Malignant transformation of nephrogenic adenoma of the bladder: case report and literature review.

A 66-year-old male patient was admitted to The Second Hospital of Dalian Medical University in February 18, 2021 complaining of intermittent dull pain in the left lower abdomen for more than half a year, which was exacerbated for 1 month and accompanied by nocturia. There was no hematuria or dysuria. Mild discomfort in the left lower abdomen on palpation and left renal percussive pain were detected. There were no abnormalities in standard blood tests, renal function tests, hepatic biochemistry, or other relevant biochemical testing, and there was no special abnormality in prior history or family history of malignancy. Ultrasonography revealed that the left renal collecting system was separated by 3.1 cm, the inner diameter of the upper left ureter was 0.8 cm, and the bladder wall around the left ureteral orifice was thickened, with the thickest section measuring 0.86 cm and exhibiting no trace of blood flow. Computed tomography urography (CTU) revealed left hydronephrosis and ureter dilation with a local thickening of the bladder wall involving the left ureteral orifice measured about 31 mm × 11 mm, the lesion was mild to moderately enhanced [37 Hounsfield unit (HU) in the plain scan phase; 45 HU in the enhancement phase], and presented a filling defect on the excretion phase ( Figure 1 ). On February 20, 2021, cystoscopy revealed a crater-like alteration with generalized thickening of the left bladder wall which involved the left ureteral orifice ( Figure 2 ). The biopsy pathology showed, tiny tubular, cystic, and papillary structures formed of single-layer cubic epithelial cells in the lamina propria coated with urothelium ( Figure 3 ). Which presented Pax-8 (+), Pax-2 (−), CK7 (+), EMA (+), p63 (a small proportion+), Ki-67 (1%+) in combination with the immunohistochemical examination. On February 23, 2021, considering the poor quality of biopsy tissue, a diagnostic transurethral resection of bladder tumor (TUR-BT) was performed. With extensive electroresection of the tumor, deep to the deep muscle layer (focally, extracapsular fat was visible), including normal mucosal tissue around the tumor. The pathology revealed a high quantity of adenoid tissues in the mucosal lamina propria and muscular, with a single-layer tubular shape, and the cells were somewhat aberrant, implying NA ( Figure 4 ). For that a robot-assisted laparoscopic partial cystectomy and reimplantation of the left ureter were performed on March 1, 2021 ( Figure 5 ). Postoperative pathological examination revealed the adenoid, single-layer tubular structured tumor cells, of which light pink homogeneous substance could be seen in some lumens, the cells were slightly atypical and in diffuse infiltration growth mode. All bladder wall layers were involved, and nerve invasion could be observed locally, so a malignant tumor was suspected ( Figure 6 ). The immunohistochemistry showed that the tumor was located in the mucosa, extensively infiltrating the deep muscularis propria (1/2 of the outer muscular layer), but not reaching the tunica adventitia; the tumor cells presented open gland duct-like morphology, with solid nest-like and cord-like arrangement. The tumor cells located in the bladder mucosa have a mild morphology, and the tumor cells infiltrating the intrinsic muscle layer show mild to moderate atypia. Meanwhile, the proliferation index and the high proliferation activity analysis were: AE1/AE3 (+), CK7 (+), CK20 (−), PAX-8 (+), P63 (partial+), GATA-3 (weak+), P53 (a small amount+), Ki-67 (+, 30% of hot spots). The final diagnosis was mesonephric adenocarcinoma of the bladder (pT2bN0M0), which was considered to be the malignant transformation of NA. Two months later, the cystoscope examination revealed alterations in scar tissue. The biopsy pathology revealed localized tissue hyperplasia with lymphocyte, neutrophil, and eosinophil infiltration, but tumor cells were not discovered ( Figure 7 ). All procedures performed in this study were in accordance with the ethical standards of the Ethics Committee of The Second Hospital of Dalian Medical University and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal. Pelvic contrast-enhanced CT localized thickening of the left bladder wall could be seen, showing mild to moderate enhancement. CT, computed tomography. Changes under the cystoscope diffuse thickening of the left bladder wall could be seen, involving the left ureteral orifice and showing “volcano-like” changes. Pathological examination of cystoscopic biopsy showed nephrogenic adenoma (HE staining, ×200). HE, hematoxylin and eosin. The pathological examination result of diagnostic TUR-BT was considered to be nephrogenic adenoma (HE staining, ×100). TUR-BT, transurethral resection of bladder tumor; HE, hematoxylin and eosin. Gross specimen. The lower segment of left ureter and the left bladder wall after surgical resection. Pathological examination after robot-assisted laparoscopic partial cystectomy suggested mesonephric adenocarcinoma of the bladder (pT2bN0M0), which was considered to be the malignant transformation of nephrogenic adenoma of the bladder (HE staining, ×200). HE, hematoxylin and eosin. Cystoscopic findings at the reexamination. The reexamination 2 months later showed scar tissue changes under the cystoscope. The biopsy pathology showed local tissue hyperplasia with infiltration by lymphocytes, neutrophils, and eosinophils, and no tumor cells were found.

Nephrogenic adenoma (NA) is a rare benign tumor that can develop at any site of the urinary system, with the bladder being the most common, followed by the urethra, ureters, renal pelvises, etc. ( 1 ). Currently, it is unclear what the pathogenesis of NA is. It is highly difficult to distinguish from mesonephric adenocarcinoma (also known as clear cell carcinoma of the bladder) due to the lack of specificity in clinical and pathological symptoms, and pathological immunohistochemistry staining is commonly utilized for a conclusive diagnosis. Despite some suggestions that NA has the potential to become malignant, the clinical evidence that supports the malignant transformation is very rare ( 2 , 3 ). Here, we describe a rare instance of a bladder tumor that changed from an NA to a mesonephric adenocarcinoma and discover that high levels of carcinoembryonic antigen (CEA) (+), P53 (+), and Ki-67 proliferative activity are crucial molecular markers for detecting malignant transition. We present the following case in accordance with the CARE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-24-440/rc ).

NA of the bladder is a benign tumor of the urinary system, usually considered as metaplastic bladder change. In 1949, Davis et al. first described this disease and named it bladder hamartoma ( 4 ). In contrast, Friedman et al. named this disease “nephrogenic adenoma” because its histological morphology was similar to that of renal tubules ( 5 ). The disease can affect any region of the urinary system, but the bladder is the most common site (approximately 80% of cases), followed by the urethra (15%) and the ureters (5%), while renal pelvis involvement is rather uncommon ( 6 ). NA of the bladder mostly occurs in adults, with male-to-female ratio of 2:1 ( 7 ). Additionally, the etiologies may be linked to kidney transplantation, use of immunosuppressants, chronic urinary tract infection, calculi, bladder diverticula, interstitial cystitis, etc. ( 6 ). At present, its pathogenesis is not clear, mainly including the inflammation theory, renal tubule implantation theory, and embryology theory ( 8 ). The inflammation theory holds that NA is a metaplastic change of urothelial cells resulting from long-term chronic inflammation. According to the theory of renal tubule implantation, exfoliated renal tubular cells are implanted into the bladder, thus forming NA. The embryology theory holds that NA is developed from the Wolffian duct left during embryonic development. Microscopically, NA consists of a single layer of columnar epithelial cells, tubular structures similar to renal tubules, which can be observed under the epithelium, cells often have transparent eosinophilic cytoplasm, small nuclei, and no distinct nucleoli, and the lamina propria can be involved. At present, the most common treatment includes TUR-BT and partial cystectomy. Because NA has borderline biological behavior and a high recurrence rate, long-term reexamination by cystoscopy is needed after the operation ( 1 ). Although several published articles have shown that NA may undergo malignant transformation, few clinical cases have been recorded. Mesonephric adenocarcinoma of the bladder, also known as clear cell carcinoma of the bladder, is an extremely rare bladder malignant tumor with high invasiveness ( 9 ). Since Dow et al. first reported the disease in 1968 ( 10 ), only about 70 cases have been reported globally so far. The tissue origin of clear cell carcinoma of the bladder is controversial. Although this disease is often referred to as mesonephric adenocarcinoma in the early literature, due to the lack of convincing evidence in the theory of mesonephric duct origin, the literature in recent years prefers to name it clear cell carcinoma of the bladder ( 11 , 12 ). When the World Health Organization (WHO) classified urothelial tumors in 2016, it classified clear cell carcinoma of the bladder as a “Müllerian tumor”, and considered that the histological morphology of clear cell carcinoma of the bladder is similar to endometriosis of the female reproductive system ( 13 ). Different from NA, this disease is more common in females, with a male-to-female ratio of 2:3. Its clinical symptoms are similar to those of NA, mainly manifested as lower urinary tract symptoms such as hematuria, frequent micturition, and urinary urgency. The most common affected site is the bladder neck and bladder triangle, followed by the anterior wall and lateral wall of the bladder, usually involving the lamina propria ( 14 ). The cancer cells are obviously atypical, with distinct nucleoli and active mitosis. The diagnosis mainly depends on pathological morphology and immunohistochemical staining results. Although some published articles have suggested that NA has the potential of malignant transformation into mesonephric adenocarcinoma of the bladder, whether NA can undergo malignant transformation is still controversial. Yi et al. reported 60 cases of NA, but no long-term malignant change was found after long-term follow-up ( 15 ). However, a case reported that one patient underwent TUR-BT after the bladder tumor was found by cystoscopy, and postoperative pathological examination revealed NA, hematuria occurred again 1 year later, and the tumor recurred at the same site ( 16 ). TUR-BT was performed again and pathological examination suggested moderately differentiated adenocarcinoma. Finally, the patient underwent radical cystectomy, and postoperative pathological examination showed a malignant transformation of NA to mesonephric adenocarcinoma of the bladder ( 16 ). This paper reports that the pathological examinations of biopsies obtained by cystoscopy and diagnostic TUR-BT both indicated mesonephric adenocarcinoma. And adipose tissue was found in the wound surface during TUR-BT, which indicated that the depth of electrosection reached the deep muscular layer. However, in the pathological examination of surgical specimens after partial cystectomy, cancer cells were found, and the tumor cells located in the bladder mucosa have a mild morphology, and the tumor cells infiltrating the intrinsic muscle layer show mild to moderate atypia. Comprehensive consideration of the distribution and load of tumor tissue suggested that the patient had a malignant transformation of mesonephric adenoma to mesonephric adenocarcinoma of the bladder. We systematically and comprehensively reviewed the related literature and found that there are only three cases with clinical evidence supporting the malignant transformation of NA ( 16 - 18 ). This article is the first case in China. At present, there is a set of views that some immunohistochemical and molecular biological indicators can be used as important evidence to judge the malignant transformation of NA. Dhaliwal and Fineron reported a 67-year-old adult male admitted to the hospital due to hematuria. Cystoscopy showed papillary lesions in the bladder diverticula ( 17 ). After resection of bladder diverticula, the pathological examination result was NA. Two years later, the patient underwent resection of bladder diverticula again due to recurrence of tumor in the bladder. The postoperative pathology was mesonephric adenocarcinoma of the bladder. Comparing the results of the two times, Dhaliwal and Fineron found that there was a significant difference in Ki-67 proliferation index. When initially diagnosed as NA, the Ki-67 proliferation index was less than 10%. When it finally progressed to mesonephric adenocarcinoma of the bladder, the proliferation index of Ki-67 had exceeded 50%, so it was considered that the change in Ki-67 proliferation index was an important index to judge whether malignant transformation of NA occurred ( 17 ). In addition, Hartmann et al. reported a 70-year-old female patient with malignant transformation of NA into clear cell carcinoma of the bladder. After a comparative analysis of the immunohistochemical staining results of the patient’s two surgical specimens, it was found that strong positivity of CEA and P53 as well as high proliferation activity of Ki-67 could be regarded as important indicators for judging malignant transformation of NA of the bladder ( 18 ). The final immunohistochemical analysis results of this patient’s surgical specimens showed positive results of P53 and Ki-67 (30% of hot spots). The immunohistochemical characteristics of the present case were consistent with the above literature. The treatment of mesonephric adenocarcinoma of the bladder is still inconclusive. Generally, mesonephric adenocarcinoma of the bladder is a malignant tumor involving the muscular layer, and radical cystectomy is the mainstream treatment at present. In addition, some patients undergo radiotherapy, preoperative neoadjuvant chemotherapy, and postoperative adjuvant chemotherapy. The chemotherapy regimens include gemcitabine, cisplatin, 5-fluoropyrimidine, paclitaxel, etc. ( 19 , 20 ). Because of the small number of clinical samples, the effect of radiotherapy and chemotherapy is not clear. In previous case reports, only two patients with clear cell carcinoma of the bladder underwent partial cystectomy, and one of them was followed up for 4 years without recurrence ( 21 ). The other died of pelvic adnexal, liver, and peritoneal metastasis at 8 months after operation ( 22 ). The patient reported in this paper underwent partial cystectomy, and no signs of recurrence was found during 1-year follow-up.

A rare benign tumor of the urinary system with questionable biological behavior is the NA of the bladder. There have not been many cases documented, but some researchers think that it can develop a malignant transition to mesonephric adenocarcinoma of the bladder (clear cell carcinoma of the bladder). The diagnosis of mesonephric adenocarcinoma of the bladder depends on the immunohistochemical examination, in which the increase in Ki-67 proliferation index, as well as the high proliferation activity of CEA (+), P53 (+), and Ki-67 may be important molecular markers for judging the malignant transformation of NA of the bladder to mesonephric adenocarcinoma of the bladder. Total cystectomy is generally used for the treatment of mesonephric adenocarcinoma of the bladder, and partial cystectomy can also be selected for patients with a strong intention to retain the bladder, but close clinical follow-up is needed to guard against recurrence.

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