Histogenesis of nonurothelial carcinomas in the human and rat urinary bladder

Exp Toxic Pathol 1998; 50: 341-355 Gustav Fischer Verlag

Center of Pathology of the University of Gottingen, Germany

Histogenesis of nonurothelial carcinomas in the human and rat urinary bladder* EKKEHARD KUNZE

With 14 figures and 1 table

Address for correspondence: Prof. Dr. E. KUNZE, Center of Pathology of the University of Gottingen, Robert-Koch-StraBe 40, D-37075 Gottingen, Germany.

Key words: Urinary bladder, carcinoma; Nonurothelial carcinoma; Transitinal cell carcinoma.

Summary

Introduction

The histogenesis of nonurothelial carcinomas (sqamous cell carcinoma, common adenocarcinoma, clear cell adenocarcinoma, signet ring cell adenocarcinoma and undifferentiated carcinomas) of the urinary bladder is difficult to understand, since the bladder is normally lined exclusively by transitional cell epithelium and contains no otherwise specified epithelia. In the present study we analysed the morphology and development of nontransitional cell carcinomas of the human and comparatively of the rat urinary bladder in an attempt to elucidate their histogenetic derivation. There is strong evidence that the underlying histogenetic principle consists in the well-known pluripotent metaplastic potency (squamous, columnar, goblet and signet ring cell, glandular and so-called nephrogenic metaplasia) of the normal and neoplastic urothelium as well, due to the complex embryologic origin of the bladder. Our findings indicate that squamous cell carcinomas, common and clear cell adenocarcinomas, and signet ring cell adenocarcinomas mainly arise secondarily from preexisting, predominantly solid transitional cell carcinomas by focally beginning and diffusely progressing metaplastic changes of various types. The second histogenetic pathway consists in the formation from primary metaplasias of the transitional cell epithelium in situ. Undifferentiated carcinomas (small, large and sarcomatoid subtypes) develop from preexistent solid urothelial carcinomas by a cellular dedifferentiation. Recognition of transitional cell carcinomas characterised by focal metaplastic processes or cellular dedifferentiation seems to be important from a clinical point of view, because of their probably more malignant biologic behaviour compared with uniformly differentiated pure urothelial carcinomas. Our comparative morphologic analysis of nonurothelial carcinomas and their histogenesis has demonstrated that the findings in the human and rat urinary bladder are largely identical. The experimental models used permit reliable extrapolation of the results obtained to the situation in man.

The great majority (more than 90 %) of carcinomas occurring in the urinary bladder represents transitional cell carcinomas, the histogenesis of which is well understood. They develop from preneoplastic lesions of the transitional cell epithelium, in particular from urothelial hyperplasia, dysplasia and carcinoma in situ. Rarely squamous cell carcinomas, adenocarcinomas and signet ring cell adenocarcinomas can be observed, the development of which seems to be problematic from a histogenetic point of view, since the bladder normally contains neither squamous nor columnar epithelium or glandular structures. The most attractive concept to explain the histogenesis of nontransitional cell carcinomas is based upon the pluripotent metaplastic capacity of the urothelium to undergo several pathways of cellular and architectural differentiation, most probably as a result of reexpression of embryologic characteristics. This seems plausible when realizing the embryologic origin of the urinary bladder from the cloacal endoderm (dome and median regions) and the mesodermal Wolffian ducts (trigone), thus implying an inherent potency of the bladder epithelium to manifest a wide variety of cellular phenotypes. To elucidate the role and significance of metaplastic phenomena during bladder carcinogenesis, the morphology of nonurothelial carcinomas observed in the human and rat urinary bladder and of transitional cell carcinomas with a focally altered cellular and structural differentiation was comparatively analysed in an attempt to better understand the histogenesis of nonurothelial bladder cancer.

* Dedicated to Prof. em. Dr. Dres. h.c. FRANZ BOLeK on the occasion of his 80th birthday on September 15, 1998.

Material and methods Material investigated consists of nonurothelial carcinomas and transitional cell carcinomas of the human urinary bladder showing areas with a nonurothelial cellular Exp Toxic Pathol 50 (1998) 4-6

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Fig.la. Hyperplastic squamous cell metaplasia of the transitional cell epithelium with slight , keratinization (human bladder). , HE; x 180.

Fig. lb. Columnar cell metaplasia of the urothelium (human urinary bladder). HE; x 180.

Fig. Ie. Transition of the transitional cell epithelium (right) into a goblet cell metaplasia (human urinary bladder). HE; x 180.

differentiation, retrieved from the surgical files of the Center of Pathology of the University of Gottingen available between January 1995 and December 1996. Paraffin section of 3 1..1 thickness were prepared and routinely stained with hematoxylin and eosin (HE), alcian blue (pH 2.5) and periodic acid-Schiff (PAS). For comparison, nonurothelial cancers of the rat bladder and transitional 342

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cell carcinomas revealing divergent structural and cellular features were reviewed; these tumors were originally induced by oral administration of N-butyl-N-( 4-hydroxybutyl)-nitrosamine or intravesical instillation of N-methyl-N-nitrosourea, as reported in several previous publications (KUNZE and SCHAUER 1977; KUNZE 1979; KUNZE and GASSNER 1986; KUNZE 1988; KUNZE et al. 1989;

Fig. 2. Signet ring cell metaplasia of the urothelium (human bladder). PAS ; x 180.

Fig. 3. Simple glandular metaplasia (so-called cystitis glandularis) of the human urinary bladder consisting of glands within the lamina propria showing an inner layer of columnar cells. PAS; x 180. KUNZE and CHOWANIEC 1990; KUNZE 1994; KUNZE et al. 1997).

Results and discussion Types of metaplasia of the normal transitional cell epithelium: It is well-known that the normal transitional cell epithelium of the human and rat urinary bladder although highly spezialized (for review of the literature see KUNZE and CHOWANIEC 1990) - has an inherent potency to undergo metaplasia of various types (MOSTOFI 1954; KUNZE 1979, 1988, 1998 a, b; KUNZE and CHOWANIEC 1990; for review of the literature see EAGAN 1989; YOUNG 1989; PETERSEN 1992; THEURING 1993; YOUNG

and EBLE 1997). Most commonly, a squamous cell metaplasia (O' FLYNN and MULLANEY 1967; WID RAN et al. 1974; REECE and KOONTZ 1975) with or without keratinization occurs (fig. la). More rarely, a columnar cell metaplasia is present which mayor may not show secretion of mucin (fig. 1b). Variants of columnar cell metaplasia with formation of goblet cells (fig. Ie) or signet ring cells (fig. 2) are found less often (BRAUN et al. 1981; CHOI et al. 1984; KVIST and SJOELEN 1990; BERNDT and WEISSBROD 1991). A simple glandular metaplasia (fig. 3) develops either from invagination of metaplastic columnar cells or secondarily from von Brunn's cell nests resulting in socalled cystitis glandularis which is frequently found in the human (von BRUNN 1893; ASCHOFF 1894; STOERCK and ZUCKERKANDLE 1907; PUND et al. 1952; for review of the Exp Toxic Pathol 50 (J 998) 4-6

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Fig. 4a. Part of a pronounced glandular metaplasia of the human urinary bladder composed of densely packed glands lined by highly mucus-producing columnar cells (glandular metaplasia of the intestinal or colonic type). HE; x 45.

literature see YOUNG 1989, EAGAN 1989; PETERSEN 1992; YOUNG and EBLE 1997), but only occasionally in the rat bladder (KUNZE and SCHAUER 1977). In rare instances, the metaplastic glands are lined by highly columnar, mucinsecreting epithelium with goblet cells (figs. 4a and 4b); because of the close resemblance with intestinal epithelium, the term "glandular metaplasia of the intestinal or colonic type" seems to be appropriate. So-called nephrogenic metaplasia in its simple form (FRIEDMAN and KUHLENBECK 1950; for review of the literature see YOUNG 1989; EAGAN 1989; PETERSEN 1992; KUNZE et al. 1993; YOUNG and EBLE 1997) is characterised by a replacement of the urothelium by a single layer of cuboidal cells with a hobnail configuration; with increasing proliferation papillary structures and tubular formations develop (fig. 5). We were unable to detect this rare type of metaplasia in the normal or cancerised urinary bladder of rats. The pluripotent metaplastic capacity is not restricted to the normal transitional cell epithelium; the neoplastic urothelium is also capable of developing a wide variety of metaplastic changes, thus helping to understand and explain the occurrence of nonurothelial bladder carcinomas.

Fig. 4b. Glandular metaplasia of the intestinal or colonic

type made up of rows of glands lined by columnar, mucinsecreting cells, found in a rat bladder following one-third resection (KUNZE 1998a). HE; x 80.

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Histogenesis of squamous cell carcinomas: There is a controversial discussion whether or not squamous cell carcinomas develop from a primary squamous cell metaplasia of the transitional cell epithelium (for review of the literature see EAGAN 1989; PETERSEN 1992; GRIGNON 1997; YOUNG and EBLE 1997). Our animal experiments provide evidence that this histogenetic pathway exists as is documented by increasing cellular atypias of the metaplastic squamous epithelium (fig. 6a and 6b) with final transition into an invasive carcinoma growth (KUNZE et al. 1976; KUNZE 1979, 1988 and 1998a; KUNZE and CHO-

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Fig. 5. Transition of the urothelium (right side) into a so-called nephrogenic metaplasia consisting of papillary structures and tubular formations within the lamina propria, covered and lined, respectively, by cuboidal to slightly columnar cells (human urinary bladder). HE; x 90.

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Fig. 6a. Keratinizing squamous cell metaplasia of the rat bladder induced with N-methyl-N-nitrosourea showing basal proliferation in association with considerable cellular atypias. Hematoxylin; x 190.

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Fig. 6 b. Higher magnification of the lesion demonstrated in figure 6a. x 400.

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Fig. 7 a. Well-differentiated transitional cell carcinoma (left side) of the human urinary bladder with transition into a squamous cell carcinoma (right side). HE; x 180.

Fig. 7b. Poorly differentiated solid transitional cell carcinoma of the rat induced with N-butylN-(4-hydroxybutyl)-nitrosamine revealing interspersed small is• lets of metaplastic carcinoma cells with a squamous cell differentiation. Hematoxylin; x 180. 1990). However, from our studies in both humans and rats it can be concluded that most of the squamous cell carcinomas arise metaplastically from preexisting transitional cell carcinomas. This histogenetic pathway is clearly indicated by gradual transitions of the neoplastic urothelial cells into those with a squamous cell differentiation (figs. 7a and 7b), resulting in mixed transitional and squamous cell carcinomas. The metaplastic process may progress and extend with time, finally leading to pure squamous cell carcinomas.

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Histogenesis of common adenocarcinomas: As with squamous cell carcinomas nonurachal common adeno346

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carcinomas mainly develop from preexisting transitional cell carcinomas by a multistep metaplastic process, confirmed in the human as well as in the rat bladder. The first step consists in the formation of microfocal necroses of the urothelial carcinoma cells causing microcysts or pseudoglandular structures (figs. 8a and 9a). The second step is characterised by a metaplastic transformation of the neoplastic urothelial cells bordering the pseudoglands into columnar cells (figs. 8b and 9b) which - in a third step - may acquire the ability to secrete mucin (fig. lOa and lOb). As a result of this metaplastic process mixed transitional cell carcinomas and adenocarcinomas are present which may finally transform to pure adenocarci-

Fig. 8a. Solid transitional cell carcinoma of the human urinary bladder with numerous microcysts (pseudoglands) due to cellular necroses (note cell debris within the lumina). HE; x 180.

Fig. 8b. Another area of the transitional cell carcinoma shown in figure 8 a exhibiting incipient formation of glands lined by columnar cells. HE; x 180.

nomas with or without mucus production. Adenocarcinomas can also be derived from a primary columnar metaplasia of the transitional cell epithelium as is supported by transitions between these two lesions (KUNZE 1998b). Whether a glandular metaplasia can be regarded as a precursor of adenocarcinomas is a matter of considerable debate (for review of the literature see EAGAN 1989; YOUNG 1989; PETERSEN 1992; GRIGNON 1997; YOUNG and EBLE 1997). There are few reports describing a transition of a glandular metaplasia - but only of the intestinal type into an adenocarcinoma (JACOB and MAU 1951 ; SHAW et al. 1958; SUSMANO et al. 1971; EDWARDS et al. 1972; LIN et al. 1980; YOUNG and PARKHURST 1984). However,

since so-called cystitis glandularis is frequently observed in the human bladder, whereas the incidence of adenocarcinomas is low, this histogenetic pathway apparently plays a minor role. Histogenesis of clear cell adenocarcinomas: Very rarely clear cell adenocarcinomas occur consisting of tubular formations lined by cuboidal tumor cells with a hobnail configuration (Dow and YOUNG 1968; SKOR and WARREN 1977; KANAKOGJ et al. 1983; SCHULTZ and BLOCK 1984; YOUNG and SCULLY 1985 and 1986; YOUNG and EBLE 1991; for review of the literature see YOUNG 1989; EAGAN 1989; GRIGNON 1997). This peculiar histoExp Toxic Pathol SO (1998) 4-6

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Fig. 9a. Solid transitional cell carcinoma of the rat induced by N-butylN-( 4-hydroxybuty I)-nitrosamine consisting of small nests of carcinoma cells separated by considerable amounts of intervening stroma with development of pseudogiands bordered by attenuated urothelial carcinoma cells. Goldner trichrome; x 180.

Fig. 9b. N-methyl-N-nitrosoureainduced solid transitional cell carcinoma revealing pseudoglands with transition into true glandular structures. Hematoxylin; x 180. logic type of bladder carcinoma was also reported to be chemically induced in the rat (fig. 11; KUNZE 1988). The histogenesis of clear cell adenocarcinomas is not yet fully understood. For a long time an embryologic derivation from mesonephric remnants was discussed, but more recently a metaplastic origin is favorised. In accordance with the histogenetic concepts concerning formation of other nonurothelial bladder carcinomas, two different pathways must be considered. Based upon our experimental findings clear cell adenocarcinomas develop from preexisting transitional cell carcinomas by a focally beginning and progressing metaplastic differentiation of the neoplastic urothelial into the typical hobnail-like carci-

noma cells with gland formation. Because of the very close structural and cellular resemblance, development from so-called nephrogenic metaplasia is suggested as a second possible histogenetic pathway. The preneoplastic 348

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potency of "nephrogenic metaplasia" is documented by its occasional transition into tubulo-papillary adenomas (KUNZE et al. 1993).

Histogenesis of signet ring cell adenocarcinomas: Development of the extremely rare signet ring cell adenocarcinomas (SAPHIR 1955; BRAUN et al. 1981; GONZALEZ et al. 1982; CHOI et al. 1984; DE FILLIPO et a11987; GRIGNON et al. 1991; for review of the literature see YOUNG 1989; EAGAN 1989; GRIGNON 1997) may follow three different histogenetic pathways. Probably in most cases they originate from preexisting mucinous adenocarcinomas as indicated by the presence of intermingled signet ring cells. The second possibility consists in the formation from solid transitional cell carcinomas: the process of transformation is characterised by an increasing secretion of mucin - initially in the form of small globular inclu-

Fig. lOa. Solid transitional cell carcinoma induced by N-methyl-N-nitrosourea exhibiting pseudoglands - partially containing cell debris - side by side with true glands lined by mucin-secreting columnar cells including goblet cells. Hematoxylin; x 180.

Fig. lOb. Area of a N-butyl-N-(4-hydrox ybutyl)-nitrosamine-induced transitional carcinoma showing metaplastic glands lined by mucus-secreting columnar cells. PAS; x 500.

Fig. 11. N-butyl-N-(4-hydroxybutyl)-nitrosamine-produced adenocarcinoma of the rat made up of glands lined by a single layer of cuboidal cells with a hobnail configuration. In between the neoplastic glands considerable amounts of intervening fibrous stroma. Goldner trichrome; x 180.

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Fig. 12a. High power view of a solid transitional cell carcinoma of the human urinary bladder disclosing tumor cells with globular inclusions of mucin, staining positively in the periodic acid-Schiff reaction. PAS; x 900.

Fig. 12 b. Same carcinoma as seen in figure 12a showing single intermingled signet ring cells. PAS; x 900.

Fig. 12c. Solid transitional cell carcinoma of the rat produced by N-butyl-N(4-hydroxybutyl)-nitrosamine with clusters of tumor cells containing granular deposits of mucin (KUNZE and SCHAUER 1977). PAS; x 500.

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Fig. 13a. Undifferentiated carcinoma of the small cell type composed of densely packed small round to oval tumor cells (left side human, right side rat bladder). Induction of the rat carcinoma with N-butyl-N-(4-hydroxybutyl)-nitrosamine. Hematoxylin; x 90.

Fig. 13b. Mixed transitional cell car- .. cinoma and undifferentiated small cell carcinoma of the rat following administration of N-butyl-N-(4-hydroxybutyl)-nitrosamine (KUNZE and SCHAUER 1977). Hematoxylin; x 190. sions in the cytoplasm of the neoplastic urothelial cells (fig. 12a) - finally resulting in the formation of typical signet ring cells (fig. 12b). The capacity of neoplastic transitional cell epithelia to secrete neutral and acid mucin is well-known and described in detail by DONHUIJSEN et al. (1992). The third histogenetic pathway consists in the development from a primary signet ring cell metaplasia of the urothelium in situ. It may be furthermore hypothetically assumed that a goblet cell and a glandular metaspi asia of the intestinal type may undergo malignant transformation into a signet ring cell carcinoma. In all our animal experiments we were unable to observe a fully developed signet ring cell carcinoma, but in a single case a solid transitional cell carcinoma was identified revealing clusters of cells containing granular deposits of mucin

that stained with periodic acid-Schiff reaction (fig. 12c), possibly representing a urothelial carcinoma transforming into a signet ring cell adenocarcinoma (KUNZE and SCHAUER 1977).

Histogenesis of undifferentiated carcinomas: Undifferentiated carcinomas of the human urinary bladder lack any cellular or structural differentiation and are subdivided into a small, large and spindle (sarcomatoid) cell type (for review of the literature see EAGAN 1989; PETERSEN 1992; GRIGNON 1997; YOUNG 1997). All three histologic subtypes were reported to be reproduced in the rat bladder (KUNZE and SCHAUER 1977; KUNZE 1979; for review of the literature see KUNZE and CHOW ANIEC 1990). The small cell type (WILLIAMS et al. 1986; MILLS et al. Exp Toxic Pathol 50 (\ 998) 4-6

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1987; SWANSON et a1. 1988; PODESTA and TRUE 1989; HoBARTH et a1. 1992) is characterised by densely packed tumor cells with small hyperchromatic nuclei and a small rim of cytoplasm closely reminiscent of small cell anaplastic carcinomas of the lung (fig. 13a).The large cell type is composed of carcinoma cells with an abundant polygonal cytoplasm and pleomorphic nuclei intermingled with some multinuclear giant cells (figs. 14a and 14b). The undifferentiated sarcomatoid carcinoma (YOUNG et a1. 1988; Ro et a1. 1988; YOUNG and EBLE 1991; TORENBEEK et a1. 1994) consists of spindle-shaped tumor cells arranged in fascicles and thus imitating a sarcomatous growth (figs. 14c and 14d). There is convincing evidence from our animal experiments (KUNZE 1979; KUNZE et a1. 1989; KUNZE et a1. 1997) that the spindle-shaped tumor cells are of urothelial origin as is concluded from interspersed cohesive cords or islets of neoplastic transitional cell epithelia merging with the pseudosarcomatous tumor component (figs. 14c and 14d). Similarly, undifferentiated carcinomas of the small and large cell type obviously develop from preexisting solid transitional cell carcinomas by a cellular dedifferentiation, indicated by a mixture of these carcinoma types (fig. 13b).

Conclusions The present morphologic study analysing the histogenesis of nonurothelial cancer occurring in the human and chemically induced in the rat urinary bladder provide evidence that squamous cell carcinomas, common and clear cell adenocarcinomas, and signet ring cell carcinomas develop by a metaplastic process (table 1). Basically, two different histogenetic pathways may be considered. Most of the nonurothelial cell carcinomas arise secondarily from preexisting - predominantly solid - transitional cell carcinomas by a focally beginning and diffusely progressing metaplastic transformation (squamous, columnar, goblet and signet ring cell, glandular and so-called nephrogenic metaplasia) of the urothelial carcinoma cells. The second histogenetic pathway consists in the formation of nonurothelial cancers directly from the various types of metaplasia of the transitional cell epithelium in situ. Undifferentiated carcinomas (small, large and spindle cell type) develop from preexistent solid transitional cell carcinomas by a cellular and structural dedifferentiation. Transitional cell carcinomas showing focally nonurothelial cellular and architectural characteristics most

Table 1. Proposed histogenetic pathways in the formation of nonurothelial carcinomas of the urinary bladder from primary metaplasias of the transitional cell epithelium in situ and preexistent transitional cell carcinomas. Columnar cell metaplasia

Glandular metaplasia of the intestinal type

Squamous cell carcinoma

Adenocarcinoma

Signet ring cell adenocarcinoma

Preexlstenttransilional cell carcinoma

Squamous cell metaplasia

Glandular metaplasia

Signet ring cell metaplasia

Dedifferentiation

Squamous cell carcinoma

Adenocarcinoma

Signet ring cell adenocarcinoma

Undifferentiated carcinomas

Fig. 14a. Undifferentiated carcinoma of the large cell type (human urinary bladder) composed of tumor cells with pleomorphic nuclei and an abundant polygonal cytoplasm. HE; x 180. Fig. 14 b. N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced undifferentiated carcinoma of the large cell type composed of tumor cells containing large pleomorphic nuclei. Goldner trichrome; x 180. Fig. 14c. Undifferentiated carcinoma of the spindle-cell type (sarcomatoid carcinoma) of the rat induced with N-methylN-nitrosourea showing an admixture of slender sheets of neoplastic urothelial cells merging with spindle-shaped pseudosarcomatous tumor cells (KUNZE et al. 1989). Hematoxylin; x 60. Fig. 14d. Another area of the sarcomatoid carcinoma demonstrated in figure 14a consisting of cohesive cords of urothelial carcinoma cells with transition into spindle-shaped pseudosarcomatous tumor cells. Hematoxylin; x 180. Exp Toxic Pathol 50 (1998) 4-6

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probably imply a higher grade of malignancy than uniformly differentiated pure transitional cell carcinomas. It is consequently important and mandatory to identify these peculiar types of bladder cancer for an accurate clinical management and an appropriate evaluation of clinical bladder cancer studies. All histologic types of nonurothelial carcinomas - except signet ring cell carcinomas observed in the human urinary bladder can be chemically induced in the rat and their histogenetic derivation particulary from preexisting transitional cell carcinomas could be experimentally confirmed. The experimental models used thus allow conclusions to the situation in man, helping to elucidate the histopathogenesis of human bladder cancer. Acknowledgement: The author wishes to express his gratitude to Miss BIRGIT JONEMANN und Miss JESSICA WANGERIN for excellent processing of the histologic sections and Mr. KLAUS MOLLER for his technical assistance concerning the photomicrographs.

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