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Differentiation of colonic metaplasia from adenocarcinoma of urinary bladder
Differentiation of Colonic Metaplasia From Adenocarcinoma of Urinary Bladder LISA B, JACOBS, MD, JAMES D, BROOKS, MD, AND JONATHAN I, EPSTEIN, MD Colonic metaplasia and primary bladder adenocarcinoma are relatively uncommon entities that can have similar gross clinical appearances. Examples of colonic metaplasia histologically mimicking cancer have only rarely been reported. We retrospectively analyzed 38 cases of cystitis glandularis (18 cases of colonic metaplasia), 12 cases of adenocarcinoma of urinary bladder (two well-differentiated, WDA), and one in situ adenocarcinoma from the surgical pathology files of Johns Hopkins Hospital. Nine patients with colonic metaplasia had widespread lesions. Two showed superficial mnscularis propria involvement, mimicking adenocarcinoma; one of these cases had been diagnosed as infiltrating WDA at both an academic center and a community hospital. Dissecting mucin pools were focally seen in four cases of widespread colonic metaplasia, also mimicking cancer. One of the nine cases showed minimal cytological atypia, but no cases showed mitoses or signet ring cells. Distinguishing WDA from colonic
metaplasia was the finding in WDA of infiltrative architectural pattern (two of two), extensive mnscle invasion (two of two), moderate anaplasia (one of two), mitotic figures (two of two), and extensive mucinons pools (one of two). The diagnosis of adenocarcinoma in situ was based on anaplasia. Clinically, colonic metaplasia may resemble cancer. Histologically, colonic metaplasia may mimic cancer based on extensive involvement of the lamina propria, focal mucinous pools, focal mnscularis propria involvement, focal mild cytological atypia, and rare mitoses. Despite overlapping features with colonic metaplasia, the diagnosis of WDA is based on the greater degree and extent of these atypical findings in cancer. HUM PATHOL28:1152-1157. Copyright © 1997 by W.B. Samlders Company Key words:colonic metaplasia, cystitis glandniarls, bladder adenocarcinoma.
Cystitis glandularis is a lesion of the urinary bladder that is thought to evolve either from von Brunn's nests in the setting of chronic irritation and infection or in some cases as a congenital process reflecting partial origin of the bladder from the embryonal cloaca. >* Two distinct patterns exist. The typical form is composed of glands lined by cuboidal to columnar epithelium overlying layers of transitional epithelium (Fig 1). The second variant is termed either cystitis glandularis, intestinal type, or colonic metaplasia. Colonic metaplasia is relatively u n c o m m o n and is characterized by glands lined with mucinous columnar epithelium (goblet cells) with basally located nuclei (Fig 1). The relation between colonic metaplasia and risk of subsequent carcinoma of the bladder is unresolved. The goal of this study was not to address this issue. Rather, we call to attention the overlapping features between colonic metaplasia and adenocarcinoma of the bladder and highlight their distinguishing characteristics.
Pathology and Laboratory Medicine at The Johns Hopkins Hospital. All available pathological material was retrieved and reviewed by the authors. A retrospective analysis was conducted of 38 cases of urinary bladder lesions in which the diagnosis of cystitis glandularis appeared. Eighteen of these cases showed colonic metaplasia and were selected for evaluation of additional histological characteristics. Twelve cases of primary adenocarcinoma of the urinary bladder were available for review and were evaluated for similar histological characteristics.
MATERIALS AND METHODS
Pathological Data Each case was evaluated for the following characteristics: extent of lesion, dissecting mucin pools, pattern and degree of infiltration of musculafis propfia, cytological atypia (nuclear hyperchromasia, pleomorphism, and pseudostratificafion), mitotic activity, presence of signet ring cells, and necrosis.
Clinical Data Clinical follow-up was obtained for the nine cases of colonic metaplasia that were extensive or mimicked adenocarcinoma and for the three cases of well-differentiated or in situ adenocarcinoma.
Case Selection All patients for whom a diagnosis of cystitis glandularis or primary bladder adenocarcinoma was made between 1984 amd 1995 were identified by a search of the surgical pathology and consultation database maintained by the Department of From the Department of Pathology, The University of Kentucky College of Medicine, Lexington, K~(;and the Departments of Pathology and Urology, The Johns Hopkins School of Medicine, Baltimore, MD. Accepted for publication January 31, 1997. Address correspondence and reprint requests to Jonathan I. Epstein, MD, Department of Pathology, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287-6971. Copyright © 1997 by W.B. Sannders Company 0046-8177/97/2810-000755.00/0
RESULTS O f t h e 18 cases o f c o l o n i c m e t a p l a s i a , n i n e s h o w e d w i d e s p r e a d lesions a n d w e r e c o n s i d e r e d to r e p r e s e n t d i a g n o s t i c d i l e m m a s (Fig 2) ( T a b l e 1). Two o f t h e s e cases s h o w e d s u p e r f i c i a l m u s c u l a r i s p r o p r i a involvem e n t m i m i c k i n g invasive a d e n o c a r c i n o m a (Figs 3, 4). O n e o f t h e two cases h a d b e e n d i a g n o s e d as i n f i l t r a t i n g w e l l - d i f f e r e n t i a t e d a d e n o c a r c i n o m a at b o t h a c o m m u nity h o s p i t a l a n d a n a c a d e m i c c e n t e r (case 2, Fig 4). D i s s e c t i n g m u c i n p o o l s w e r e focally p r e s e n t in f o u r o f t h e n i n e cases o f c o l o n i c m e t a p l a s i a , also m i m i c k i n g a d e n o c a r c i n o m a (Fig 5). I n a n o t h e r case, c a u t e r y arti-
1152
URINARY BLADDER METAPLASIAVERSUSADENOCARCINOMA (Jacobs et al)
FIGURE 1. Cystitis glandularis of the usual type (left & right) with colonic metaplasia (center).
FIGURE 2. Extensive colonic metaplasia (case 9).
fact within colonic metaplasia mimicked colloid carcinoma. One case showed minimal cytological atypia, with slight pseudostratification and enlargement of nuclei when c o m p a r e d with neighboring glands of colonic metaplasia and a mitotic figure (not shown) (Fig 6). No cases showed signet ring cells or necrosis. We identified two cases of well-differentiated adenocarcinoma and one in situ adenocarcinoma. Both adenocarcinomas displayed infiltration of the muscularis propria. T h e pattern of infiltration of muscularis propria differed from colonic metaplasia in that it showed less of a broad, pushing front, appeared more irregularly infiltrating, and was accompanied by a desmoplastic response (Fig 7). Moderate cytological atypia was focally present in one of the two cases of infiltrating adenocarcinoma, and in the case of in situ adenocarcin o m a (Figs 8, 9). Mitotic figures were seen in all cases of adenocarcinoma. Extensive dissecting mucin pools
(Fig 10) were present in one case of infiltrating adenocarcinoma. Clinical follow-up and predisposing conditions of the nine cases of colonic metaplasia are depicted in Table 2. Assessing the natural history of these lesions was difficult because of either insufficient follow-up or complete resection of the lesion. Four of the patients had bladder extrophy, and a fifth had a neurogenic bladder after a spinal cord injury. No predisposing conditions were f o u n d in the other four cases of extensive colonic metaplasia. The patient whose denocarcinoma is illustrated in Fig 7 had unresectable tumor and developed metastases to the lung shortly after diagnosis of the bladder primary (Table 2). The other case of well-differentiated adenocarcinoma (Figs 8, 10) was treated by partial cystectomy. The tumor infiltrated through the muscularis propria into perivesicle adipose tissue; the patient is free of disease 4 years after resection. The one case of
TABLE 1.
Histological Characteristics of Nine Cases of Colonic Metaplasia and Three Cases of Well-Differentiated Primary Bladder Adenocarcinoma (WDA) Dissecting
Muscularis Propria
Cytological
Mitotic
Signet
Pathology
Case
Extent
Pools
Involvement
Atypia
Figures
Cells
Colonic metaplasia
1 9*
+ + ++
+ +
+
_
_ _
-
_
WDA
NOTE:
+, minimal;
Mucinous
3
++
.
4
++
-
.
5 6
++ ++
+ .
. .
.
.
.
.
.
.
-
7
++
.
8
++
-
+
_
_
9 l0 t
++ +
+ _
_
+ ++
+ ++
11
+++
12
+++
++,
moderate;
+ ++,
* O r i g i n a l l y c l a s s i f i e d as w e l l - d i f f e r e n t i a t e d J- A d e n o c a r c i n o m a in situ.
-
+++
+
+
+
+++
extensive. adenocarcinoma.
1153
_
++
++
++
Necrosis
HUMAN PATHOLOGY
Volume 28, No. 10 (October 1997)
FIGURE 3. Colonic metaplasia with a single focus of superficial muscularis propria involvement mimicking invasive adenocarcinoma (case 8).
in situ adenocarcinoma had coexistent flat transitional cell carcinoma in situ. The patient was treated with Bacillus Calmette-Gudrin (BCG), yet developed an extensive muscle invasive transitional cell carcinoma 2 years after diagnosis. Despite radiation therapy and chemotherapy, the patient died 3 months after discovery of invasive tumor.
FIGURE 5. Dissecting mucin pools were focally present in four cases of colonic metaplasia mimicking adenocarcinoma (case 5).
glandularis. The high incidence of colonic metaplasia among our cases of cystitis glandularis can probably be attributed to pathologists' greater likelihood to report colonic metaplasia than ordinary cystitis glandularis.
DISCUSSION Cystitis glandularis of the intestinal type (colonic metaplasia) is a relatively u n c o m m o n finding relative to cystitis cystica and the nonintestinal pattern of cystitis
FIGURE 4. Broad, pushing fronts of colonic metaplasia extending just beyond bundles of smooth muscle of muscularis propria (case 2).
FIGURE 6. One case of colonic metaplasia showed minimal cytological atypia (top), with slight pseudostratification and enlargement of nuclei when compared with more typical colonic metaplasia (bottom) (case 9),
1154
URINARY BLADDER METAPLASiA VERSUS ADENOCARCINOMA (Jacobs et al)
FIGURE 8. Well-differentiated adenocarcinoma of the bladder, which in areas showed marked architectural and moderate cytological atypia (case 12).
m o r e than 2 years, a d e n o c a r c i n o m a developed in two patients and undifferentiated carcinoma in one. Young and others have also described individual cases of progression f r o m colonic metaplasia to primary bladder
FIGURE 7. (A) Well-differentiated a d e n o c a r c i n o m a of the bladder with an infiltrative pattern and accompanying desmoplastic reaction. The pattern of infiltration of muscularis propria differed from colonic metaplasia in that it a p p e a r e d more irregularly infiltrating (case 11). (B) Well-differentiated adenocarcinoma with minimal cytological atypia (case 11).
T h e relation of cystitis glandularis of the intestinal type (colonic metaplasia) to carcinoma of the bladder remains unclear.8-12Bullock et al 9 reviewed the literature and described 10 cases in which "substantial areas of transitional cell epithelium were completely replaced by colonic mucosa."9 O f the three patients followed for 1155
FIGURE 9. Adenocarclnoma in situ of the bladder. Note nuclear hyperchromasia and pleomorphism (case 10).
HUMAN PATHOLOGY
Volume 28, No. 10 (October 1997)
FIGURE I0. Well-differentiated adenocarcinoma of bladder with extensive dissecting mucin pools (case 12),
adenocarcinoma. 9'11-14 It is difficult to make sweeping statements based on the limited n u m b e r of cases evaluated, a n d the significance of focal colonic metaplasia is even m o r e obscure. In o u r series, m a n y of the patients had b l a d d e r extrophy and were treated either by partial resection or cystectomy, such that the natural history could not be determined. P r i m a r y a d e n o c a r c i n o m a of the urinary b l a d d e r is a relatively rare malignancy, a c c o u n t i n g for 0.5% to 2.0% of all p r i m a r y b l a d d e r tumors. 7'15q7 However, in b l a d d e r e x t r o p h y , p r i m a r y a d e n o c a r c i n o m a accounts for g r e a t e r t h a n 90% malignancies. 18'19Several a u t h o r s have discussed theories r e g a r d i n g the origin of p r i m a r y b l a d d e r a d e n o c a r c i n o m a , a n d m o s t agree on a distinction b e t w e e n those arising f r o m u r a c h a l r e m n a n t s a n d those of n o n u r a c h a l origin. M o r e t h a n o n e theory has b e e n p r o p o s e d to explain a d e n o c a r c i n o m a s of n o n u r a c h a l origin, including m a l d e v e l o p m e n t in cloacal division a n d m e t a p l a s i a o f transitional e p i t h e l i u m . 1'8'14'16'17'19'2° A l t h o u g h these a u t h o r s dis-
TABLE 2.
cuss the histological a p p e a r a n c e of p r i m a r y a d e n o c a r cinomas, they do n o t address the distinction b e t w e e n colonic m e t a p l a s i a a n d a d e n o c a r c i n o m a . T a l b e r t a n d Y o u n g 6 discuss o n e case of a p r i m a r y a d e n o c a r c i n o m a of the urinary b l a d d e r with loci of deceptively b e n i g n histological a p p e a r a n c e . T h e y c o n c l u d e that any case with architectural or cytological atypia shoutd be evalu a t e d cautiously. Occasionally, extensive colonic metaplasia is difficult to distinguish f r o m a d e n o c a r c i n o m a of the urinary bladder. Both may present clinically as large, exophytic masses, a n d histologically, the benign lesion may mimic well-differentiated a d e n o c a r c i n o m a . 2'3'58 A l t h o u g h t h e r e was overlap b e t w e e n colonic m e t a p l a s i a a n d well-differentiated a d e n o c a r c i n o m a in s o m e o f the histological features (dissecting mucin, infiltration o f muscularis p r o p r i a , atypia, a n d mitoses), the d e g r e e a n d e x t e n t of these findings diff e r e d b e t w e e n the two conditions. In c o n t r a s t to the extensive m u c i n o u s pools seen in s o m e adenocarcinomas, colonic m e t a p l a s i a h a d only focal areas of m u c i n extravasation. W h e r e a s a d e n o c a r c i n o m a s typically showed d e e p muscle invasion, as was the case in the two well-differentiated a d e n o c a r c i n o m a s in o u r series, the muscle invasion seen in colonic m e t a p l a s i a was m o r e limited. In o n e o f o u r cases, muscle infiltration consisted o f a p u s h i n g b o r d e r of extensive coionic metaplasia, which e x t e n d e d j u s t past superficial muscle b u n d l e s of the muscularis p r o p r i a . In the o t h e r case, t h e r e was o n e small focus of colonic metaplasia in muscle in an extensively s a m p l e d cystectomy s p e c i m e n that otherwise showed typical colonic metaplasia c o n f i n e d to the mucosa. A l t h o u g h rare a d e n o c a r c i n o m a s may show b l a n d cytology, m o s t will have areas of the t u m o r with overt cytological atypia. T h e atypia seen in colonic m e t a p l a s i a is n o t as severe a n d by itself would n o t be diagnostic of malignancy. Similarly, mitoses, a l t h o u g h f r e q u e n t in a d e n o c a r c i n o m a , were f o u n d only rarely in only o n e case o f colonic metaplasia. O t h e r cases of a d e n o c a r c i n o m a that are less d i f f e r e n t i a t e d show signet ceils a n d necrosis, which are n o t f o u n d in colonic metaplasia. Recogni-
Follow-Up of Patients With Extensive Cystitis Glanduiaris and Well-Differentiated A d e n o c a r c i n o m a (WDA)
Pathology
Case
Age
Predisposing Conditions
Procedure
Follow-up
Colonic metaplasia
1 2 3 4 5 6 7 8 9 10 11 12
7 30 36 2 38 18 33 53 52 87 54 36
Extrophy None Extrophy Extrophy None None Extrophy N e u r o g e n i c bladder None None None None
Biopsy Transurethral resection Cystectomy Cystectomy Partial resection Biopsy Partial resection Cystectomy Transurethral resection Biopsy T r a n s u r e t h r a l resection Partial cystectomy
Lost to follow-up Lost to follow-up NED 9 years NED 6 years NED 3 years NED 1 year Lost to follow-up NED 4 years NED 9 years Dead of cancer 2 years Metastases to l u n g 1 year NED 4 years
WDA
Abbreviation: NED, no evidence of disease.
1156
URINARY BLADDER METAPLASIA VERSUS ADENOCARCINOMA (Jacobs et al)
tion of the overlapping and differentiating features between colonic metaplasia and adenocarcinoma will minimize the potential of misdiagnosis. ADDENDUM Another report on this topic has recently been published. Young RH and Bostwick DG: Florid cystitis glandularis of intestinal type with mucin extravasation: A mimic of adenocarcinoma. Am J Surg Pathol 20:14621468, 1996.
REFERENCES 1. Bell TE, Wendel RG: Cystitis glandularis: Benign or malignant? J Urol 100:462-465, 1968 2. Emmett JL, McDonald JR: Proliferation of glands of the urinary bladder simulating malignant neoplasm. J Uro148:25%265, 1942 3. Patch FS, Rhea LJ: The genesis and development of Brunn's nests and their relation to cystitis cystica, cystitis glandularis and primary adenocarcinoma of the bladder. Can Med Assoc J 33:597-606, 1935 4. Davies G, Castro JE: Cystitis glandularis. Urology 10:128-129, 1977 5. Sauer HR, Blick MS: Cystitis glandularis: A consideration of symptoms, diagnosis and clinical course of the disease. J Urol 61:446458, 1948 6. Talbert ML, Young RH: Carcinomas of the urinary bladder with deceptively benign-appearing foci: A report of three cases. Am J Surg Pathol 13:374-381, 1989
1157
7. Thomas DG, Ward AIM, Williams JL: A study of 52 cases of adenocarcinoma of the bladder. B r J Urol 43:4-15, 1971 8. Young RH: Pathology of the Urinary- Bladder: Contemporary Issues in Surgical Pathology. New York, NY, Churchill Livingstone, 1989 9. Bullock PS, Thoni DE, Murphy WM: The significance of colonic mucosa (intestinal metaplasia) involving the urinary tract. Cancer 59:2086-2090, 1987 10. Shaw JL, Gislason J, hnbriglia JE: Transition of cystitis glandularis to primary adenocarcinoma of the bladder.J Urol 79:815-822, 1958 11. Edwards PD, Hurm RA, Jaeschke WH: Conversion of cystitis glandularis to adenocarcinoma. J Urol 108:568-570, 1972 12. Susmano D, Rubenstein AB, Dakin AR, et ah Cystitis glandularis and adenocarcinoma of the bladder. J Urol 105:671-674, 1971 13. Lin JI, Tseng CH, Choy C, et al: Diffuse cystitis glandularis associated with adenocarcinomatous change. Urology 15:411-415, 1980 14. Young RH, Parkhurst EC. Mucinous adenocarcinoma of bladder. Urology 24:192-195, 1984 15. Abenoza P, Manivel C, Fraley EE: Primary adenocarcinoma of urinary bladder: Clinicopathologic study of 16 cases. Urology 29:914, 1987 16. Grignon DJ, RoJY, Ayala AG, et al: Primary adenocarcinoma of the urinary bladder. Cancer 67:2165-2172, 1991 17. Mostofi FK, Thomson RV, Dean AL: Mucous adenocarcinoma of the urinary bladder. Cancer 8:741-757, 1955 18. Culp D: The histology of the exstrophied bladder. J Urol 91:538-548, 1964 19. McIntoshJF, Worley G: Adenocarcinoma arising in extrophy of the bladder: Report of two cases and review of the literature. J Urol 73:820-829, 1955 20. Wells M, Anderson K: Mucin histochemistry of cystitis glandularis and primary adenocarcinoma of the urinary bladder. Arch Pathol Lab Med 109:59-61, 1985
metaplasia was the finding in WDA of infiltrative architectural pattern (two of two), extensive mnscle invasion (two of two), moderate anaplasia (one of two), mitotic figures (two of two), and extensive mucinons pools (one of two). The diagnosis of adenocarcinoma in situ was based on anaplasia. Clinically, colonic metaplasia may resemble cancer. Histologically, colonic metaplasia may mimic cancer based on extensive involvement of the lamina propria, focal mucinous pools, focal mnscularis propria involvement, focal mild cytological atypia, and rare mitoses. Despite overlapping features with colonic metaplasia, the diagnosis of WDA is based on the greater degree and extent of these atypical findings in cancer. HUM PATHOL28:1152-1157. Copyright © 1997 by W.B. Samlders Company Key words:colonic metaplasia, cystitis glandniarls, bladder adenocarcinoma.
Cystitis glandularis is a lesion of the urinary bladder that is thought to evolve either from von Brunn's nests in the setting of chronic irritation and infection or in some cases as a congenital process reflecting partial origin of the bladder from the embryonal cloaca. >* Two distinct patterns exist. The typical form is composed of glands lined by cuboidal to columnar epithelium overlying layers of transitional epithelium (Fig 1). The second variant is termed either cystitis glandularis, intestinal type, or colonic metaplasia. Colonic metaplasia is relatively u n c o m m o n and is characterized by glands lined with mucinous columnar epithelium (goblet cells) with basally located nuclei (Fig 1). The relation between colonic metaplasia and risk of subsequent carcinoma of the bladder is unresolved. The goal of this study was not to address this issue. Rather, we call to attention the overlapping features between colonic metaplasia and adenocarcinoma of the bladder and highlight their distinguishing characteristics.
Pathology and Laboratory Medicine at The Johns Hopkins Hospital. All available pathological material was retrieved and reviewed by the authors. A retrospective analysis was conducted of 38 cases of urinary bladder lesions in which the diagnosis of cystitis glandularis appeared. Eighteen of these cases showed colonic metaplasia and were selected for evaluation of additional histological characteristics. Twelve cases of primary adenocarcinoma of the urinary bladder were available for review and were evaluated for similar histological characteristics.
MATERIALS AND METHODS
Pathological Data Each case was evaluated for the following characteristics: extent of lesion, dissecting mucin pools, pattern and degree of infiltration of musculafis propfia, cytological atypia (nuclear hyperchromasia, pleomorphism, and pseudostratificafion), mitotic activity, presence of signet ring cells, and necrosis.
Clinical Data Clinical follow-up was obtained for the nine cases of colonic metaplasia that were extensive or mimicked adenocarcinoma and for the three cases of well-differentiated or in situ adenocarcinoma.
Case Selection All patients for whom a diagnosis of cystitis glandularis or primary bladder adenocarcinoma was made between 1984 amd 1995 were identified by a search of the surgical pathology and consultation database maintained by the Department of From the Department of Pathology, The University of Kentucky College of Medicine, Lexington, K~(;and the Departments of Pathology and Urology, The Johns Hopkins School of Medicine, Baltimore, MD. Accepted for publication January 31, 1997. Address correspondence and reprint requests to Jonathan I. Epstein, MD, Department of Pathology, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287-6971. Copyright © 1997 by W.B. Sannders Company 0046-8177/97/2810-000755.00/0
RESULTS O f t h e 18 cases o f c o l o n i c m e t a p l a s i a , n i n e s h o w e d w i d e s p r e a d lesions a n d w e r e c o n s i d e r e d to r e p r e s e n t d i a g n o s t i c d i l e m m a s (Fig 2) ( T a b l e 1). Two o f t h e s e cases s h o w e d s u p e r f i c i a l m u s c u l a r i s p r o p r i a involvem e n t m i m i c k i n g invasive a d e n o c a r c i n o m a (Figs 3, 4). O n e o f t h e two cases h a d b e e n d i a g n o s e d as i n f i l t r a t i n g w e l l - d i f f e r e n t i a t e d a d e n o c a r c i n o m a at b o t h a c o m m u nity h o s p i t a l a n d a n a c a d e m i c c e n t e r (case 2, Fig 4). D i s s e c t i n g m u c i n p o o l s w e r e focally p r e s e n t in f o u r o f t h e n i n e cases o f c o l o n i c m e t a p l a s i a , also m i m i c k i n g a d e n o c a r c i n o m a (Fig 5). I n a n o t h e r case, c a u t e r y arti-
1152
URINARY BLADDER METAPLASIAVERSUSADENOCARCINOMA (Jacobs et al)
FIGURE 1. Cystitis glandularis of the usual type (left & right) with colonic metaplasia (center).
FIGURE 2. Extensive colonic metaplasia (case 9).
fact within colonic metaplasia mimicked colloid carcinoma. One case showed minimal cytological atypia, with slight pseudostratification and enlargement of nuclei when c o m p a r e d with neighboring glands of colonic metaplasia and a mitotic figure (not shown) (Fig 6). No cases showed signet ring cells or necrosis. We identified two cases of well-differentiated adenocarcinoma and one in situ adenocarcinoma. Both adenocarcinomas displayed infiltration of the muscularis propria. T h e pattern of infiltration of muscularis propria differed from colonic metaplasia in that it showed less of a broad, pushing front, appeared more irregularly infiltrating, and was accompanied by a desmoplastic response (Fig 7). Moderate cytological atypia was focally present in one of the two cases of infiltrating adenocarcinoma, and in the case of in situ adenocarcin o m a (Figs 8, 9). Mitotic figures were seen in all cases of adenocarcinoma. Extensive dissecting mucin pools
(Fig 10) were present in one case of infiltrating adenocarcinoma. Clinical follow-up and predisposing conditions of the nine cases of colonic metaplasia are depicted in Table 2. Assessing the natural history of these lesions was difficult because of either insufficient follow-up or complete resection of the lesion. Four of the patients had bladder extrophy, and a fifth had a neurogenic bladder after a spinal cord injury. No predisposing conditions were f o u n d in the other four cases of extensive colonic metaplasia. The patient whose denocarcinoma is illustrated in Fig 7 had unresectable tumor and developed metastases to the lung shortly after diagnosis of the bladder primary (Table 2). The other case of well-differentiated adenocarcinoma (Figs 8, 10) was treated by partial cystectomy. The tumor infiltrated through the muscularis propria into perivesicle adipose tissue; the patient is free of disease 4 years after resection. The one case of
TABLE 1.
Histological Characteristics of Nine Cases of Colonic Metaplasia and Three Cases of Well-Differentiated Primary Bladder Adenocarcinoma (WDA) Dissecting
Muscularis Propria
Cytological
Mitotic
Signet
Pathology
Case
Extent
Pools
Involvement
Atypia
Figures
Cells
Colonic metaplasia
1 9*
+ + ++
+ +
+
_
_ _
-
_
WDA
NOTE:
+, minimal;
Mucinous
3
++
.
4
++
-
.
5 6
++ ++
+ .
. .
.
.
.
.
.
.
-
7
++
.
8
++
-
+
_
_
9 l0 t
++ +
+ _
_
+ ++
+ ++
11
+++
12
+++
++,
moderate;
+ ++,
* O r i g i n a l l y c l a s s i f i e d as w e l l - d i f f e r e n t i a t e d J- A d e n o c a r c i n o m a in situ.
-
+++
+
+
+
+++
extensive. adenocarcinoma.
1153
_
++
++
++
Necrosis
HUMAN PATHOLOGY
Volume 28, No. 10 (October 1997)
FIGURE 3. Colonic metaplasia with a single focus of superficial muscularis propria involvement mimicking invasive adenocarcinoma (case 8).
in situ adenocarcinoma had coexistent flat transitional cell carcinoma in situ. The patient was treated with Bacillus Calmette-Gudrin (BCG), yet developed an extensive muscle invasive transitional cell carcinoma 2 years after diagnosis. Despite radiation therapy and chemotherapy, the patient died 3 months after discovery of invasive tumor.
FIGURE 5. Dissecting mucin pools were focally present in four cases of colonic metaplasia mimicking adenocarcinoma (case 5).
glandularis. The high incidence of colonic metaplasia among our cases of cystitis glandularis can probably be attributed to pathologists' greater likelihood to report colonic metaplasia than ordinary cystitis glandularis.
DISCUSSION Cystitis glandularis of the intestinal type (colonic metaplasia) is a relatively u n c o m m o n finding relative to cystitis cystica and the nonintestinal pattern of cystitis
FIGURE 4. Broad, pushing fronts of colonic metaplasia extending just beyond bundles of smooth muscle of muscularis propria (case 2).
FIGURE 6. One case of colonic metaplasia showed minimal cytological atypia (top), with slight pseudostratification and enlargement of nuclei when compared with more typical colonic metaplasia (bottom) (case 9),
1154
URINARY BLADDER METAPLASiA VERSUS ADENOCARCINOMA (Jacobs et al)
FIGURE 8. Well-differentiated adenocarcinoma of the bladder, which in areas showed marked architectural and moderate cytological atypia (case 12).
m o r e than 2 years, a d e n o c a r c i n o m a developed in two patients and undifferentiated carcinoma in one. Young and others have also described individual cases of progression f r o m colonic metaplasia to primary bladder
FIGURE 7. (A) Well-differentiated a d e n o c a r c i n o m a of the bladder with an infiltrative pattern and accompanying desmoplastic reaction. The pattern of infiltration of muscularis propria differed from colonic metaplasia in that it a p p e a r e d more irregularly infiltrating (case 11). (B) Well-differentiated adenocarcinoma with minimal cytological atypia (case 11).
T h e relation of cystitis glandularis of the intestinal type (colonic metaplasia) to carcinoma of the bladder remains unclear.8-12Bullock et al 9 reviewed the literature and described 10 cases in which "substantial areas of transitional cell epithelium were completely replaced by colonic mucosa."9 O f the three patients followed for 1155
FIGURE 9. Adenocarclnoma in situ of the bladder. Note nuclear hyperchromasia and pleomorphism (case 10).
HUMAN PATHOLOGY
Volume 28, No. 10 (October 1997)
FIGURE I0. Well-differentiated adenocarcinoma of bladder with extensive dissecting mucin pools (case 12),
adenocarcinoma. 9'11-14 It is difficult to make sweeping statements based on the limited n u m b e r of cases evaluated, a n d the significance of focal colonic metaplasia is even m o r e obscure. In o u r series, m a n y of the patients had b l a d d e r extrophy and were treated either by partial resection or cystectomy, such that the natural history could not be determined. P r i m a r y a d e n o c a r c i n o m a of the urinary b l a d d e r is a relatively rare malignancy, a c c o u n t i n g for 0.5% to 2.0% of all p r i m a r y b l a d d e r tumors. 7'15q7 However, in b l a d d e r e x t r o p h y , p r i m a r y a d e n o c a r c i n o m a accounts for g r e a t e r t h a n 90% malignancies. 18'19Several a u t h o r s have discussed theories r e g a r d i n g the origin of p r i m a r y b l a d d e r a d e n o c a r c i n o m a , a n d m o s t agree on a distinction b e t w e e n those arising f r o m u r a c h a l r e m n a n t s a n d those of n o n u r a c h a l origin. M o r e t h a n o n e theory has b e e n p r o p o s e d to explain a d e n o c a r c i n o m a s of n o n u r a c h a l origin, including m a l d e v e l o p m e n t in cloacal division a n d m e t a p l a s i a o f transitional e p i t h e l i u m . 1'8'14'16'17'19'2° A l t h o u g h these a u t h o r s dis-
TABLE 2.
cuss the histological a p p e a r a n c e of p r i m a r y a d e n o c a r cinomas, they do n o t address the distinction b e t w e e n colonic m e t a p l a s i a a n d a d e n o c a r c i n o m a . T a l b e r t a n d Y o u n g 6 discuss o n e case of a p r i m a r y a d e n o c a r c i n o m a of the urinary b l a d d e r with loci of deceptively b e n i g n histological a p p e a r a n c e . T h e y c o n c l u d e that any case with architectural or cytological atypia shoutd be evalu a t e d cautiously. Occasionally, extensive colonic metaplasia is difficult to distinguish f r o m a d e n o c a r c i n o m a of the urinary bladder. Both may present clinically as large, exophytic masses, a n d histologically, the benign lesion may mimic well-differentiated a d e n o c a r c i n o m a . 2'3'58 A l t h o u g h t h e r e was overlap b e t w e e n colonic m e t a p l a s i a a n d well-differentiated a d e n o c a r c i n o m a in s o m e o f the histological features (dissecting mucin, infiltration o f muscularis p r o p r i a , atypia, a n d mitoses), the d e g r e e a n d e x t e n t of these findings diff e r e d b e t w e e n the two conditions. In c o n t r a s t to the extensive m u c i n o u s pools seen in s o m e adenocarcinomas, colonic m e t a p l a s i a h a d only focal areas of m u c i n extravasation. W h e r e a s a d e n o c a r c i n o m a s typically showed d e e p muscle invasion, as was the case in the two well-differentiated a d e n o c a r c i n o m a s in o u r series, the muscle invasion seen in colonic m e t a p l a s i a was m o r e limited. In o n e o f o u r cases, muscle infiltration consisted o f a p u s h i n g b o r d e r of extensive coionic metaplasia, which e x t e n d e d j u s t past superficial muscle b u n d l e s of the muscularis p r o p r i a . In the o t h e r case, t h e r e was o n e small focus of colonic metaplasia in muscle in an extensively s a m p l e d cystectomy s p e c i m e n that otherwise showed typical colonic metaplasia c o n f i n e d to the mucosa. A l t h o u g h rare a d e n o c a r c i n o m a s may show b l a n d cytology, m o s t will have areas of the t u m o r with overt cytological atypia. T h e atypia seen in colonic m e t a p l a s i a is n o t as severe a n d by itself would n o t be diagnostic of malignancy. Similarly, mitoses, a l t h o u g h f r e q u e n t in a d e n o c a r c i n o m a , were f o u n d only rarely in only o n e case o f colonic metaplasia. O t h e r cases of a d e n o c a r c i n o m a that are less d i f f e r e n t i a t e d show signet ceils a n d necrosis, which are n o t f o u n d in colonic metaplasia. Recogni-
Follow-Up of Patients With Extensive Cystitis Glanduiaris and Well-Differentiated A d e n o c a r c i n o m a (WDA)
Pathology
Case
Age
Predisposing Conditions
Procedure
Follow-up
Colonic metaplasia
1 2 3 4 5 6 7 8 9 10 11 12
7 30 36 2 38 18 33 53 52 87 54 36
Extrophy None Extrophy Extrophy None None Extrophy N e u r o g e n i c bladder None None None None
Biopsy Transurethral resection Cystectomy Cystectomy Partial resection Biopsy Partial resection Cystectomy Transurethral resection Biopsy T r a n s u r e t h r a l resection Partial cystectomy
Lost to follow-up Lost to follow-up NED 9 years NED 6 years NED 3 years NED 1 year Lost to follow-up NED 4 years NED 9 years Dead of cancer 2 years Metastases to l u n g 1 year NED 4 years
WDA
Abbreviation: NED, no evidence of disease.
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URINARY BLADDER METAPLASIA VERSUS ADENOCARCINOMA (Jacobs et al)
tion of the overlapping and differentiating features between colonic metaplasia and adenocarcinoma will minimize the potential of misdiagnosis. ADDENDUM Another report on this topic has recently been published. Young RH and Bostwick DG: Florid cystitis glandularis of intestinal type with mucin extravasation: A mimic of adenocarcinoma. Am J Surg Pathol 20:14621468, 1996.
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7. Thomas DG, Ward AIM, Williams JL: A study of 52 cases of adenocarcinoma of the bladder. B r J Urol 43:4-15, 1971 8. Young RH: Pathology of the Urinary- Bladder: Contemporary Issues in Surgical Pathology. New York, NY, Churchill Livingstone, 1989 9. Bullock PS, Thoni DE, Murphy WM: The significance of colonic mucosa (intestinal metaplasia) involving the urinary tract. Cancer 59:2086-2090, 1987 10. Shaw JL, Gislason J, hnbriglia JE: Transition of cystitis glandularis to primary adenocarcinoma of the bladder.J Urol 79:815-822, 1958 11. Edwards PD, Hurm RA, Jaeschke WH: Conversion of cystitis glandularis to adenocarcinoma. J Urol 108:568-570, 1972 12. Susmano D, Rubenstein AB, Dakin AR, et ah Cystitis glandularis and adenocarcinoma of the bladder. J Urol 105:671-674, 1971 13. Lin JI, Tseng CH, Choy C, et al: Diffuse cystitis glandularis associated with adenocarcinomatous change. Urology 15:411-415, 1980 14. Young RH, Parkhurst EC. Mucinous adenocarcinoma of bladder. Urology 24:192-195, 1984 15. Abenoza P, Manivel C, Fraley EE: Primary adenocarcinoma of urinary bladder: Clinicopathologic study of 16 cases. Urology 29:914, 1987 16. Grignon DJ, RoJY, Ayala AG, et al: Primary adenocarcinoma of the urinary bladder. Cancer 67:2165-2172, 1991 17. Mostofi FK, Thomson RV, Dean AL: Mucous adenocarcinoma of the urinary bladder. Cancer 8:741-757, 1955 18. Culp D: The histology of the exstrophied bladder. J Urol 91:538-548, 1964 19. McIntoshJF, Worley G: Adenocarcinoma arising in extrophy of the bladder: Report of two cases and review of the literature. J Urol 73:820-829, 1955 20. Wells M, Anderson K: Mucin histochemistry of cystitis glandularis and primary adenocarcinoma of the urinary bladder. Arch Pathol Lab Med 109:59-61, 1985