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1 INVERTED PAPILLOMA AND PAPILLARY TRANSITIONAL CELL CARCINOMA OF URINARY BLADDER Report of Four Cases of Inverted Papilloma, One Showing Papillary Malignant Transformation and Review of the Literature BOZIDAR LAZAREVIC, MD,* AND RUDOLF GARRET, MDT Four new cases of inverted urothelial papillomas are described and added to the 47 cases previously reported in the literature. Three papillomas present benign gross and microscopic characteristics. The fourth case, however, demonstrates inverted papilloma and papillary transitional cell carcinoma in a single polypoid lesion. This papillary malignant transformation, not previously observed in inverted papillomas, cautions against overconfidence in benign nature of inverted papilloma. Cancer 42: , NVERTED PAPILLOMA IS A rare, benign I polypoid lesion of urothelial origin first recognized in Since then, several case ~eports,l,2,5-ll,13-16 and two recent series of case^,^'^ appeared in the literature bringing the number of reported inverted papillomas to 4'7. More than 90% of the papillomas are located in the urinary bladder with overwhelming predilection for the bladder neck and trigone. The rare extravesical ones are seen in the renal pelvis,1 and prostatic ureth~-a.~>"j The cases reported had benign clinical course, absence of invasion, and, with one e~ception,~ no recurrence. The purpose of this communication is to report four new cases of inverted papilloma: two single, one multiple (two papillomas), and one demonstrating transformation to papillary transitional cell carcinoma. Case 1 CASE REPORTS A 5 1 -year-old Japanese businessman complained of pain and hematuria of three weeks duration. He noticed blood stained urine which persisted for several days and then continued as intermittent light hematuria for about 2 weeks. IVP demonstrated a small polyp arising from the left side of the From the Department of Pathology, The Roosevelt Hospital, New York, New York. * Attending Pathologist. t Director, Department of Pathology. Address for reprints: Bozidar Lazarevic, MD, Roosevelt Hospital, 428 West 59th Street, New York, NY Accepted for publication May 22, bladder neck. The remaining urinary tract was negative. The prostate was small on physical examination and the genital organs were unremarkable. He was in good health and had no history of previous urological problems. He complained of frequent headaches. Laboratory data were within normal limits. Cystoscopy disclosed a smooth pedunculated polyp measuring 1.5 by 0.8 cm located on the bladder neck at 5 o'clock position. The stalk was approximately 2 mm long. The polyp was resected with a small portion of the prostate. Histologically, the polyp shows the surface lined with smooth benign transitional epithelium from which cords of the same epithelium invert and extend deep into the core of the polyp creating a mosaic of epithelial tissue separated by fibrous stroma. Often these epithelial cords are separated creating spaces of varied size some containing scanty proteinaceous material (Fig. 1). This material is PAS positive diastase resistant and colloidal iron positive not sensitive to treatment with hyaluronidase. Stain for much occasionally demonstrated a small amount of mucicarminophilic material. There were no areas of squamous metaplasia or papillary formation, and the underlying tissue showed unremarkable muscle and benign prostatic glands. Four years of follow-up at 4-6 month intervals showed no evidence of recurrence. Case X/78/1000/1904 $ American Cancer Society A 78-year-old female and retired librarian had a urinary retention of 18 hours during which time she passed a blood clot. She had no urinary symptoms or hematuria prior to that time. When hematuria recurred, she was admitted to the Roosevelt Hospital where catheterization showed hemorrhagic urine with clotted blood. She had 1904

2 No. 4 INVERTED UROTHELIAL PAPILLOMAS * Lazarevic and Garret 1905 FIG. 1. Inverted papilloma demonstrating smooth epithelial surface and anastomising cords of inverted urothelium traversing the loose stroma (H & E, x25). hypertension for several years, frequent nose bleeds, and a hysterectomy in 1964 for a malignant disease, the nature of which is unknown to us. The IVP was unremarkable. On cystoscopy there were numerous blood clots and grossly bloody urine. Two small sessile polypoid lesions, 5 and 4 mm in diameter, were found on the left posterior wall. These were excised and their bases cauterized. Histological examination disclosed two polyps composed of benign transitional epithelium lining the surface and traversing the fibrous core. This pattern is similar to Case 1. One year postexcision there has been no recurrence. Case 3 A 63-year-old man had had chronic urticaria and diabetes mellitus for the previous 3% years. Diabetes mellitus was controlled with diabenase. Urticaria was due to allergy to dust, and was treated with antihistamine medications. He developed urinary frequency and 1-5X nocturia. There was no history of hematuria, pain, or burning sensations. On examination, the prostate was slightly enlarged, nodular and nontender. The cystoscopy disclosed a pedunculated polyp 2 x 1 cm on the right trigonum, 1 cm from the right ureteral orifice. The tumor was resected and right lateral wall of urinary bladder biopsied. The gross specimen was a polyp 2 x 1 cm with smooth surface and whitish-tan core. On microscopic examination the polyp showed smooth benign transitional epithelium covering the surface and inverting deep into the fibrous core similar to Case 1. The right bladder wall biopsy showed chronic cystitis. This report is written 3 weeks postsurgery, a time too short for follow-up information. Case 4 A 50-year-old Maltese male had painless hematuria without frequency for more than one year. His personal and family history were negative. On examination, urine showed blood and 2+

3 CANCER October Vol. 42 FIG. 2. Area of tumor showing papillary transitional cell carcinoma (H & E, X35). protein. The culture showed no growth. The IVP revealed a large tumor mass on the right wall of the urinary bladder. Cystoscopy disclosed a papillary tumor 4 cm in diameter attached to the wall by a narrow short stalk. This tumor was completely resected. There was no other urinary bladder pathology and the prostate gland was normal on palpation. The gross specimen was composed of multiple fragments of partly papillary and partly solid tissue. Microscopic examination revealed papillary transitional cell carcinoma with nuclear atypia, varying from Grade I up to Grade I1 (Fig. 2). In addition, there were fragments of inverted papilloma with typical histology (Fig. 3). In areas the two lesions were seen in the same fragment where papillary carcinoma grew from inverted papilloma (Figs. 4 and 5). Approximately 75% of the tissue

4 Vol. 49 INVERTED UROTHELIAL PAPILLOMAS. Lazarevic and Garret 1907 FIG. 3. Detail of typical anastomosing epithelial cords of inverted papilloma, with spaces containing proteinaceous material. The epithelium shows benign uniform nuclei and absence of mitoses (H & E, x 125). was papillary carcinoma, and 25% inverted pa@- loma. The base of the tissue was free of infiltration. in which benign transitional epithelium and fibrovascular stroma comprised polypoid A ten month follow-up showed no recurrence. growth. Grossly characterized by smooth DISCUSSION external surface and solid appearing core, the lesion is usually pedunculated and less com- In 1963, Potts and Hirst12 described a monly sessile. Microscopically, a nonpapillary unique polypoid lesion of the urinary bladder urothelium covers the surface from which

5 1908 CANCER October 1978 Vol. 42 FIG. 4. Papillary transitional cell carcinoma growing from the surface of inverted papilloma (H & E, X25). cords of same epithelium invert and extend connective tissue. The epithelial cords often deep into the core (Fig. 1) in an anastomosing separate creating spaces frequently containpattern, always maintaining its benign histo- ing precipitate of proteinaceous material (Fig. logical characteristics. The epithelial cells have 3). Histochemically, this precipitate is PAS rather uniform oval benign nuclei and usually positive diastase resistant and colloidal iron rare or no mitoses. The epithelium is sup- positive, not sensitive to treatment with ported with varying amounts of usually loose hyaluronidase. This indicates the presence of

6 No. 4 INVERTED UROTHELIAL PAPILLOMAS * Lazarevic and Garret 1909 FIG. 5. Detail of papillary carcinoma from figure 4. Urothelial cells show moderate variation of nuclear size and significant nuclear hyperchromasia (H & E, X450). neutral and acid mucopolysaccharides. Occasionally, a small amount of mucicarminophilic material is also present. In reviewing the 47 cases described to date in the world literature and four cases reported here, there are 42 male and 9 female patients, an approximate ratio of 5: 1. The patients ages span from 26 to 79 years with peak incidence in the 4th, 5th, and 6th decades. More than half of the papillomas are located on the bladder neck and trigone (Table 1) while the others are scattered in the urinary bladder, prostatic urethra and one in the renal pelvis. Their size varies from 0.5 to 4 cm. It is

7 1910 CANCER October 1978 Vol. 42 TABLE 1. Location of 51 Cases of Inverted Urothelial Papillomas Including the 4 Cases in this Report Bladder neck Trigone Bladder near ureteral orifices Prostatic urethra Bladder base Lateral bladder wall* Renal pelvis Urinary bladder, unspecified TOTAL * Includes inverted papilloma of the right wall with papillary malignant transformation. important to note that three patients had two simultaneously documented inverted papillomas in the urinary bladder.3,6 Seen concomitantly with inverted papilloma were a variety of benign and malignant lesions of the urinary tract and prostate. One large Grade I1 papillary transitional cell carcinoma was found on the left vesical wall,9 seemingly distant from the inverted papilloma located on the right urinary bladder wall close to the urethral orifice. Another patient had simultaneous adenocarcinoma of the pro~tate.~ Benign lesions include frequent benign prostatic hyperplasia, cystitis glandularis, cystitis cystica, and Von Brunn s nests in the urinary bladder. Frequent inflammatory changes in the urinary bladder were seen in one ~eries.~ Inverted papilloma bears close histological resemblance to papillary transitional cell carcinoma; and many papillomas gained proper classification upon re-examination or consultation. Furthermore, the inverted characteristics of epithelial cords simulate infiltration and only awareness of the existence of inverted papilloma can bring proper interpretation. Other urinary bladder lesions such as hamartoma and von Brunn s nests hyperplasia may have certain resemblance to inverted papilloma and have frequently been designated so on first interpretation. The etiology of the development of inverted papilloma is not yet fully understood. It is currently thought that inverted papilloma represents a benign polyp of urothelial origin. Follow-up of 5 years and longer of quite a few inverted papillomas show no malignant behavior. Frequent association with proliferation of von Brunn s nests or inflammatory process suggest hyperplastic or inflammatory etiology. The clinical symptoms have been most commonly mild painless hematuria usually of short duration. Occasionally hematuria has been significant. Urinary obstruction was a common symptom attributed to the frequent location of inverted papillomas at the urinary bladder outlet or prostatic urethra. Pedunculated tumors located near the bladder neck can occasionally produce obstruction due to ball-valve phenomenon. Case 4 in this report is of considerable importance because it demonstrates inverted papilloma and papillary transitional cell carcinoma in a single polypoid mass. Histologically there is papillary carcinoma surrounding and arising from the surface of in- verted papilloma. Although it is not possible to elaborate on the circumstances initiating this association, their co-existence implies malignant papillary alteration of inverted papilloma. It is important to note that this patient had hematuria for longer than one year, while the typical case history of inverted papilloma is short hematuria of several days or weeks. It is speculative whether a common histological type of inverted papilloma would show papillary transformation if unresected for an extended period of time. The presence of papillary carcinoma growing with inverted papilloma should neither alter nor minimize the previous impression that inverted papillomas have benign clinical behavior. However, this points to a possibility of malignant alteration in inverted papilloma and suggests long follow-up of all resected inverted papillomas. REFERENCES 1. Assor, D., and Taylor, T. N.: Inverted papilloma of 4. Henderson, D. W., Allen, P. W., and Bourne, A. J.: the b1adder.j. Urol. 104: , Inverted urinary papilloma-report of five cases and re- 2. Cummings, R.: Inverted papilloma of the bladder. J. Pathol. 112: , view of the literature. Virchows Arch. Pathol. Anat. Histol. 336~ , DeMeester, L. T., Farrow, G. H., and Utz, D. S.: In- 5. Hasselstrom, K.: Inverted papilloma of the bladder verted papilloma of the urinary bladder. Cancer 36: (Engl. Abst.). Ugeskr. Laeger. 137: , , (DAN).

8 No. 4 INVERTED UROTHELIAL PAPILLOMAS. Lazareuic and Garret Hefter, L. G., and Young, I. S.: Inverted papilloma of bladder. Urology 5: , Inada, T., and Ochiai, K.: Inverted papilloma./pn. J. Cancer Clin. 17: , 1971 (Japanese). 8. Jacques, S.: Inverted papilloma of the urinary bladder. Arch. Pathol. Lab. Med. 100:559, 1976 (Letter to the Editor). 9. Klein, H. L.: Inverted papilloma and transitional cell carcinoma of the bladder. Proc. of the Kimbrough Urological Seminar 8:45-46, 1974 (22nd Meeting, Nov , 1974 Brooke Army Med. Center). 10. Matz, L. R., Wishart, V. A., and Goodman, M. A,: Inverted urothelial papilloma. Pathology 6:37-44, Pienkos, E. J., Iglescos, F., and Jablokow, V. R.: Inverted papilloma of bladder. Urology 2: , Potts, I. F., and Hirst, E.: Inverted papilloma of the bladder. J. Urol. 90: , Simard, C., Tayot, J., FranGois, H., Bertrand, G., Soret, J. Y., and Pantin, J.: Le papillome inverse urothelial de Potts et Hirst. Arch. Anat. Pathol. 23: , Sullivan, T. T., Watson, J. G., Kingston, C. W., and Yaxley, R. P.: Inverted papilloma of the urinary bladder: A report of two cases. Aust. N. Z. Journal of Surgery 41: 60-62, Tannenbaum, M.: Inverted papilloma: Urothelial tumor of benign biologic potential. Urology 7:76-79, Trites, A. E. W.: Inverted urothelial papilloma: Report of two cases./. Urol. 101: , 1969.