CYTOLOGY OF TRANSITIONAL
CELL CARCINOMA
IN SITU OF URINARY BLADDER WITH EXTENSIVE PROSTATIC INVOLVEMENT M. NISARAHMED, ALEXIJ
M.B.,
LUSHPIHAN,
CLAUDE
LOUIS,
F.R.C.P.
(C)
A.R.T. (CSLT), C.M.I.A.C.
R.T. (CSLT), C.M.I.A.C.
THOMAS A. SEEMAYER, WILLIAM
B.S.,
L. THELMO,
NAI-SAN WANG, M.D.,
M.D., M.D.,
F.R.C.P. F.R.C.P.
(C) (C)”
PH.D., F.R.C.P.
(C)
From The Department of Pathology, McGill University, Montreal, Quebec, Canada
ABSTRACT - Cytologic diff erences in the urine of 6 patients with transitional cell carcinoma in situ (CZS) of the urinary bladder with and without prostatic duct involvement are described. In the former group, there was an admixture of CZS cells along with many bizarre malignant cells which increased with time and showed malignant criteria indicative of changes more than CZS alone. -
Transitional cell carcinoma in situ (CIS) of the urinary bladder is well recognized both cytologically and histologically. Recently we reported the occurrence of prostatic duct involvement in patients with carcinoma in situ of the urinary bladder. ’ Prostatic duct involvement appears to be both frequent and clinically silent. The diagnosis was established on assessment of the prostate, either as part of a radical cystectomy or after transurethral resection. The purpose of this article is to describe the cytologic differences in the urine of patients with carcinoma in situ of the urinary bladder with and without prostatic duct involvement. Material and Method Only cases of carcinoma in situ of the urinary bladder without clinical and/or histologic papillary tumors were included. The diagnosis of CIS was made only when there was a full-thickness *Present address: Westchester Valhalla, New York.
538
County Medical Center,
failure of maturation of the urothelium. The cases studied were those in which prostatic tissue was available for histologic examination at some time during the course of the patient’s assessment. Of the 6 patients suitable for this study, 4 demonstrated prostatic duct involvement while 2 did not. Multiple voided urine preparations from these 6 patients collected over an extended period of time were available for review. The urine specimens had been prepared by millipore filter technique and stained by a modified Papanicolaou stain. Results Cytology The age of the patients ranged from sixty-six to seventy-eight years. In the 2 patients without prostatic duct involvement, the urine specimens contained from few to many CIS cells, either singly or in small groups of three to four. The diameter of the mononucleated cells varied from 10 to 29F. and that of the bi- or multinucleated cells from 30 to 38~. Their shape was either round
UROLOGY
I
MAY 1976 / VOLUME
VII,
NUMBER 5
FIGURE 1. Two single cellsfiom carcinoma in situ of urinary bladder. (Modijed Papanicolaou stain, mugnijkation X 1,200.)
or oval, or occasionally elongated. The cytoplasm was basophilic, dense, and occasionally vacuolated. The nuclear-cytoplasmic ratio was altered and varied from 1: 1.2 to 1.5. The nuclei were generally single but occasionally two or more per cell were present. Nuclei were round to oval and occasionally irregular, hyperchromatic with a well-defined nuclear membrane which varied in thickness and showed occasional indentations. The chromatin was fine to slightly coarse and evenly distributed (Fig. 1). Less than 10 per cent of these cells contained nucleoli which were single, round, and small. In addition, an occasional bizarre cell was noted. The background of these specimens was generally clean with a few to moderate number of inflammatory cells. Of the 4 patients with prostatic duct involvement, the urine specimens in the earlier phase of the disease were available for only 2 patients. They showed CIS cells similar to the ones described previously. However, the later specimens of all 4 patients showed CIS cells admixed with bizarre malignant cells. The latter had increased in number with time in the case of the 2 patients whose urines were reviewed in the earlier phase. The time interval for this change was approximately one year. The bizarre malignant cells were seen singly, in small groups, or in
syncytial arrangement although the majority were in small groups. The diameter of the mononucleated cells varied from 8 to 28~. and that of the bi- or multinucleated cells from 20 to 40~. Their shape was either oval, elongated, or bizarre. Cytoplasm was basophilic and either dense or vacuolated. Nuclear-cytoplasmic ratio was altered and close to 1: 1. Nuclei were generally irregular and hyperchromatic with coarse, unevenly distributed chromatin. There was also some parachromatin clearing (Fig. 2). Most cells contained multiple nucleoli which ranged in size from small to relatively large and were round to irregular in shape. In an occasional specimen malignant “epidermoid” cells were also present. The background of these specimens showed many inflammatory cells, red blood cells, and an occasional focus of necrotic debris. The pleomorphism and the malignant criteria of these cells were indicative of changes more than a carcinoma in situ alone. In fact many of these specimens were initially reported as “malignant cells present consistent with transitional cell carcinoma grade III to IV.” Histology In 3 of 4 patients there was superficial invasion of the bladder lamina propria, but none had muscle invasion. The prostatic involvement, however, was remarkably extensive in the cases studied after radical cystectomy. Numerous intraprostatic ducts were involved with tumor. In some areas, prostatic duct lumina were partially filled with neoplastic cells, but the normal ductal epithelium was still identifiable. In other areas, the ducts were filled and lined with neoplastic cells (Fig. 3A). The prostatic duct involvement occasionally assumed epidermoid features. Despite extensive prostatic intraductal involvement, true stromal invasion was difficult to demonstrate.
FIGURE 2. Bizarre malignant cells fi-om 2 patients with prostatic duct involvement. Cytoplasm is not clearly seen; a few CIS cells are also present in photomicrograph on right. (Modified Papanicolaou stain, magnijication x 1,350.)
UROLOGY
/ MAY
1976 / VOLUME VII, NUMBER 5
539
FIGURE 3. (A) Section of prostate showing intraductal involvement by malignant cells. On right malignant cells are lining duct, while on l.ej-tnormal ductal epithelium is identifiable. (Hematorylin and eosin stain, original magnijcation x 175.) (B) Section of urinary bladder showing transitional cell carcinoma in situ. Neoplastic cells are reduced in thickness to about three layers. (Hematoxylin and eosin stain, original magnification x 400.) Comment Cells from transitional cell carcinoma in situ of the urinary bladder exfoliate readily because of poor cellular cohesion. 2 However, because of rapid exfoliation, the mucosal surface may be reduced to a single or only a few layers of neoplastic cells (Fig. 3B). The malignant cells shed singly or in small clusters, are slightly larger than normal cells, and have an increased nuclearcytoplasmic ratio. The nuclei are hyperchromatic and generally round to oval. Occasional bizarre cells may be present. The background is generally clean.2s3 In a small number of CIS cells, nucleoli may be present. In our cases the cytologic presentation was markedly different in the two groups studied: CIS of urinary bladder with and without intraductal prostatic involvement. The 2 patients in the first group, earlier in their course when presumably there was no involvement of the prostatic ducts, showed malignant cells in the urine specimens with morphologic characteristics of CIS cells. During the later part of the disease the urine specimens showed, in addition, more anaplastic cells. The increasing numbers of anaplastic cells in patients known to have CIS and negative cytoscopic findings may be an indication of the possible extension of CIS into the prostatic ducts. In none of our patients did the prostatic involvement antedate the urinary bladder carcinoma. The incidence of pure CIS of the urinary bladder with silent extensive prostatic duct involvement may be considerable, since 4 of our 6 patients manifested this association.
540
With regard to the pathogenetic mechanism of the prostatic duct involvement, two possible hypotheses are suggested: either it is due to multiple epithelial sites responding to a carcinogen and/or carcinogens, or it reflects the physical extension of neoplastic cells along contiguous epithelial surfaces. It is our impression that the former hypothesis is the probable mechanism, because in the radical cystectomy specimens of 2 patients, multiple noncontiguous epithelial sites, bladder, prostate, ureters, and seminal vesicles were involved by carcinoma in situ. It would appear that after the diagnosis of carcinoma in situ of the urinary bladder has been established, consideration should be given to the possibility that the disease may be present in the intraductal system of the prostate. Routine urinary cytologic assessment is recommended, since a change in the cytologic presentation may be a helpful diagnostic adjuvant. 3775 University Street Montreal, Quebec, Canada H3A 2B4 (DR. AHMED) References SEEMAYER, T. A., et al. : Further observations on carcinoma in situ of the urinary bladder, Cancer 36: 514 (1975). MELAMED, M. R., VOUSTA, N. G., and GRABSTALD, H.: Natural history and clinical behavior of in situ carcinoma of the human urinary bladder, ibid. 17: 1533 (1964). VOUSTA, N. G., and MELAMED, M. R.: Cytology of in situ carcinoma of the human urinary bladder, ibid. 16: 1307 (1963).
UROLOGY
I MAY 1976 I VOLUME VII, NUMBER 5
CELL CARCINOMA
IN SITU OF URINARY BLADDER WITH EXTENSIVE PROSTATIC INVOLVEMENT M. NISARAHMED, ALEXIJ
M.B.,
LUSHPIHAN,
CLAUDE
LOUIS,
F.R.C.P.
(C)
A.R.T. (CSLT), C.M.I.A.C.
R.T. (CSLT), C.M.I.A.C.
THOMAS A. SEEMAYER, WILLIAM
B.S.,
L. THELMO,
NAI-SAN WANG, M.D.,
M.D., M.D.,
F.R.C.P. F.R.C.P.
(C) (C)”
PH.D., F.R.C.P.
(C)
From The Department of Pathology, McGill University, Montreal, Quebec, Canada
ABSTRACT - Cytologic diff erences in the urine of 6 patients with transitional cell carcinoma in situ (CZS) of the urinary bladder with and without prostatic duct involvement are described. In the former group, there was an admixture of CZS cells along with many bizarre malignant cells which increased with time and showed malignant criteria indicative of changes more than CZS alone. -
Transitional cell carcinoma in situ (CIS) of the urinary bladder is well recognized both cytologically and histologically. Recently we reported the occurrence of prostatic duct involvement in patients with carcinoma in situ of the urinary bladder. ’ Prostatic duct involvement appears to be both frequent and clinically silent. The diagnosis was established on assessment of the prostate, either as part of a radical cystectomy or after transurethral resection. The purpose of this article is to describe the cytologic differences in the urine of patients with carcinoma in situ of the urinary bladder with and without prostatic duct involvement. Material and Method Only cases of carcinoma in situ of the urinary bladder without clinical and/or histologic papillary tumors were included. The diagnosis of CIS was made only when there was a full-thickness *Present address: Westchester Valhalla, New York.
538
County Medical Center,
failure of maturation of the urothelium. The cases studied were those in which prostatic tissue was available for histologic examination at some time during the course of the patient’s assessment. Of the 6 patients suitable for this study, 4 demonstrated prostatic duct involvement while 2 did not. Multiple voided urine preparations from these 6 patients collected over an extended period of time were available for review. The urine specimens had been prepared by millipore filter technique and stained by a modified Papanicolaou stain. Results Cytology The age of the patients ranged from sixty-six to seventy-eight years. In the 2 patients without prostatic duct involvement, the urine specimens contained from few to many CIS cells, either singly or in small groups of three to four. The diameter of the mononucleated cells varied from 10 to 29F. and that of the bi- or multinucleated cells from 30 to 38~. Their shape was either round
UROLOGY
I
MAY 1976 / VOLUME
VII,
NUMBER 5
FIGURE 1. Two single cellsfiom carcinoma in situ of urinary bladder. (Modijed Papanicolaou stain, mugnijkation X 1,200.)
or oval, or occasionally elongated. The cytoplasm was basophilic, dense, and occasionally vacuolated. The nuclear-cytoplasmic ratio was altered and varied from 1: 1.2 to 1.5. The nuclei were generally single but occasionally two or more per cell were present. Nuclei were round to oval and occasionally irregular, hyperchromatic with a well-defined nuclear membrane which varied in thickness and showed occasional indentations. The chromatin was fine to slightly coarse and evenly distributed (Fig. 1). Less than 10 per cent of these cells contained nucleoli which were single, round, and small. In addition, an occasional bizarre cell was noted. The background of these specimens was generally clean with a few to moderate number of inflammatory cells. Of the 4 patients with prostatic duct involvement, the urine specimens in the earlier phase of the disease were available for only 2 patients. They showed CIS cells similar to the ones described previously. However, the later specimens of all 4 patients showed CIS cells admixed with bizarre malignant cells. The latter had increased in number with time in the case of the 2 patients whose urines were reviewed in the earlier phase. The time interval for this change was approximately one year. The bizarre malignant cells were seen singly, in small groups, or in
syncytial arrangement although the majority were in small groups. The diameter of the mononucleated cells varied from 8 to 28~. and that of the bi- or multinucleated cells from 20 to 40~. Their shape was either oval, elongated, or bizarre. Cytoplasm was basophilic and either dense or vacuolated. Nuclear-cytoplasmic ratio was altered and close to 1: 1. Nuclei were generally irregular and hyperchromatic with coarse, unevenly distributed chromatin. There was also some parachromatin clearing (Fig. 2). Most cells contained multiple nucleoli which ranged in size from small to relatively large and were round to irregular in shape. In an occasional specimen malignant “epidermoid” cells were also present. The background of these specimens showed many inflammatory cells, red blood cells, and an occasional focus of necrotic debris. The pleomorphism and the malignant criteria of these cells were indicative of changes more than a carcinoma in situ alone. In fact many of these specimens were initially reported as “malignant cells present consistent with transitional cell carcinoma grade III to IV.” Histology In 3 of 4 patients there was superficial invasion of the bladder lamina propria, but none had muscle invasion. The prostatic involvement, however, was remarkably extensive in the cases studied after radical cystectomy. Numerous intraprostatic ducts were involved with tumor. In some areas, prostatic duct lumina were partially filled with neoplastic cells, but the normal ductal epithelium was still identifiable. In other areas, the ducts were filled and lined with neoplastic cells (Fig. 3A). The prostatic duct involvement occasionally assumed epidermoid features. Despite extensive prostatic intraductal involvement, true stromal invasion was difficult to demonstrate.
FIGURE 2. Bizarre malignant cells fi-om 2 patients with prostatic duct involvement. Cytoplasm is not clearly seen; a few CIS cells are also present in photomicrograph on right. (Modified Papanicolaou stain, magnijication x 1,350.)
UROLOGY
/ MAY
1976 / VOLUME VII, NUMBER 5
539
FIGURE 3. (A) Section of prostate showing intraductal involvement by malignant cells. On right malignant cells are lining duct, while on l.ej-tnormal ductal epithelium is identifiable. (Hematorylin and eosin stain, original magnijcation x 175.) (B) Section of urinary bladder showing transitional cell carcinoma in situ. Neoplastic cells are reduced in thickness to about three layers. (Hematoxylin and eosin stain, original magnification x 400.) Comment Cells from transitional cell carcinoma in situ of the urinary bladder exfoliate readily because of poor cellular cohesion. 2 However, because of rapid exfoliation, the mucosal surface may be reduced to a single or only a few layers of neoplastic cells (Fig. 3B). The malignant cells shed singly or in small clusters, are slightly larger than normal cells, and have an increased nuclearcytoplasmic ratio. The nuclei are hyperchromatic and generally round to oval. Occasional bizarre cells may be present. The background is generally clean.2s3 In a small number of CIS cells, nucleoli may be present. In our cases the cytologic presentation was markedly different in the two groups studied: CIS of urinary bladder with and without intraductal prostatic involvement. The 2 patients in the first group, earlier in their course when presumably there was no involvement of the prostatic ducts, showed malignant cells in the urine specimens with morphologic characteristics of CIS cells. During the later part of the disease the urine specimens showed, in addition, more anaplastic cells. The increasing numbers of anaplastic cells in patients known to have CIS and negative cytoscopic findings may be an indication of the possible extension of CIS into the prostatic ducts. In none of our patients did the prostatic involvement antedate the urinary bladder carcinoma. The incidence of pure CIS of the urinary bladder with silent extensive prostatic duct involvement may be considerable, since 4 of our 6 patients manifested this association.
540
With regard to the pathogenetic mechanism of the prostatic duct involvement, two possible hypotheses are suggested: either it is due to multiple epithelial sites responding to a carcinogen and/or carcinogens, or it reflects the physical extension of neoplastic cells along contiguous epithelial surfaces. It is our impression that the former hypothesis is the probable mechanism, because in the radical cystectomy specimens of 2 patients, multiple noncontiguous epithelial sites, bladder, prostate, ureters, and seminal vesicles were involved by carcinoma in situ. It would appear that after the diagnosis of carcinoma in situ of the urinary bladder has been established, consideration should be given to the possibility that the disease may be present in the intraductal system of the prostate. Routine urinary cytologic assessment is recommended, since a change in the cytologic presentation may be a helpful diagnostic adjuvant. 3775 University Street Montreal, Quebec, Canada H3A 2B4 (DR. AHMED) References SEEMAYER, T. A., et al. : Further observations on carcinoma in situ of the urinary bladder, Cancer 36: 514 (1975). MELAMED, M. R., VOUSTA, N. G., and GRABSTALD, H.: Natural history and clinical behavior of in situ carcinoma of the human urinary bladder, ibid. 17: 1533 (1964). VOUSTA, N. G., and MELAMED, M. R.: Cytology of in situ carcinoma of the human urinary bladder, ibid. 16: 1307 (1963).
UROLOGY
I MAY 1976 I VOLUME VII, NUMBER 5
