Britislr Joional of Urology (1976). 48, 567-577
0
Inverted Papilloma of the Lower Urinary Tract K A T H A R I N E M. CAMERON
and
CHARLES H. LUPTON
Iiutitute of Urology and Department of Pathology, St Peter’s Hospitals, London
The classical “inverted papilloma” is a polypoidal tumour of distinctive histological appearance. It occurs mainly in males and in the region of the trigone, bladder neck or posterior urethra. The lesion appears to behave in a benign fashion and must, therefore, be distinguished from the more common tumours of transitional epithelium. The name “inverted papilloma” was first used by Potts and Hirst who described a single case in 1963; 10 years later they presented 8 more examples at the 16th Congress of the lnternaticnal Society of Urology in Amsterdam. Altogether 35 other cases have been reported under this name in the English language literature (Table I), and several apparently identical lesions have been described under a variety of different titles (e. g . Salm, 1967, case 3). The largest series is that of De Meester, Farrow and Utz (1975) who noted that 4 inverted papillomas had been reported much earlier in the German literature by Paschkis (1927) as “adenoma-like polyps” of the bladder. They are described also in the most recent AFIP fascicle on tumours of the urinary bladder (Koss, 1975). This benign urothelial lesion has been recognised in this laboratory for some years. In this paper 35 typical cases are presented and the differential diagnosis of other epithelial lesions of the bladder which are also “inverted” is discussed. The series consists of 18 patients investigated at St Peter’s Hospitals (Group 1) and 17 cases referred for histological opinion (Group 11). Sex, age, site and follow-up data have been obtained for the majority of patients in both groups; full clinical details are available only in Group I.
Clinical Features Of the 35 patients only 2 were females. The ages ranged from 22 to 78 years, with a peak incidence in the 6th and 7th decades. The most common presenting symptom in Group I was haematuria (Table I I ) which occurred in 13 patients, 3 of whom also gave a history of recent infection; this was urinary in 2 cases and epididymal in 1 and all 3 had already received treatment when first seen in hospital. 3 of the patients with haematuria also had a degree of bladder outflow obstruction. Obstructive symptoms were present altogether in 7 men, being the sole symptom in 4, but how much they were due to the tumours in the older age-group is difficult to say. 1 patient complained only of penile soreness following the passage of a stone. Intravenous urography, performed on 13 of the I8 patients, showed normal upper tracts in 10. The abnormal findings were a ureteric calculus, unilateral pyelonephritis and an enlarged kidney of uncertain aetiology in one instance each. Midstream urine specimens taken on the first visit in 16 patients proved to be sterile in 15. I n 1 of the cases with a history of urinary infection E. coli was isolated but the organisms were scanty and no pus cells were seen in the sediment. Read at the 32nd Annual Meeting of the British Association of Urological Surgeons in London, June 1976. 567
I 3
I
Potts and Hirst (1963) Trites (1969)
Assor and Taylor (1970) Sullivan el al. (1971)
5
20
35
79
DeMeester et a/., (1975)
Present series
Total
*
1
5
1 1 1 1
Pienkos e f a/. (1 973) Cummings (1 974) Matz et aI. (1974) Hefter and Young (1975) Henderson et al. (1 975)
8
2
5
1
22-79
22-78 40-61
44-78 46-62
46 68 75 65 49-79
63 56 79 59 26 71 45
See Table II
+
Main symptoms Obstruction Haematuria
+ (3)
+
Infection
*
*
1
See Fig. 1
base Posterior urethra Trigone Bladder neck Bladder neck Bladder neck Bladder neck Left lateral wall (Bladder neck (8) Trigone (5) ' Around ureteric orifices (4) Left lateral wall (1) ,Posterior urethra ( 1 )
p::::
Bladder neck Prostatic urethra Bladder neck Prostatic urethra Apex of trigone Bladder neck
Site of Turnour
Correlation between site and other features not attempted due to lack of information (Potts and Hirst) or complexity (DeMeester ef d.).
71
-~
33
15
I
1 1
8
7
2
1
I 3
Sex ~Male Female Age
Potts and Hirst (1973)
L
7
Number
Authprs
Table I Summary of Cases of Inverted Papilloma of Bladder and Posterior Urethra reported in the English Language Literature
INVERTED PAPILLOMA OF THE LOWER URINARY TRACT
569
“Anterior wall ’I ....1. “posterior wall” ....1 Pig. 1. Inverted papillomas of the lower urinary tract: site of 37 lesions in 35 patients (Groups I and 11).
Cystoscopic Appearances The lesions were sometimes described as “papillomas” but more commonly as solid-looking polyps, often pedunculated, with a smooth or slightly nodular surface; sometimes the adjectives “unusual” or “curious” were applied. The largest estimated size was 3 cm. In 2 men 2 separate lesions were present-making 37 tumours in all (Fig. 1). 17 were situated at the bladder neck, 9 around the ureteric orifices, 7 in the region of the trigone, 1 just above the interureteric bar and 1 in the urethra at the internal meatus. In 2 cases the site was stated to be the anterior and posterior wall respectively without detailed localisation.
Table I1 Main Symptoms of the 18 Patients in Group I. Group I (18 cases) Haematuria +infection +obstruction Obstruction Penile soreness
“4’
1
18
}7
570
BRITISH JOURNAL OF UROLOGY
Fig. 2. Small inverted papilloma described as a "curiou', lesion'' o n the trigone of a 63-year-old male and showing the typical polypoidal nature of the lesion. H & H 10. Enlargement x 4. Fig. 3. Surface of an inverted papilloma showing attenuated covering epithelium, with small surt'ace papillations, rrom which trabeculae or transitional epithelium extend into the underlying vascular connectivc tissuc. H & tl -10. Enlargement x 4.
Treatment
I n each case the lesion was resected, usually endoscopically, and the base fulgurated. Macroscopic Appearances
As the resected specimens (Group I ) consisted frequently of fragments their orientation was often dificult. The fixed tissue was cream to light brown in colour and the cut surface fleshy and homogeneous. The weight of the resected tissue ranged from under 0.1 g to 4.9 g. Microscopic Appearances
The typical lesion is polypoidal (Fig. 2) with a surface layer of transitional epithelium, sometimes attenuated. From the surface, trabeculae and nests of similar epithelium extend down into the supporting connective tissue to occupy much of the centre of the polyp. A few tiny surface papillations are sometimes seen (Fig. 3). In some cases the appearances suggest the exuberant formation of von Brunn's nests, which at times show central lumen formation (Fig. 4). Thc structure of other lesions is more bizarre, with branching and anastomosing cords ofepithelial cells roughly twice the thickness of normal urothelium (Fig. 5) and outlined by an intact basement membrane. These epithelial cords resemble papillary processes turned outside in, with the stroma
INVERTED PAPILLOMA OF THE LOWER URINARY TRACT
57 1
and basal layer of cells on the outside and differentiation occurring towards the centre, where there is sometimes lumen or cyst formation. The outer layers of cells are arranged at right angles to the adjacent basement membrane, while the central ones may be parallel to it, and sometimes show cytoplasmic vacuolation and nuclear pyknosis. Lumina when present (Figs. 4 and 5) are lined by flattened to low columnar cells with basal nuclei, and sometimes contain Alcian BluePeriodic Acid-Schiff (AB-PAS) positive secretions and occasionally crystals. Focal squamous metaplasia, usually in the form of epithelial whorls, is not uncommon ; intercellular bridges are present in these areas, but no keratin. Although a modest degree of cellular pleomorphism is occasionally seen, mitotic figures are characteristically absent or very rare. The cords of cells are separated by a variable amount of loose delicate stroma, often rich in capillaries. Lymphocytes and plasma cells may be scattered throughout the stroma, but are not usually prominent and, in some cases, are totally absent. In AB-PAS stained sections, secretion is often coloured by both Alcian Blue and the PAS: cytoplasmic vacuoles of cells lining cystic spaces react similarly. At times inspissated secretions within these spaces show either double staining or more commonly only strong coloration by the PAS. Small amounts of glycogen are present in the cells of areas showing squamous metaplasia. Where the epithelium is looser, especially in foci undergoing cytolysis, pale Alcian Blue staining is seen between the cells. Ground substance of the oedematous stromal tissue is also coloured faintly by Alcian Blue. Reticulin stains (modified Laidlaw’s technique) show fibres in the stroma which surround and clearly outline nests and islands of epithelial cells.
Fig. 4. Same lesion as Figure 2 showing resemblance t o von Brunn’s nests. H & E x 40. Enlargement x 4.
Fig. 5 . Centre of a n inverted papilloma showing branching cords of transitional epithelium, roughly twice the thickness of normal urothelium and resembling papillary processes turned outside in. T h e stroma,and basal layers of cells are o n the outside and there I S central lumen lbrmation in places. H & E x 40. Enlargement x 4.
BRITISH JOURNAL OF UROLOGY
572
Symptom free and cystoscopy negative Symptom free Further fulguration
2
4
6
Years
8
10
12
14
Fig. 6. Follow-up of 18 patients in Group I (St Peter’s series).
Symptom free and cystoscopy negative Symptom free
Vault lesion fulgurated Died of unrelated causes
m
2
4
8
6 Years
Fig. 7. Follow-up of 17 patients in Group I1 (referred cases).
10
12
14
INVERTED PAPILLOMA OF THE LOWER URINARY TRACT
573
Fig. 8. Tumour from the renal pelvis of a 58-year-old woman showing histological similarity to the inverted papilloma of bladder. H & E x 16. Enlargement x 4 . Fig. 9. Edge of polypoidal transitional cell carcinoma of bladder showing a n inverted pattern of growth. Note the surPace layer of transitional epithelium a n d underlying bulbous masses of epithelial cells. H & E x 16. Enlargement x 4.
FoIIo W-UP The 18 Group I patients have been followed up for periods ranging from I 1 months to almost 13 years (Fig. 6)-11 by regular check cystoscopy. 17 have shown no evidence of local recurrence or any other urothelial lesions. In the 18th man, 2 years after his initial treatment, a tiny “mossy’ area was seen on cystoscopy at a short distance from the original site and was fulgurated without a biopsy; his bladder mucosa remains cystoscopically clear 6 years later. Follow-up information is available also for 15 of the 17 Group 11 patients (Fig. 7) the remaining 2 cases being too recent to assess. 1 female was found to have a lesion at the bladder vault which was fulgurated without biopsy 9 months after the initial resection. The remainder have developed no further urothelial lesions during periods of up to 14 years, though 3 have died of unrelated causes. Similar Lesions in the Upper Urinary Tract A large lesion (maximum dimension 3 cm) with a histological appearance similar to that of the inverted bladder papilloma (Fig. 8), but which arose in the renal pelvis of a 58-year-old female, has been shown to us by Professor A. C. Thackray, formerly of the Middlesex Hospital. The tumour was rather more complex than the bladder lesions in this series but showed essentially the same inverted pattern with very rare mitotic figures and an intact basement membrane. Treatment was by nephroureterectomy. At the same time a Wertheim’s hysterectomy was performed for carcinoma of the endometrium, whose spread caused death 4 years later.
574
BRIT-ISH JOURNAL 0 1 UROLOGY
Fia. 10. Area resembling an inverted papilloma in a bladder tumour composed elsewhere of transitional cell carcinoma of both inverted and exophytic pattern (same case as illustrated in Figures 1 1 and 12). H RC E x 16. Enlargement i.4. Fig. 1 1 . Area of transitional cell carcinoma of inverted pattern in tumour illustrated in Figures 10 and 12. t l XI E Enlargement
x
x
10.
4.
Fig. 12. Area of transitional cell carcinoma of exophytic type in a tuniour of mixed pattern (same case Figures 10 and 1 1 ) . H RC E x 4 0 . Enlargement x 4 .
ils
illustrated in
Other Bladder Lesions having an inverted Papillary Pattern An inverted pattern is not confined to benign lesions but is seen also in certain carcinomas, the whole or part of which may be of this structure. The tumour illustrated in Figure 9, designated as a transitional cell carcinoma, is of this type and was situated on the posterior wall of the urinary bladder, medial to the left ureteric orifice, in a 66-year-old male; it measures 2.5 x 1-8 x 1.5 cm. The lesion is polypoidal with a surface layer of urothelium from which masses of cells extend downwards into the lamina propria though the basement membrane is everywhere intact. I n contrast to the slender trabeculae of the typical inverted papilloma there are bulbous masses of proliferating epithelium showing some differentiation toward the centre in places but rarely cyst formation. Mitotic figures are relatively numerous. The relationship of this lesion to the
INVERTED PAPILLOMA OF THE LOWER URINARY TRACT
575
benign inverted papilloma seems analogous to that of papillary transitional cell carcinoma to transitional cell papilloma. This tumour had been preceded, and was followed, by multiple transitional cell carcinomas which showed both exophytic and inverted features and led to cystectomy 5 years later. Various patterns of growth may co-exist within a single neoplasm. 1 such tumour, situated at the base of the bladder of a 64-year-old female, contained 1 area indistinguishable from an inverted papilloma (Fig. 10) along with areas of transitional cell carcinoma of both inverted and exophytic patterns (Figs. 11 and 12). This tumour was removed by open diathermy excision followed by radium implant and the patient has remained tumour free for 7 years. Discussion 33 of the 35 patients with inverted papillomas of the lower urinary tract in this series were men; this concurs with other published cases in which 38 of 44 patients were males. The age range (22 to 78 years) of the patients is also similar to that reported by others, exceptions being two 79-year-olds described by Trites (1969) and Henderson, Allen and Bourne (1975). Presenting symptoms in this series were not unlike those reported elsewhere (Table I) except that bladder obstruction appeared to be less frequent. I n view of the proximity of many of the lesions to the bladder outlet obstructive symptoms are not surprising, though in many cases prostatism may be a contributory factor. The gross and microscopic appearances resemble closely those described by others. According to Koss (1975) the largest tumour recorded measured 7.5 cm in greatest diameter. The lesion reported by Cummings (1974) is unique in that it is composed entirely of squamous cells. In addition to Professor Thackray’s case, an inverted papilloma of the renal pelvis has been reported by Matz, Wishart and Goodman (1974), and Pienkos, lglesias and Jablokow (1973) state that Price has also seen such a lesion. Opinions concerning the histogenesis and nature of the lesion differ. Potts and Hirst (1963) considered it to be a neoplasm and postulated origin from subtrigonal glands but clearly this does not explain the lesions in the renal pelvis. The epithelium of the trigone and the posterior wall of the urethra down to the ejaculatory ducts-the site of origin of the great majority of the lesions-is generally believed to be of mesodermal origin, differing embryologically from the remainder of the bladder lining which is derived from the endoderm. Is it possible that this mesodermal epithelium, when stimulated, tends to proliferate into the underlying tissue rather than into the bladder cavity‘? If so then similar lesions would not be unexpected in the renal pelves and ureters which bud from the mesonephric ducts and also originate from mesoderm. Cummings (1974) believes that persistent or recurrent inflammation secondary to lower urinary tract obstruction causes these lesions. However, this seems unlikely in our patients in whom neither the histological nor the clinical findings support this idea. The significance of the crystalline material seen in a few cases is not clear but is considered secondary rather than primary. Matz et al. (1974) showed by serial sections that their lesions consisted of intercommunicating crypts in continuity with the bladder lumen and considered them to be an exaggerated form of von Brunn’s nest formation-that is, hyperplastic rather than neoplastic. Salm (1967) considered his “adenoma” to have originated in von Brunn’s nests and cystitis cystica. Origin from “the irritated bladder mucosa of proliferative cystitis” was suggested by DeMeester et al. (1975), who saw some mucosal proliferations at the margins in the majority of their lesions. They disagreed with Matz and considered the lesions to be neoplastic. In our specimens the surrounding bladder mucosa was not usually available for study. When a small amount of adjacent epithelium was present, von Brunn’s nests were more often absent than present. Nevertheless, parts of some inverted papillomas d o resemble the focal proliferative lesions common in bladder (and other) urothelium and such an origin for these tumours is therefore an attractive suggestion.
576
BRITISH JOURNAL Oh UROLOGY
Whatever its cause we consider this a neoplastic lesion, and if the analogy to the inverting form of transitional cell carcinoma is accepted then one has to consider, as did Trites (1969), that the lesion is an inverting variant of the urothelial papilloma. The benign course in patients with the typical inverted papilloma is well established with only 1 reported recurrence (DeMeester ri d., 1975) and no proved subsequent malignancy. The fact that 2 lesions may occur either simultaneously or consecutively does not alter the favourable outlook. Co-existence of inverted papillomatous and carcinomatous areas in some tumours does not necessarily imply that a typical lesion may undergo malignant transformation. It would appear that in the case illustrated in Figure 9 the natural history of the “inverted” form of papillary carcinoma resembles that of the exophytic papillary variety. The inverted papilloma of the bladder has been likened by some workers to the lesion with the same name seen on the lateral wall of the nose and in the nasal sinuses. There ate some important differences. The nasal mucosal lesions consist of essentially epidermoid instead of transitional epithelium; also, crypt formation is much more conspicuous in the nasal lesions with a thicker proliferating epithelium lining sinus tracts which extend downwards from the surface (Michaels and Hyams, 1975). In the nasal passages there is a strong tendency for local recurrence and a few become malignant. I n our opinion the nasal lesion resembles the inverted transitional cell bladder carcinoma more than the classical inverted urothelial papilloma.
Summary A study of 35 cases of inverted papilloma of urothelium confirms that it is a distinctive entity
and typically benign. These lesions occur mainly in males, may be multiple, and are sometimes situated elsewhere than in or near the trigone, which is their characteristic site. Their precise histogenesis remains uncertain. I t must be stressed that not all transitional cell tumours of inverted pattern are of this type; some will have the appearance of and behave as malignant tumours. The same diagnostic criteria of malignancy established for the more common exophytic papillary neoplasms must be applied also to the inverted papillary tumours herein described. We thank Dr R. C . B. Pugh and Professor R. W. Mowry for their very helpful advice in the preparation of this paper and also the Departments of Medical Art and Medical Photography of the Institute of Urology. We are also grateful to those who referred the cases in Group I1 for perniission to use their niaterial and for their help with the follow-up.
References ASSOR.D. and TAYLOR, J. N. (1970). Inverted papilloma of the bladder. Jorrrnal uf Urology, 104, 715-717. CUMMINGS, R. (1974). Inverted papilloma of the bladder. Jortrrinl of futhology, 112, 225-227. L. J., FARROW, G. M. and UTZ, D. C . (1975). Inverted papilloma of the urinary bladder. Curtcer, 36, DEMEESTER, 505-5 13. HEti-ER, L. G . and YOUNG, I . S. (1975). Inverted papilloma of bladder. Urology, 5, 688-690. HENU~RSON, D. W., ALLEN,P. W. and BOURNE, A. J. (1975). Inverted urinary papilloma. Report of live cases and review of the literature. VircliowJ Arclriv A, fatlrological Anatomy and HiJlology, 366, 177-186. Koss,L. G. (1975). Tumors of the urinary bladder. Atlas of frrriior Potlrology, 2nd series, fascicle I I . Washington, D.C., Armed Forces Institute of Pathology, pp. 10-12. Mxrz, L. R., WISHART, V. A. and GOODMAN, M. A. (1974). Inverted urothelial papilloma. P u h l o g y , 6, 37-44. L. and HYAMS, V. J. (1975). Objectivity in the classification of tuniours of the nasal cpithelium. fostMICHAELS, groilrtutr Merlicrrl Jorrrnul, 51, 695-707. PASCHKIS, R. (1927). uher Adenome der Harnblase. Zritsclrrifr fiir Urologischr Cliirtrrgie, 21, 3 15-325. PIENKOS, E. J., IGLESIAS, F. and JARLOKOW,V. R. (1973). Inverted papilloma of bladder. Urology, 2, 178-179. POTTS,I. F. and HIRST,E. (1963). Inverted papilloma of the bladder. Jorrrnal of Urology, 90, 175-179. POTTS,I . F., and HIRST,E. (1973). Inverted papilloma of the bladder. 16th Congress of the International Socicty of Urology, Amsterdam. Part 2, Paris: Doin, 535.
INVERTED PAPILLOMA OF THE LOWER URINARY TRACT
577
SALM, R. (1967). Neoplasia of the bladder and cystitis cystica. Britisli Jorrrnal of Urology, 39, 67-72. SULLIVAN, J. J., WATSON,J. G., KINGSTON, C. W. and YAXLEY, R. P. (1971). Inverted papilloma of the urinary bladder: a report of two cases. Australian and New Zealand Journal of Surgery, 41, 60-62. TRITES, A. E. W. (1969). Inverted urothelial papilloma: report of two cases. Jorirnal of Urohgy, 101, 216-219.
The Authors Katharine M. Cameron, FRCPath, Senior Lecturer in Pathology, Institute of Urology. Charles H. Lupton, Jr., MD, Visiting Professor, Department of Pathology, St Peter’s Hospitals(Pr0fessor of Pathology, University of Alabama in Birmingham, USA). Request for reprints to Dr K. Cameron, Department of Pathology, St Paul’s Hospital, 24 Endell Street, London WC2.
0
Inverted Papilloma of the Lower Urinary Tract K A T H A R I N E M. CAMERON
and
CHARLES H. LUPTON
Iiutitute of Urology and Department of Pathology, St Peter’s Hospitals, London
The classical “inverted papilloma” is a polypoidal tumour of distinctive histological appearance. It occurs mainly in males and in the region of the trigone, bladder neck or posterior urethra. The lesion appears to behave in a benign fashion and must, therefore, be distinguished from the more common tumours of transitional epithelium. The name “inverted papilloma” was first used by Potts and Hirst who described a single case in 1963; 10 years later they presented 8 more examples at the 16th Congress of the lnternaticnal Society of Urology in Amsterdam. Altogether 35 other cases have been reported under this name in the English language literature (Table I), and several apparently identical lesions have been described under a variety of different titles (e. g . Salm, 1967, case 3). The largest series is that of De Meester, Farrow and Utz (1975) who noted that 4 inverted papillomas had been reported much earlier in the German literature by Paschkis (1927) as “adenoma-like polyps” of the bladder. They are described also in the most recent AFIP fascicle on tumours of the urinary bladder (Koss, 1975). This benign urothelial lesion has been recognised in this laboratory for some years. In this paper 35 typical cases are presented and the differential diagnosis of other epithelial lesions of the bladder which are also “inverted” is discussed. The series consists of 18 patients investigated at St Peter’s Hospitals (Group 1) and 17 cases referred for histological opinion (Group 11). Sex, age, site and follow-up data have been obtained for the majority of patients in both groups; full clinical details are available only in Group I.
Clinical Features Of the 35 patients only 2 were females. The ages ranged from 22 to 78 years, with a peak incidence in the 6th and 7th decades. The most common presenting symptom in Group I was haematuria (Table I I ) which occurred in 13 patients, 3 of whom also gave a history of recent infection; this was urinary in 2 cases and epididymal in 1 and all 3 had already received treatment when first seen in hospital. 3 of the patients with haematuria also had a degree of bladder outflow obstruction. Obstructive symptoms were present altogether in 7 men, being the sole symptom in 4, but how much they were due to the tumours in the older age-group is difficult to say. 1 patient complained only of penile soreness following the passage of a stone. Intravenous urography, performed on 13 of the I8 patients, showed normal upper tracts in 10. The abnormal findings were a ureteric calculus, unilateral pyelonephritis and an enlarged kidney of uncertain aetiology in one instance each. Midstream urine specimens taken on the first visit in 16 patients proved to be sterile in 15. I n 1 of the cases with a history of urinary infection E. coli was isolated but the organisms were scanty and no pus cells were seen in the sediment. Read at the 32nd Annual Meeting of the British Association of Urological Surgeons in London, June 1976. 567
I 3
I
Potts and Hirst (1963) Trites (1969)
Assor and Taylor (1970) Sullivan el al. (1971)
5
20
35
79
DeMeester et a/., (1975)
Present series
Total
*
1
5
1 1 1 1
Pienkos e f a/. (1 973) Cummings (1 974) Matz et aI. (1974) Hefter and Young (1975) Henderson et al. (1 975)
8
2
5
1
22-79
22-78 40-61
44-78 46-62
46 68 75 65 49-79
63 56 79 59 26 71 45
See Table II
+
Main symptoms Obstruction Haematuria
+ (3)
+
Infection
*
*
1
See Fig. 1
base Posterior urethra Trigone Bladder neck Bladder neck Bladder neck Bladder neck Left lateral wall (Bladder neck (8) Trigone (5) ' Around ureteric orifices (4) Left lateral wall (1) ,Posterior urethra ( 1 )
p::::
Bladder neck Prostatic urethra Bladder neck Prostatic urethra Apex of trigone Bladder neck
Site of Turnour
Correlation between site and other features not attempted due to lack of information (Potts and Hirst) or complexity (DeMeester ef d.).
71
-~
33
15
I
1 1
8
7
2
1
I 3
Sex ~Male Female Age
Potts and Hirst (1973)
L
7
Number
Authprs
Table I Summary of Cases of Inverted Papilloma of Bladder and Posterior Urethra reported in the English Language Literature
INVERTED PAPILLOMA OF THE LOWER URINARY TRACT
569
“Anterior wall ’I ....1. “posterior wall” ....1 Pig. 1. Inverted papillomas of the lower urinary tract: site of 37 lesions in 35 patients (Groups I and 11).
Cystoscopic Appearances The lesions were sometimes described as “papillomas” but more commonly as solid-looking polyps, often pedunculated, with a smooth or slightly nodular surface; sometimes the adjectives “unusual” or “curious” were applied. The largest estimated size was 3 cm. In 2 men 2 separate lesions were present-making 37 tumours in all (Fig. 1). 17 were situated at the bladder neck, 9 around the ureteric orifices, 7 in the region of the trigone, 1 just above the interureteric bar and 1 in the urethra at the internal meatus. In 2 cases the site was stated to be the anterior and posterior wall respectively without detailed localisation.
Table I1 Main Symptoms of the 18 Patients in Group I. Group I (18 cases) Haematuria +infection +obstruction Obstruction Penile soreness
“4’
1
18
}7
570
BRITISH JOURNAL OF UROLOGY
Fig. 2. Small inverted papilloma described as a "curiou', lesion'' o n the trigone of a 63-year-old male and showing the typical polypoidal nature of the lesion. H & H 10. Enlargement x 4. Fig. 3. Surface of an inverted papilloma showing attenuated covering epithelium, with small surt'ace papillations, rrom which trabeculae or transitional epithelium extend into the underlying vascular connectivc tissuc. H & tl -10. Enlargement x 4.
Treatment
I n each case the lesion was resected, usually endoscopically, and the base fulgurated. Macroscopic Appearances
As the resected specimens (Group I ) consisted frequently of fragments their orientation was often dificult. The fixed tissue was cream to light brown in colour and the cut surface fleshy and homogeneous. The weight of the resected tissue ranged from under 0.1 g to 4.9 g. Microscopic Appearances
The typical lesion is polypoidal (Fig. 2) with a surface layer of transitional epithelium, sometimes attenuated. From the surface, trabeculae and nests of similar epithelium extend down into the supporting connective tissue to occupy much of the centre of the polyp. A few tiny surface papillations are sometimes seen (Fig. 3). In some cases the appearances suggest the exuberant formation of von Brunn's nests, which at times show central lumen formation (Fig. 4). Thc structure of other lesions is more bizarre, with branching and anastomosing cords ofepithelial cells roughly twice the thickness of normal urothelium (Fig. 5) and outlined by an intact basement membrane. These epithelial cords resemble papillary processes turned outside in, with the stroma
INVERTED PAPILLOMA OF THE LOWER URINARY TRACT
57 1
and basal layer of cells on the outside and differentiation occurring towards the centre, where there is sometimes lumen or cyst formation. The outer layers of cells are arranged at right angles to the adjacent basement membrane, while the central ones may be parallel to it, and sometimes show cytoplasmic vacuolation and nuclear pyknosis. Lumina when present (Figs. 4 and 5) are lined by flattened to low columnar cells with basal nuclei, and sometimes contain Alcian BluePeriodic Acid-Schiff (AB-PAS) positive secretions and occasionally crystals. Focal squamous metaplasia, usually in the form of epithelial whorls, is not uncommon ; intercellular bridges are present in these areas, but no keratin. Although a modest degree of cellular pleomorphism is occasionally seen, mitotic figures are characteristically absent or very rare. The cords of cells are separated by a variable amount of loose delicate stroma, often rich in capillaries. Lymphocytes and plasma cells may be scattered throughout the stroma, but are not usually prominent and, in some cases, are totally absent. In AB-PAS stained sections, secretion is often coloured by both Alcian Blue and the PAS: cytoplasmic vacuoles of cells lining cystic spaces react similarly. At times inspissated secretions within these spaces show either double staining or more commonly only strong coloration by the PAS. Small amounts of glycogen are present in the cells of areas showing squamous metaplasia. Where the epithelium is looser, especially in foci undergoing cytolysis, pale Alcian Blue staining is seen between the cells. Ground substance of the oedematous stromal tissue is also coloured faintly by Alcian Blue. Reticulin stains (modified Laidlaw’s technique) show fibres in the stroma which surround and clearly outline nests and islands of epithelial cells.
Fig. 4. Same lesion as Figure 2 showing resemblance t o von Brunn’s nests. H & E x 40. Enlargement x 4.
Fig. 5 . Centre of a n inverted papilloma showing branching cords of transitional epithelium, roughly twice the thickness of normal urothelium and resembling papillary processes turned outside in. T h e stroma,and basal layers of cells are o n the outside and there I S central lumen lbrmation in places. H & E x 40. Enlargement x 4.
BRITISH JOURNAL OF UROLOGY
572
Symptom free and cystoscopy negative Symptom free Further fulguration
2
4
6
Years
8
10
12
14
Fig. 6. Follow-up of 18 patients in Group I (St Peter’s series).
Symptom free and cystoscopy negative Symptom free
Vault lesion fulgurated Died of unrelated causes
m
2
4
8
6 Years
Fig. 7. Follow-up of 17 patients in Group I1 (referred cases).
10
12
14
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Fig. 8. Tumour from the renal pelvis of a 58-year-old woman showing histological similarity to the inverted papilloma of bladder. H & E x 16. Enlargement x 4 . Fig. 9. Edge of polypoidal transitional cell carcinoma of bladder showing a n inverted pattern of growth. Note the surPace layer of transitional epithelium a n d underlying bulbous masses of epithelial cells. H & E x 16. Enlargement x 4.
FoIIo W-UP The 18 Group I patients have been followed up for periods ranging from I 1 months to almost 13 years (Fig. 6)-11 by regular check cystoscopy. 17 have shown no evidence of local recurrence or any other urothelial lesions. In the 18th man, 2 years after his initial treatment, a tiny “mossy’ area was seen on cystoscopy at a short distance from the original site and was fulgurated without a biopsy; his bladder mucosa remains cystoscopically clear 6 years later. Follow-up information is available also for 15 of the 17 Group 11 patients (Fig. 7) the remaining 2 cases being too recent to assess. 1 female was found to have a lesion at the bladder vault which was fulgurated without biopsy 9 months after the initial resection. The remainder have developed no further urothelial lesions during periods of up to 14 years, though 3 have died of unrelated causes. Similar Lesions in the Upper Urinary Tract A large lesion (maximum dimension 3 cm) with a histological appearance similar to that of the inverted bladder papilloma (Fig. 8), but which arose in the renal pelvis of a 58-year-old female, has been shown to us by Professor A. C. Thackray, formerly of the Middlesex Hospital. The tumour was rather more complex than the bladder lesions in this series but showed essentially the same inverted pattern with very rare mitotic figures and an intact basement membrane. Treatment was by nephroureterectomy. At the same time a Wertheim’s hysterectomy was performed for carcinoma of the endometrium, whose spread caused death 4 years later.
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Fia. 10. Area resembling an inverted papilloma in a bladder tumour composed elsewhere of transitional cell carcinoma of both inverted and exophytic pattern (same case as illustrated in Figures 1 1 and 12). H RC E x 16. Enlargement i.4. Fig. 1 1 . Area of transitional cell carcinoma of inverted pattern in tumour illustrated in Figures 10 and 12. t l XI E Enlargement
x
x
10.
4.
Fig. 12. Area of transitional cell carcinoma of exophytic type in a tuniour of mixed pattern (same case Figures 10 and 1 1 ) . H RC E x 4 0 . Enlargement x 4 .
ils
illustrated in
Other Bladder Lesions having an inverted Papillary Pattern An inverted pattern is not confined to benign lesions but is seen also in certain carcinomas, the whole or part of which may be of this structure. The tumour illustrated in Figure 9, designated as a transitional cell carcinoma, is of this type and was situated on the posterior wall of the urinary bladder, medial to the left ureteric orifice, in a 66-year-old male; it measures 2.5 x 1-8 x 1.5 cm. The lesion is polypoidal with a surface layer of urothelium from which masses of cells extend downwards into the lamina propria though the basement membrane is everywhere intact. I n contrast to the slender trabeculae of the typical inverted papilloma there are bulbous masses of proliferating epithelium showing some differentiation toward the centre in places but rarely cyst formation. Mitotic figures are relatively numerous. The relationship of this lesion to the
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benign inverted papilloma seems analogous to that of papillary transitional cell carcinoma to transitional cell papilloma. This tumour had been preceded, and was followed, by multiple transitional cell carcinomas which showed both exophytic and inverted features and led to cystectomy 5 years later. Various patterns of growth may co-exist within a single neoplasm. 1 such tumour, situated at the base of the bladder of a 64-year-old female, contained 1 area indistinguishable from an inverted papilloma (Fig. 10) along with areas of transitional cell carcinoma of both inverted and exophytic patterns (Figs. 11 and 12). This tumour was removed by open diathermy excision followed by radium implant and the patient has remained tumour free for 7 years. Discussion 33 of the 35 patients with inverted papillomas of the lower urinary tract in this series were men; this concurs with other published cases in which 38 of 44 patients were males. The age range (22 to 78 years) of the patients is also similar to that reported by others, exceptions being two 79-year-olds described by Trites (1969) and Henderson, Allen and Bourne (1975). Presenting symptoms in this series were not unlike those reported elsewhere (Table I) except that bladder obstruction appeared to be less frequent. I n view of the proximity of many of the lesions to the bladder outlet obstructive symptoms are not surprising, though in many cases prostatism may be a contributory factor. The gross and microscopic appearances resemble closely those described by others. According to Koss (1975) the largest tumour recorded measured 7.5 cm in greatest diameter. The lesion reported by Cummings (1974) is unique in that it is composed entirely of squamous cells. In addition to Professor Thackray’s case, an inverted papilloma of the renal pelvis has been reported by Matz, Wishart and Goodman (1974), and Pienkos, lglesias and Jablokow (1973) state that Price has also seen such a lesion. Opinions concerning the histogenesis and nature of the lesion differ. Potts and Hirst (1963) considered it to be a neoplasm and postulated origin from subtrigonal glands but clearly this does not explain the lesions in the renal pelvis. The epithelium of the trigone and the posterior wall of the urethra down to the ejaculatory ducts-the site of origin of the great majority of the lesions-is generally believed to be of mesodermal origin, differing embryologically from the remainder of the bladder lining which is derived from the endoderm. Is it possible that this mesodermal epithelium, when stimulated, tends to proliferate into the underlying tissue rather than into the bladder cavity‘? If so then similar lesions would not be unexpected in the renal pelves and ureters which bud from the mesonephric ducts and also originate from mesoderm. Cummings (1974) believes that persistent or recurrent inflammation secondary to lower urinary tract obstruction causes these lesions. However, this seems unlikely in our patients in whom neither the histological nor the clinical findings support this idea. The significance of the crystalline material seen in a few cases is not clear but is considered secondary rather than primary. Matz et al. (1974) showed by serial sections that their lesions consisted of intercommunicating crypts in continuity with the bladder lumen and considered them to be an exaggerated form of von Brunn’s nest formation-that is, hyperplastic rather than neoplastic. Salm (1967) considered his “adenoma” to have originated in von Brunn’s nests and cystitis cystica. Origin from “the irritated bladder mucosa of proliferative cystitis” was suggested by DeMeester et al. (1975), who saw some mucosal proliferations at the margins in the majority of their lesions. They disagreed with Matz and considered the lesions to be neoplastic. In our specimens the surrounding bladder mucosa was not usually available for study. When a small amount of adjacent epithelium was present, von Brunn’s nests were more often absent than present. Nevertheless, parts of some inverted papillomas d o resemble the focal proliferative lesions common in bladder (and other) urothelium and such an origin for these tumours is therefore an attractive suggestion.
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Whatever its cause we consider this a neoplastic lesion, and if the analogy to the inverting form of transitional cell carcinoma is accepted then one has to consider, as did Trites (1969), that the lesion is an inverting variant of the urothelial papilloma. The benign course in patients with the typical inverted papilloma is well established with only 1 reported recurrence (DeMeester ri d., 1975) and no proved subsequent malignancy. The fact that 2 lesions may occur either simultaneously or consecutively does not alter the favourable outlook. Co-existence of inverted papillomatous and carcinomatous areas in some tumours does not necessarily imply that a typical lesion may undergo malignant transformation. It would appear that in the case illustrated in Figure 9 the natural history of the “inverted” form of papillary carcinoma resembles that of the exophytic papillary variety. The inverted papilloma of the bladder has been likened by some workers to the lesion with the same name seen on the lateral wall of the nose and in the nasal sinuses. There ate some important differences. The nasal mucosal lesions consist of essentially epidermoid instead of transitional epithelium; also, crypt formation is much more conspicuous in the nasal lesions with a thicker proliferating epithelium lining sinus tracts which extend downwards from the surface (Michaels and Hyams, 1975). In the nasal passages there is a strong tendency for local recurrence and a few become malignant. I n our opinion the nasal lesion resembles the inverted transitional cell bladder carcinoma more than the classical inverted urothelial papilloma.
Summary A study of 35 cases of inverted papilloma of urothelium confirms that it is a distinctive entity
and typically benign. These lesions occur mainly in males, may be multiple, and are sometimes situated elsewhere than in or near the trigone, which is their characteristic site. Their precise histogenesis remains uncertain. I t must be stressed that not all transitional cell tumours of inverted pattern are of this type; some will have the appearance of and behave as malignant tumours. The same diagnostic criteria of malignancy established for the more common exophytic papillary neoplasms must be applied also to the inverted papillary tumours herein described. We thank Dr R. C . B. Pugh and Professor R. W. Mowry for their very helpful advice in the preparation of this paper and also the Departments of Medical Art and Medical Photography of the Institute of Urology. We are also grateful to those who referred the cases in Group I1 for perniission to use their niaterial and for their help with the follow-up.
References ASSOR.D. and TAYLOR, J. N. (1970). Inverted papilloma of the bladder. Jorrrnal uf Urology, 104, 715-717. CUMMINGS, R. (1974). Inverted papilloma of the bladder. Jortrrinl of futhology, 112, 225-227. L. J., FARROW, G. M. and UTZ, D. C . (1975). Inverted papilloma of the urinary bladder. Curtcer, 36, DEMEESTER, 505-5 13. HEti-ER, L. G . and YOUNG, I . S. (1975). Inverted papilloma of bladder. Urology, 5, 688-690. HENU~RSON, D. W., ALLEN,P. W. and BOURNE, A. J. (1975). Inverted urinary papilloma. Report of live cases and review of the literature. VircliowJ Arclriv A, fatlrological Anatomy and HiJlology, 366, 177-186. Koss,L. G. (1975). Tumors of the urinary bladder. Atlas of frrriior Potlrology, 2nd series, fascicle I I . Washington, D.C., Armed Forces Institute of Pathology, pp. 10-12. Mxrz, L. R., WISHART, V. A. and GOODMAN, M. A. (1974). Inverted urothelial papilloma. P u h l o g y , 6, 37-44. L. and HYAMS, V. J. (1975). Objectivity in the classification of tuniours of the nasal cpithelium. fostMICHAELS, groilrtutr Merlicrrl Jorrrnul, 51, 695-707. PASCHKIS, R. (1927). uher Adenome der Harnblase. Zritsclrrifr fiir Urologischr Cliirtrrgie, 21, 3 15-325. PIENKOS, E. J., IGLESIAS, F. and JARLOKOW,V. R. (1973). Inverted papilloma of bladder. Urology, 2, 178-179. POTTS,I. F. and HIRST,E. (1963). Inverted papilloma of the bladder. Jorrrnal of Urology, 90, 175-179. POTTS,I . F., and HIRST,E. (1973). Inverted papilloma of the bladder. 16th Congress of the International Socicty of Urology, Amsterdam. Part 2, Paris: Doin, 535.
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SALM, R. (1967). Neoplasia of the bladder and cystitis cystica. Britisli Jorrrnal of Urology, 39, 67-72. SULLIVAN, J. J., WATSON,J. G., KINGSTON, C. W. and YAXLEY, R. P. (1971). Inverted papilloma of the urinary bladder: a report of two cases. Australian and New Zealand Journal of Surgery, 41, 60-62. TRITES, A. E. W. (1969). Inverted urothelial papilloma: report of two cases. Jorirnal of Urohgy, 101, 216-219.
The Authors Katharine M. Cameron, FRCPath, Senior Lecturer in Pathology, Institute of Urology. Charles H. Lupton, Jr., MD, Visiting Professor, Department of Pathology, St Peter’s Hospitals(Pr0fessor of Pathology, University of Alabama in Birmingham, USA). Request for reprints to Dr K. Cameron, Department of Pathology, St Paul’s Hospital, 24 Endell Street, London WC2.
