Immunohistochemical demonstration of tumor-associated antigens in prostatic carcinomas of various histological differentiations

Prostate acid phosphatase (PAP), prostate-specific antigen (PSA), carcinoembryonic antigen (CEA) and keratin were determined immunohistochemically in paraffin sections from 64 prostatic carcinomas fixed in formalin according to the conventional method. The results obtained with PSA led to the correct diagnosis of prostatic carcinoma in 90.7% of the cases. 80.3% of the diagnoses obtained with PAP were correct. The intensity of the staining of the marker decreased with increasing differentiation. 3 utricular carcinomas were positive for PAP and PSA. CEA and keratin may be considered unspecific tumor markers only. However, metaplastic squamous epithelium from poorly differentiated carcinomas was always positive for keratin. PAP and PSA are also suitable for differentiating between tumors of prostatic and nonprostatic origin and could thus be successfully used to determine immunohistochemically the histogenesis of 15 invasive, poorly differentiated carcinomas of the prostate and bladder. PSA again proved to be a more specific epithelial marker than PAP.     

Immunohistochemical demonstration of tumor-associated antigens with the aid of monoclonal and polyclonal antisera in carcinoma of the bladder

Summary Keratin was identified with the aid of polyclonal antisera in the cytoplasm in over 90% of the transitional cell carcinomas investigated. The intensity of staining increased with the degree of dedifferentiation. Detection of cytokeratin with monoclonal antibodies was successful in over 80% of samples. All squamous cell carcinomas of the bladder were strongly positive for keratin and cytokeratin. CEA was found in 20% of the G1 and 40% of the G2 and G3 carcinomas of the bladder. Both the prostatic epithelium markers PSA and PAP and the monoclonal antibody Ca1 were negative in all cases.     

Behavior of epithelial differentiation antigens (carcinoembryonic antigen, epithelial membrane antigen, keratin and cytokeratin) in transitional cell carcinomas of the bladder.

Results of an immunohistochemical study in normal urothelium and transitional cell carcinomas of the bladder are presented. Paraffin-embedded material was confronted with immunoantisera against carcinoembryonic antigen (CEA), keratin (K), cytokeratin (CK) and epithelial membrane antigen (EMA). Immunohistochemical findings confirm the changes in reactivity of dysplastic urothelium and carcinoma in situ for CEA, CK and EMA, in comparison with normal urothelium. Statistically significant differences were also found, depending upon tumor stage, in staining of transitional cell carcinomas for K and CK. Expression of CK correlated with the tumor differentiation grade: normal urothelium and well-differentiated carcinomas showed a specific pattern of immunostaining for the basal cells, this pattern being lost in poorly differentiated carcinomas.     

Adenosquamous Carcinoma of the Prostate

We present an unusual variant of prostatic adenocarcinoma with obvious squamous differentiation. The squamous component is represented by cells that contain vesicular or hyperchromatic nuclei and large acidophilic cytoplasm. We could demonstrate immunohistochemically the presence of prostate specific antigen (PSA) and glial fibrillary acidic protein (GFAP) in these tumour cells. Either in adenocarcinomatous or malignant squamous components, the prostatic epithelial cells showed the two markers, namely PSA, GFAP, which may reflect the multidirectional differentiation of these cells from a pluripotent origin.     

Benign polyps with prostatic-type epithelium of the urethra and the urinary bladder. A suggestion of histogenesis based on histologic and immunohistochemical studies

The clinicohistologic features of seven urethral and four urinary bladder polyps with prostatic-type epithelium are described. The average age of the patients was 50 years. Seven patients had prior cystoscopies and in none of them was the lesion noted initially. Histologically the lesions were papillary or polypoid and the surface was lined predominantly by prostatic-type epithelium with interspersed transitional epithelial cells or by transitional epithelium with interspersed prostatic-type epithelial cells. The prostatic-type columnar cells contained foamy, faintly eosinophilic cytoplasm, which stained strongly for prostate specific antigen and prostatic acid phosphatase. In all the lesions, there were prostatic acini in the underlying fibrovascular stroma, which was devoid of smooth muscle. The intermingling of prostatic-type cells and transitional epithelium, on the surface of the polyps, the absence of lesions at previous cystoscopies, the coexistence of cystitis cystica glandularis (a metaplastic lesion), and the older age group of our patients suggest that the prostatic-type epithelium in the polyps of urethra and urinary bladder is an acquired lesion, most likely a metaplastic response of transitional epithelium, which embryologically was multipotential.     

A case of primary transitional cell carcinoma of the prostate

A 58-year-old man was admitted to our hospital with the complaint of pollakisuria and micturitional pain. The urine cytology showed malignant cells suggesting the urothelial cancer, but various examinations could not reveal the malignant lesion. The prostate was also normal by the digital examination, endoscopy, roentgenography, ultrasonography and serum markers, and the transperineal prostate biopsy showed no malignancy. Three years after the first admission the prostate showed slight hardness and the transperineal biopsy suggested adenocarcinoma of the prostate. Hormonal therapy was then started and the prostate showed no remarkable change until about two years later, when rapid progression of the prostatic tumor was recognized. The transperineal biopsy of the prostate revealed the transitional cell carcinoma with negative staining of Alcian-Blue, PAS and PSA (prostate specific antigen). The epithelia of the bladder and posterior urethra were normal. The radical cystoprostatectomy was done and the histological diagnosis was the pure type of primary transitional cell carcinoma of the prostate. The literatures were reviewed and the clinical differentiation between transitional cell carcinoma and adenocarcinoma of the prostate was discussed.     

Small cell carcinoma of the genitourinary tract: an immunohistochemical, electron microscopic and clinicopathological study.

We examined 13 cases of small cell carcinoma of the genitourinary tract to evaluate and compare the immunocytochemical and ultrastructural features as well as the clinicopathological behavior. Immunohistochemical stains revealed that neuron specific enolase and chromogranin showed differences in staining between the bladder and prostate, as well as between the small cell and adenocarcinomatous components of the prostate. Also, synaptophysin was negative over-all in 12 of 13 cases. Epithelial membrane antigen, carcinoembryonic antigen and keratin showed strong focal positivity within the small cell component. Electron microscopy was performed in 4 cases, with 3 demonstrating neurosecretory granules. Clinically, 6 of the 7 patients with adenocarcinoma/small cell carcinoma of the prostate did poorly, all with a survival of 15 months or less. Of 5 patients with transitional cell/small cell carcinoma of the bladder 2 fared better (both had no evidence of disease at 12 months and 11 years, respectively). Based upon the immunostaining and electron microscopic findings, small cell carcinoma of the genitourinary tract is heterogeneous in appearance and, therefore, may arise from a multipotential cell of origin. This cell of origin may be organ-specific, as demonstrated by the variability in staining characteristics among the prostate, bladder and kidney, as well as by the differences in the clinical behavior of these malignancies. Small cell carcinoma of the prostate has a poor prognosis, while small cell carcinoma of the bladder may portend a better prognosis if diagnosed at an early stage.     

Clinical study of transitional cell carcinoma of the prostate associated with bladder transitional cell carcinoma

BACKGROUND: Transitional cell carcinoma of the prostate in patients with bladder cancer appears to influence the prognosis and affects the decision about therapeutic modality. Therefore, it is important to characterize transitional cell carcinoma associated with bladder cancer. METHODS: From April 1980 to December 1998, 81 male patients underwent total cystoprostatectomies for transitional cell carcinoma of the bladder. The 81 cystoprostatectomy specimens were examined to clarify the characteristics of prostatic involvement by transitional cell carcinoma. The extent, origin, mode of spread and risk factor of prostatic involvement as well as the prognosis were investigated. In 13 of 15 patients with prostatic involvement the prostate was examined by sequential step sections. RESULTS: Prostatic involvement was observed in 15 of 81 patients (18.5%). Prostatic urethral involvement, invasion to prostatic duct/acinus, prostatic stromal invasion and extraprostatic extension and/or seminal vesicle involvement were recognized in 12 (80%), 14 (93.3%), six (40%), and five (33.3%) of the 15 patients, respectively. Twelve of the 15 patients (80%) with prostatic involvement had papillary or non-papillary tumors (i.e. carcinoma in situ) both in the prostatic urethra and prostatic duct. In 10 of these 12 patients (88.3%), there was contiguity between prostatic urethral and ductal tumors. Seven of the 23 patients (30.4%) with carcinoma in situ of the bladder showed prostatic involvement, which increased to 50% in the presence of carcinoma in situ of the trigone or bladder neck. CONCLUSIONS: Eighty per cent of the patients with prostatic involvement showed papillary or non-papillary tumors both in the prostatic urethra and prostatic duct. There was a high level of contiguity between both tumors. Patients with carcinoma in situ of the trigone or bladder neck revealed significantly higher incidence of prostatic involvement.     

Prostate carcinoma with squamous differentiation: an analysis of 33 cases

BACKGROUND: Only sporadic cases of prostate carcinomas with squamous differentiation have been reported. DESIGN: The files of two institutions were reviewed for prostate cancers with squamous differentiation. RESULTS: A total of 33 cases were studied. The average age at diagnosis was 68 years (range 49-86 years). The most common presenting symptoms included bladder outlet obstruction and dysuria. Thirteen men had a positive digital rectal examination. Diagnosis was made by needle biopsy (n = 23); transurethral resection of the prostate (n = 5); needle and transurethral resection of the prostate (n = 1); transurethral resection of the bladder (n = 1); or biopsy of metastases (n = 3). In 21 of 33 cases, there was a prior diagnosis of adenocarcinoma of the prostate; 8 patients were treated with hormones, 4 were treated with radiation, and 1 received both radiation and hormone therapy. Of the 12 men without a prior diagnosis of adenocarcinoma, 2 patients had received hormonal therapy for benign prostatic hyperplasia. Eight of 33 cases were pure squamous carcinomas. The remaining cases were adenosquamous carcinoma (n = 16), adenosquamous and urothelial carcinoma (n = 3), and adenosquamous carcinoma and sarcoma (n = 6). The squamous carcinoma component of these mixed cases averaged 40% of the tumor volume (range 5%-95%) and had a range of cytologic atypia (mild [n = 6], moderate [n = 17], severe [n = 10]). In the 25 cases with adenocarcinoma, the glandular component tended to be high-grade (Gleason grade >6 in 19 cases). Immunohistochemistry for prostate specific acid phosphatase and prostate specific antigen was positive in a large percentage of the adenocarcinomas (85% and 75%, respectively) and only very focally positive in 12% of the squamous carcinomas. 34 beta E12 was diffusely positive in >95% of the squamous carcinomas and only focally positive in <10% of the adenocarcinomas. Cytokeratins 7 and 20 did not differentiate the squamous and adenocarcinoma components. Follow-up was available on 25 of 33 cases, with the average survival being 24 months (range 0-63 months). CONCLUSION: Squamous differentiation in prostate cancer is uncommon, often but not necessarily arising in the setting of prior hormone or radiation therapy, and is associated with a poor prognosis. In addition to pure squamous cell carcinoma and adenosquamous cancer, other patterns may be seen. Whereas the adenocarcinoma component is typically high grade, the squamous component has a wide range of differentiation.     

膀胱前列腺共存肿瘤的诊断和治疗（附14例报告）

目的：提高对膀胱前列腺共存肿瘤的诊断与治疗水平。方法：结合文献回顾性分析14例膀胱前列腺共存肿瘤患者的临床和病理资料。结果：以膀胱肿瘤首诊11例,术前均经膀胱镜活检病理证实为膀胱移行细胞癌（9例）、鳞癌（2例）,该组有3例行经直肠前列腺穿刺活检,结果2例为前列腺癌,1例为前列腺增生症,该例与余8例行膀胱前列腺切除或TURBT＋TURP后病理证实为前列腺癌。术后随访6～37个月。1例术后23个月死于心梗;1例术后10个月死于全身广泛转移和并发症;1例失访;8例无瘤生存。以前列腺肿瘤首诊3例分别行膀胱部分切除术＋双睾丸切除术、前列腺癌根治术＋TURBT、姑息性输尿管皮肤造瘘术,随访42、16、25个月,2例术后死于多发性转移,1例无瘤生存。结论：膀胱前列腺共存肿瘤是较少见的一种多原发肿瘤,临床上易漏诊。直肠指检、经直肠B超、PsA测定、活检和膀胱镜检的综合应用是目前诊断膀胱前列腺共存肿瘤的主要方法。两者共存并不提示预后不良。     

Clear cell carcinoma of the urinary bladder: a report and comparison of four tumors of mullerian origin and nine of probable urothelial origin with discussion of histogenesis and diagnostic problems.

Carcinomas of the bladder that resemble clear cell carcinoma of mullerian type are rare. Whether such neoplasms 1) arise from mullerian elements in the bladder and are histogenetically identical to the female genital tract cancer, 2) are a peculiar variant of vesical adenocarcinoma of nonmullerian derivation, or 3) represent a peculiar morphologic expression of transitional cell (urothelial) carcinoma with gland differentiation is often uncertain. We reviewed the clinical, conventional pathologic, and immunohistochemical features of 13 neoplasms with exclusive, or predominant, morphologic features of clear cell carcinoma. The 11 female and two male patients were 22-83 (mean 57) years of age. The clinical and gross features had no unique aspects. On microscopic examination the most common pattern, present in all cases, was tubulocystic, with a papillary pattern, present in six tumors and a predominant solid growth in one. Cells with abundant clear cytoplasm were conspicuous in nine tumors and hobnail cells were seen in eight. Four tumors showed focally recognizable patterns of transitional cell (urothelial) carcinoma in the available material. In five other tumors pseudostratified epithelium reminiscent of transitional epithelium was present focally. Endometriosis was present in two cases. In two other cases benign cysts focally lined by ciliated epithelium and surrounded by elastosis were interpreted as most likely mullerian. Immunohistochemistry was performed in 10 cases. All tumors stained for CA 125 (usually strong, ranging from focal to diffuse) and nine tumors stained for CK7 (usually strong and diffuse). CK20 was focally and weakly positive in four tumors and extensively positive in another. The same immunohistochemical panel was performed on 10 typical transitional cell carcinomas, 4 transitional cell carcinomas with gland differentiation, not otherwise specified, and 5 pure adenocarcinomas of the bladder (one of urachal origin). Minimal CA 125 positivity was seen in two transitional cell carcinomas. CA 125 staining was seen in the areas of gland differentiation in three of four transitional cell carcinomas and three of five pure adenocarcinomas but was focal in most cases. All transitional cell carcinomas and transitional cell carcinomas with gland differentiation showed extensive CK7 positivity. In contrast, only one of four positive pure adenocarcinomas showed >5% CK7-positive cells. Although all groups showed CK20 positivity, the percentage of CK20 positive cells was higher in pure adenocarcinomas. Prostate specific antigen was negative in all tumors. The cytokeratin immunoprofile of clear cell carcinomas of the bladder is closer to transitional cell carcinomas and transitional cell carcinomas with gland differentiation than pure adenocarcinomas arguing against an unusual form of adenocarcinoma. Our finding of CA 125 expression in bladder tumors of apparent urothelial origin contrasts with some studies that have regarded CA 125 expression as evidence for a mullerian origin. The frequency of gland differentiation in transitional cell carcinomas and the rarity of vesical endometriosis could be taken to suggest that these tumors are mostly of urothelial derivation, but the strong female preponderance in our series argues for a mullerian origin in at least some cases, and this is almost certain in the four cases with benign mullerian components. In the absence of endometriosis or conventional foci of transitional cell carcinoma, it may be impossible to determine whether a tumor with the morphology of clear cell carcinoma is of mullerian or transitional (urothelial) cell lineage, and at this time immunochemistry does not solve this problem.     

UNME/K1: an IgG2a monoclonal antibody specific to cytokeratin of human urinary bladder squamous cell carcinoma

Summary The main distinctive feature of carcinoma in schistosomal bladder is keratinized squamous cell carcinoma. Keratins/cytokeratins constitute a multigeneic family of structurally related polypeptide markers for the malignant state of epithelial cells. A monoclonal antibody (UNME/K1) regognizing keratins associated with squamous cell carcinoma of the human urinary bladder was generated at the Urology and Nephrology Center, Mansoura, Egypt (UNME), by fusion of spleenocytes from a BALB/c mouse immunized with a keratin extract (K1) of human squamous cell carcinoma and P3X63Ag8/U1 syngeneic myeloma cells. UNME/K1 was purified by a protein-A affinity column and was of the IgG2a type, as determined by immunoelectrophoresis and gel diffusion techniques. When tested against keratins of different types of urinary bladder tumors using enzym linked immunosorbent assay (ELISA), UNME/K1 reacted only with the high molecular weight keratin of squamous cell carcinoma and showed selectivity towards specific histopathological grades of tumors.     

A prostatic duct carcinoma difficult to distinguish from transitional cell carcinoma: a case report

A 77-year-old male with a complaint of dysuria and gross hematuria for 3 months visited our hospital. Abdominal ultrasonography, computed tomographic scan and magnetic resonance imaging revealed a prominent tumor from the bladder neck. Serum prostate specific antigen (PSA) level was high (1,130 ng/ml) suggesting prostate cancer, but transitional cell carcinoma (TCC) was detected by transurethral biopsy. Bone scintigraphy revealed multiple bone metastasis. Since gross hematuria requiring bladder tamponade continued, simple cystoprostatectomy and cutaneous ureterostomy were performed. Pathological findings showed prostatic acinar carcinoma and prostatic duct carcinoma mimicking TCC, and PSA immunohistochemically weak positive. The final diagnosis was prostate cancer consisting of acinar and ductal component. Adjuvant hormonal therapy was performed, but was ineffective. The patient died 2.5 months after operation. We reviewed and discussed 66 cases of prostatic duct carcinoma, including our case, in the Japanese literature.     

Detection of P-glycoprotein in human urogenital carcinomas and its relationship to epidermal growth factor receptor expression.

P-glycoprotein and epidermal growth factor (EGF) receptor expression were surveyed immunohistochemically in the tissue of urogenital carcinomas including 12 renal cell carcinomas, 9 bladder transitional cell carcinomas, 2 prostate adenocarcinomas and 1 penile squamous cell carcinoma. Three bladder carcinomas and the penile carcinoma were following initial chemotherapy at the time of relapse. P-glycoprotein expression was detected in 3 of 12 renal cell carcinomas and in all recurrent carcinomas. EGF receptor was not detected in any of the specimens.     

Changing patterns of keratin expression could be associated with functional maturation of the developing human bladder

PURPOSE: We investigate the keratin phenotype of human transitional epithelium at various gestational ages and whether keratin composition of transitional epithelium is related to bladder function and morphology. MATERIALS AND METHODS: Consecutive sections from formalin fixed paraffin embedded blocks of autopsy bladder tissue from 21 male and 5 female fetuses, gestational age 12 to 40 weeks and 7 infants 2 days to 19 months old were cut and stained with antibodies recognizing basal cell keratins 5, 14 and 17, intermediate squamous cell keratin 13 and columnar cell keratins 7, 8, 18 and 20. RESULTS: With gestational age there were distinct changes in expression of keratins recognizing columnar cells, consisting of focal loss of keratin 7 in transitional epithelium, restriction of keratin 20 expression to umbrella cells and expression of keratin 18 throughout the full thickness of transitional epithelium. Basal cell keratin 5 was found above the basal cell layer while keratins 14 and 17 were not found. Squamous cell keratin 13 was found throughout the full thickness of the urothelium. CONCLUSIONS: The changes with gestational age in expression of some keratins may be related to the development of the reservoir function of the bladder. The impermeability of transitional epithelium, particularly during early fetal development, is possibly a function of umbrella and intermediate transitional cells.     

Demonstration of cytokeratins by immunoperoxidase staining in prostatic tissue

The presence and distribution of cytokeratins (CK) have been investigated using an epidermal keratin antiserum in various dilutions and the PaP (peroxidase-antiperoxidase) and avidin-biotin-peroxidase (ABC) immunohistochemical methods. A total of 44 samples of prostatic tissue were divided into alcohol-fixed (22 cases) and formaldehyde-fixed (22 cases). Each group included 12 non-malignant lesions (hyperplasias and prostatitis) and 10 adenocarcinomas. The best results were achieved with the ABC method in alcohol-fixed tissues, while formaldehyde-fixed tissues gave poor staining despite the use of different enzymes to unmask antigenic determinants. With similar dilutions of the specific antiserum the PaP method gave less intense staining. Cytokeratins were detected in basal and columnar cells, in areas of transitional and squamous metaplasia and in normal transitional epithelium. Columnar cells showed strong staining in the supranuclear portion. Adenocarcinomas gave positive staining for cytokeratins varying from weak to strong. The intensity of staining showed no correlation with the degree of differentiation of the tumor. Different degrees of intensity were frequently observed within the same tumor. High dilutions of the specific antiserum (greater than 1/400) failed to stain carcinomas or stained them poorly, whereas they still stained normal or hyperplastic tissues. Gland-forming tumors showed a highly polarized labelling with the strongest staining in the luminal portion of the cell. The conclusion is that all epithelial prostatic tissues, benign and malignant, express cytokeratins.     

Histogenesis of nonurothelial carcinomas of the urinary bladder from pre-existent transitional cell carcinomas. A histopathological and immunohistochemical study

The histogenesis of nonurothelial carcinomas of the urinary bladder is difficult to understand, since the bladder is normally lined exclusively by transitional cell epithelium. To gain more insights into the pathogenesis of nonurothelial carcinomas, the morphology and immunohistochemistry of transitional cell carcinomas (TCC), mixed transitional cell and nonurothelial carcinomas, and pure nonurothelial carcinomas were comparatively studied. Of papillary and of nonpapillary (solid) TCC (overall incidence 6.8%), 4.8% and 15.4%, respectively, disclosed foci of altered celllular and architectural phenotypes, consisting of squamous epithelium, pseudoglandular formations, and true glands with or without mucus production. The diverse phenotypic variants develop obviously by a metaplastic process as a result of the well-known inherent potential of the urothelium to undergo several pathways of cellular differentiation. There is strong evidence that squamous cell carcinomas arise secondarily from a squamous metaplasia and adenocarcinomas from metaplastic glandular epithelium within pre-existing TCC following complete carcinogenic transformation of the initially bland-looking metaplastic tumor cells. The metaplastic origin of nonurothelial bladder carcinomas is supported by immunohistochemical findings. The high molecular weight cytokeratin 34betaE12 identifies tumor cells with squamous characteristics, helping to explain the development of squamous cell carcinomas. Secretion of MUC5AC apomucin is assumed to play a central role in the histogenesis of nonurachal mucus-producing adenocarcinomas, including signet ring cell carcinomas. Metaplastic phenotypic variants of TCC should be recognized as distinct tumor entities with the potential to transform into nonurothelial carcinomas and thus possibly implying a poorer clinical outcome than typical, uniform TCC.     

Studies on the proliferation, secretory activities, and epidermal growth factor receptor expression in benign prostatic hyperplasia explant cultures.

Short term explant cultures of benign prostatic hyperplasia (BPH) tissues were studied immunohistochemically to characterise both the morphological changes within the explant tissue and the cellular origin of the epithelial cell outgrowth. Altered patterns of expression of cytokeratins, prostate specific antigen (PSA) prostatic acid phosphatase (PAP), and epidermal growth factor (EGF) receptor were observed. After sloughing of the secretory epithelium in the majority of the acini repopulation and outgrowth of a monolayer was accomplished by cells which were strongly positive for stratifying keratin and EGF receptor and negative for PAP and PSA, indicative of a basal cell phenotype. The peak of proliferation in the acini, as assessed by Ki-67 immunohistochemistry, occurred after 2-4 days in culture. Preliminary studies on BPH tissue xenografts in nude mice indicated that better preservation of normal morphology, secretory activity, and antigen expression could be achieved.     

Immunohistochemical distribution of epithelial membrane antigen in bladder carcinomas as detected with a monoclonal antibody

Summary Expression of epithelial membrane antigen (EMA) was investigated immunohistochemically in 27 cases of bladder carcinoma using a monoclonal antibody. Normal urothelial epithelium showed EMA staining restricted to the upper layer of the surface epithelium. G-I transitional cell carcinomas demonstrated positive EMA staining which could be divided into the following 3 types; type 1, in which highly stained cells occurred in the upper layer of the neoplastic epithelium; type 2, in which the whole tumour focus was slightly stained; and type 3, in which cells strongly positive for EMA were scattered throughout the tumour focus. G-III (undifferentiated) transitional cell lesions exhibited irregular expression of EMA whereas squamous cell demonstrated specific intense EMA staining within keratinized tumour cells.