress). He died 8 months after diagnosis.

Fig. 3.

Suspicious whitish change of the bladder mucosa of a trabeculated bladder.

Case 4

The 71–years–old male patient with complete paraplegia Th 4 (AIS A) since 1970 after a fall. The bladder management was reflex voiding for a period of 45 years, with sphincterotomy and bladder neck resection in 1983. Due to increased post-void residual urine and recurrent urinary tract infections a suprapubic catheter was placed in 2015. Based on a change of the medical care provider, he presented in 2019 for a regular, annually control in our institution. He reported an asymptomatic course without recurrent UTIs, incontinence, or hematuria. The suprapubic catheter has been changed regularly every six weeks. The ultrasound of the bladder revealed a suspicious formation in the bladder (Fig. 4). The cystoscopy indicated a huge tumor mass, and after TUR-B, a muscle-invasive tumor was identified. The patient underwent cystectomy and uretero-cutaneostomy. The histological result showed a squamous cell carcinoma (pT3b, pN0 (0/14), G2, R0). Nine months after the surgery the patient has been in good condition and is still today free of cancer recurrence.

Fig. 4.

Sonography of the bladder with unilateral and broad-based thickening of the left bladder wall with an inserted suprapubic catheter.

Case 5

This young patient (36 years old, complete spinal cord injury Th 4 AIS A since 1984 after a car accident), was admitted to our hospital due to increasing autonomic dysreflexia and increased sweating. In addition, the patient described a foul odor in the area of his cystostomy with induration, localized pain, and provocable spasticity when this area was touched. Hematuria was not described except after manipulation (Botox injections or catheter changes). Due to the suspicion of catheter-associated urinary tract infections, multiple antibiotic treatments had already been administered. The current urine culture showed a mixed culture with a pan-sensitive Enterococcus faecalis and Actinomyces urogenitalis. Bladder management was IC over a period of more than 20 years. Due to recurrent urinary tract infections a suprapubic catheter was inserted in 2017. Regular changes and injections of onabotulinumtoxin were performed in another hospital. The last injection was performed 4 weeks before allocation. In addition, a new suprapubic catheter was inserted. During the initial exam a necrotizing puncture site was detected. On ultrasound, a solid mass in the bladder and an hydronephrotic kidney on the left side was detected (Fig. 5). Because of these findings a CT scan was performed and revealed a suspect formation in the bladder (Fig. 6) and enlarged paravesical, ilacal and inguinal lymph nodes. In addition, nodular tissue was seen in the cystostomy area. For further evaluation, a diagnostic cystoscopy with biopsy and resection of the nodular finding subcutaneously in the area of the cystostomy was performed. Cystoscopy revealed a small-capacity bladder with diffuse bleeding at a maximum filling volume of 100 ml. There were tumor-specific lesions in multiple locations which were resected subsequently. Until histology was obtained, staging was completed with additional evidence of metastasis to the right lung. Histology revealed a mixture of a poorly differentiated urothelial carcinoma of the urinary bladder with tumor necrosis in the bladder resectate and squamous parts, particularly in the excidate of the cystostomy canal as a subcutaneous metastasis (pT4b (SKI) pL1 pV0 pPn0 cM1 (PUL) R1 G3 stage IV). The tumor board recommended primary palliative chemotherapy with palliative cystectomy in case of bleeding complications. With existing renal insufficiency and known hydronephrosis, bilateral nephrostomies were inserted. Chemotherapy was initiated using gemcitabine and carboplatin after postinterventional urosepsis was treated. However, chemotherapy had to be discontinued in the first cycle due to very poor tolerability. The patient died at the age of 37 years.

Fig. 5.

Hydronephrosis of the left kidney in sonography.

Fig. 6.

CT scan showing asymmetric bladder wall thickening with suprapubic catheter in place.

Case 6

The 66-years female patient had been under regular urologic control since 1986 due to a traumatic paraplegia Th10 AIS A. Initially, bladder emptying was performed via intermittent self-catheterization, which was changed to anterior root stimulation after nine years. 13 years later, a large-capacity low compliance bladder developed, thus a suprapubic catheter was inserted, as IC was not possible for anatomical reasons. During the annual follow-up in 2019, urine next to the catheter with bloody contamination and three symptomatic urinary tract infections were described. The urodynamic assessment revealed a slight detrusor overactivity. Urine cytology described severe chronic cystitis with reactive urothelial changes without atypia or signs of malignancy. Cystoscopy indicated marked trabeculation of the bladder with pseudodiverticula, inflammatory altered bladder mucosa with catheter artifacts, and atypical calcifications in the area of the cystostomy. Therefore, a biopsy was performed, which revealed evidence of squamous cell carcinoma. A CT scan showed enlarged lymph nodes in the area of the external iliac artery. Radical cystectomy with extended lymphadenectomy and placement of an ileum conduit was performed 2 weeks later. Histologic workup revealed a moderately keratinizing, high-grade squamous cell of 4.2 cm with invasion of perivesical adipose tissue and 30 tumor-free lymph nodes (pT3b pN0 (0/30) cM0 L1 V1 Pn1 R0 high grade, IIIA AJCC8th Edition). In the follow-up, a progressive enlarged right inguinal lymph node occurred. A fine needle aspiration confirmed a lymphogenic metastasis of squamous cell carcinoma (08/2020). Palliative radiotherapy of the inguinal lymph nodes was performed, resulting in necrotic meltdown of these (12/2020). Nine months after cystectomy a progressive pulmonary metastasis occurred and palliative chemotherapy with carboplatin and gemcitabine was administered via oncology. In addition, with proof of PD-L1 expression, anti-PD-L1 antibody therapy was considered for progression. The patient died one year later at the age of 66 years.

Discussion

Several studies have demonstrated a 16–28 fold increased relative risk of bladder cancer in patients with SCI [1]. In particular, chronic irritation of the urinary tract via bacteria, foreign bodies, catheterization, or stones has been identified as risk-factors for the development of squamous bladder carcinoma [11–13].

The six cases described underline that the occurrence of urothelial carcinoma of the bladder is not uncommon in cases of NLUTD and that these patients have a poor prognosis related to their etiology of neurogenic bladder and the shift to squamous cell carcinoma. Therefore these patients require special attention and regular control.

Histological changes

The most common tumor of the neurogenic bladder is the squamous cell carcinoma (SCC, 46.9%) subtype followed by transitional cell carcinoma (TCC, 31.3%). A mixed form of TCC and SCC is present in about 12.5% of patients and adenocarcinoma in about 10% [13]. Thus, SCC occurs about 10% more frequently than in the general population (1.2–4.5% [1]). At the same time, the occurrence of a metastasized SCC is associated with a worse prognosis. The reasons for the predominantly squamous histological changes is due to a mixture of inflammatory and proliferative conditions, most probably provoked by irritation of the bladder mucosa via indwelling catheters or changes in the bladder microbiome [11, 12].

Challenges in the diagnostic work-up

As highlighted by the presented cases, symptoms for bladder cancer like hematuria can occur, but can also be absent even in gross tumor mass.

Based on this variability, each new symptom like increased spasticity, hard and bleeding wild tissue, a new onset of detrusor overactivity or onset of autonomous dysreflexia should be considered as a possible symptom of cancer unless otherwise explained. The diagnostic is challenging, especially identifying cancer-specific lesions, as chronic inflammation and thus edematous changes in the bladder mucosa due to the natural bacterial environment or catheter irritation are often present [12]. Standard urine cytology cannot be relied upon in most cases either, as the chronic inflammatory processes make the cells difficult to assess and should therefore always be assessed by experienced uropathologists [14]. The combination of cystoscopy and urine cytology has shown an improvement of bladder tumor detection (specificity 43.7%, sensitivity 83,3%) rates and could reduce the number of unnecessary biopsies [10]. The use of photodynamic cystoscopy improves the detection of bladder cancer [15], but data in patients with chronic inflammation and/or indwelling catheters are not available. The main problem with this approach may be the chronic inflammation of the bladder wall with inadequate results. Special markers for screening urothelial carcinoma, using urine or blood have been in development for some time, but have not yet been clinically convincing [16]. A convincing method to identify urothelial carcinomas such as the squamous carcinomas is not available. Therefore, an individualized approach must be conducted like regular controls of urine cytology and annual cystoscopies [9].

Prevention

Screening for bladder cancer in neuro-urological patients is still under debate. Even in persons with NLUTD, the absolute risk to develop bladder cancer is between 0.3% and 0.6% about 15–30 years after SCI. However, the aggressive nature of the disease, implicates the high risk of mortality [17]. The risk of developing squamous cell carcinoma in patients with an indwelling catheter is about 8% [18]. Length of indwelling catheterization ranged from 6 to 29 years, with an average of 16 years [2] so that a correlation between the duration of catheter management and tumorigenesis can be assumed.

Our in-house standard is therefore regular cystoscopy at annually from the 5th year of long-term catheter drainage. In the case of unclear findings, we send the urine cytology to a uropathologist for further diagnosis. In case of suspicious findings, we perform a resection or a control after 3 months.

However, it should be noted that in a retrospective study by Kalisvaart et al., it was shown, that 50% of patients with a bladder cancer did not use an indwelling catheter for bladder emptying [13]. For this reason, signs such as new overactivity of the bladder, hyperhidrosis, autonomic dysreflexia, or a new spastic but also hematuria must be particularly observed. Additionally, we recommend an early cystoscopy to exclude suspicious findings. Biopsy should be performed in the case of unclear findings, as all other diagnostic tools are not reliable.

Unfortunately, even with this procedure some tumors are not detected in early stage. Therefore, the need for appropriate, specific tool to detect bladder cancer in this population remains a challenge. Maybe mRNA marker will provide an option in the future.

Author contributions

PL: Data collecting and analysis, write the Manuscript. JJ: Provision of histopathological images and description of the findings in them. JP: Advice and helped write the manuscript. JW: Helped write the manuscript.

Competing interests

The authors declare no competing interests.

Informed consent

Written informed consent was obtained from all subjects described in the publication.