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Table I: Summary of our case and literature review of cases of villous adenoma arising in the female urethra.

In the etiology, it has been considered that urinary tract VAs might develop from the cloacal remnants from which the distal colorectum, bladder and urethra originate during embryogenesis. On the other hand, they may also be a product of the chronic irritation-metaplasia-dysplasiacarcinoma sequence ³.

In patients with bladder augmentation cystoplasty, it is reported that the risk of carcinoma development increases ⁴. Most of these carcinomas develop in the neobladder or anastomosis line. Only 2 cases of VA that developed from the native bladder mucosa have been reported (Table II) ^4,12. It is thought that the development of VA in patients with bladder augmentation supports the second theory.

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Table II: Villous adenoma arising from the urinary mucosa in the patients with a history of augmentation.

We present the first VA case arising in the urethra of a female patient with intestinal bladder augmentation.

She was diagnosed as postrenal acute renal failure. A catheter was inserted and the urea-creatinine levels began to decrease. She had bilateral hydroureteronephrosis. After 4 months, physical examination revealed a carunculalike structure protruding from the urethral meatus. The urinary USG revealed that there was no relation with the bladder. The urethral lesion was excised, and then the bilateral hydroureteronephrosis regressed. CIC was not recommended for postoperative follow-up, as the patient had no residual urine.

The macroscopic examination of the lesion revealed a cream-white colored, fragile and polypoid mass, 4.5x2x1.5 cm in size. Its base was 1.5x1 cm in size, hemorrhagic and brown colored. On the cut sections, it was composed of thin papillary structures adhering to a fibrous core.

On microscopic examination, the tumor consisted of villous structures covered with pseudostratified intestinal type epithelium. Low-grade dysplasia and occasional squamous metaplasia areas were present in the epithelium (Figure 1A-D). All material was investigated and high-grade dysplasia or in-situ / invasive carcinoma was not observed. Immunohistochemical study showed positivity for CK7, CK20, EMA, CEA and CDX2 (Figure 2A-E).

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Figure 1: Microscopic view of the urethral villous adenoma. A) A slide photograph shows thin papillary structures adhering to a fibrous core (H&E; x4). B) Villous structures covered with pseudostratified intestinal type epithelium (H&E; x100). C) Squamous metaplasia areas (H&E; x40). D) Low-grade dysplasia of adenomatous epithelium (H&E; x400).

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Figure 2: Immunohistochemical panel. Positivity for A) CK7 (IHC; x200), B) CK20 (IHC; x200), C) EMA (IHC; x200), D) CEA (IHC; x200), E) CDX2 (IHC; x200).

The case was reported as VA of the urethra. The adenomatous epithelium was adjacent to the surgical margin. However, there was no surgical recurrence in the 28-month followup. During follow-up, there was no renal dysfunction or hydronephrosis. The patient stated that she was more comfortable after the operation and could urinate.

In the past, various terms have been used to describe these tumors as villous adenoma, tubulovillous adenoma, villous metaplasia of the intestinal type with dysplasia, and enteric adenoma. However, using the villous tumor or villous polyp terms must be avoided because they can lead to confusion with prostatic-type polyps ¹⁹.

Urinary tract VAs mostly arise in the urachus, dome, or trigone of the bladder ^1,4. Cases located in the urethra, renal pelvis, and ureter have also been reported ^6,20-22. Dong et al. have reported that they found only 8 cases of pelvic VA in the English literature and presented 2 additional cases ²². Qin et al. also reported that they found only 11 cases with urethral VA between 1981 and 2003. Six of these, and the case which they presented, were female ⁶. Our presented case is therefore the eighth VA case arising in the female urethra, as far as we are aware.

Two possibilities have been reported in the etiology of VAs. According to the first theory, the distal colorectum, bladder and urethra originate from the cloacal tissue during embryogenesis, and these tumors may develop from the cloacal remnants. This also explains the morphological and cytogenetic similarity of the urinary tract lesions and their counterparts in the gastrointestinal system. According to the second theory, VAs are a product of the irritationmetaplasia- dysplasia-carcinoma sequence ³. Intestinal metaplasia of the urinary tract is often associated with chronic inflammation, in particular infection, stones and chemical injury ¹⁶. The presence of neutral mucins, acidic sulfomucins, and sialomucins in both cystitis glandularis and VA, and the similar genetic characteristics in the dysplastic regions of the metaplastic mucosa and VA support this theory ^3,23.

Augmentation cystoplasty using the colon, ileum or stomach is an accepted reconstructive option for patients with intractable incontinence and poor bladder compliance due to neurogenic and non-neurogenic disorders ⁶. However, it has been reported that the risk of developing bladder carcinoma increases 7-8 times with ileum and colon segments, and 14-15 times with gastric segments ^4,12. The most common histologic types are adenocarcinoma and urothelial carcinoma ¹². The incidence of VAs after cystoplasty is very low and most of them develop in the neobladder or anastomosis line ²⁴. To our knowledge, only 2 cases of VAs originating from the native bladder mucosa have been reported ^4,12. It is thought that the development of bladder VA in patients with a history of augmentation supports the irritation-metaplasia-dysplasiacarcinoma sequence theory ^4,12.

Our presented case had a history of intestinal augmentation cystoplasty 30 years ago. However, VA had developed in the urethral mucosa and protruded from the urethral meatus. USG revealed that there was no relation with the bladder. Our case is the first VA in a female urethra with a bladder augmentation history. This case could also be another example supporting the second theory.

Histologically, VAs consist of long villoglandular structures with a central fibrovascular core and these structures are lined by pseudostratified columnar epithelium ^1,13. The epithelial cells display nuclear stratification, crowding, hyperchromasia and occasional prominent nucleoli. Variable mitotic figures are seen in situ and in the invasive component ¹. There is frequently a background of chronic cystitis and association with intestinal/squamous metaplasia, cystitis cystica and cystitis glandularis ².

Two-thirds of the cases may have simultaneous malignant tumors such as urothelial carcinoma, and in situ or infiltrative adenocarcinoma ². Therefore, all of the excision material should be examined carefully ². In our case, we investigated all excision material and there was no high-grade dysplasia or in situ/invasive carcinoma focus.

Immunohistochemically, CK20 positivity was reported at a rate of 100%, while CEA and EMA can be positive. CDX2 positivity is also reported ²⁵. CK7 positivity is observed in approximately half of the cases ^1,3,26. Our case showed positivity for all these markers.

Distinction from tumor metastasis of adjacent organs such as colon, the female genital system, and the prostate is important. For females with genital system adenocarcinoma, Ca125, ER, PR can be helpful as diagnostic markers ⁶. Morphological differential diagnosis between metastatic adenocarcinoma of the gastrointestinal system and urinary tract VAs is impossible. CK7 positivity can support VAs of the urinary tract ^3,6. In the male urethra, morphological features of prostatic ductal adenocarcinoma can easily mimic VA ²⁷. Expression of prostatic lineage markers such as PSA and PSMA could be helpful to differentiate the two entities ¹³.

Cytologically, it is difficult to distinguish VAs from other glandular lesions. However, VAs must be considered in the differential diagnosis when many glandular cells or mucinous cells without atypia are recognized in the urine ²⁸.

Excision is curative for pure VAs. Carcinoma transformation and recurrence were not reported in pure cases during a mean follow up of 9.9 years ¹. However, more aggressive treatment may be indicated for the VAs coexisting with a malignant tumor as adenocarcinoma to prevent recurrence and metastasis ^1,6. In VAs of yjr calyx, the adenoma may result in atypical hyperplasia and cancerization due to continuous inflammation stimulation, and surgical resection is therefore recommended ²². In the ureters, tumor growth with mucus retention may be the main cause of ureteral obstruction, and total excision of the tumor prevents early obstruction ²⁹. In patients with bladder augmentation, long-term active surveillance is necessary in terms of neoplasia development ^12,24. In our presented case, the urethral tumor was excised. Although the surgical margin was microscopically positive, there was no recurrence in 28-month follow-up.

In conclusion, our case is the first VA arising in the female urethra with a history of bladder augmentation. The present case report supports the irritation-metaplasia-dysplasiacarcinoma sequence theory. Excision is curative for pure VAs. Transformation to carcinoma or recurrence has not been reported. However, there may be an accompanying malignant tumor such as adenocarcinoma, urothelial carcinoma etc. in one-third of the cases. Therefore, all excision material should be examined carefully. Routine endoscopic follow-up should be performed in cases with bladder augmentation. Further studies are needed to establish the nature of urinary tract VAs.

CONFLICT of INTEREST
The authors declare no conflict of interest.

AUTHORSHIP CONTRIBUTIONS
Concept: HD, Design: HD, NU, Data collection or processing: HD, SC, SC, Analysis or Interpretation: HD, NU, Literature search: HD, Writing: HD, Approval: NU.

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