Immunohistochemical staining of precursor forms of prostate-specific antigen (proPSA) in metastatic prostate cancer

Precursors of prostate-specific antigen (proPSA) have been previously shown to be more concentrated in prostate cancer tissue. This study characterizes the immunohistochemical staining (IHS) of proPSA forms in metastatic prostate cancer compared with prostate specific antigen (PSA) and prostatic acid phosphatase (PAP). A tissue microarray, consisting of 74 cases of metastatic prostate carcinoma and control tissues, was used. IHS, using monoclonal antibodies against proPSA with a truncated proleader peptide containing 2 amino acids ([-2]pPSA), native ([-5/-7]pPSA), PSA, and PAP, was analyzed. The monoclonal antibodies were specific for both benign and malignant prostatic glandular tissue. IHS with [-5/-7]pPSA showed the least number of cases with negative staining (3%), and the most number of cases with moderate or strong staining (76%). In the 60 cases where all 4 stains could be evaluated, none of them were negative for proPSA and positive for PSA or PAP, and all 7 cases that were negative for both PSA and PAP showed IHS to proPSA. [-5/-7]pPSA (native proPSA) may be a better marker than PSA and PAP in characterizing metastatic prostate adenocarcinoma, with most of the cases showing positivity for the marker. Even cases that were negative for PSA and PAP, were reactive for proPSA. Such enhanced detection is particularly important in poorly differentiated carcinomas involving metastatic sites where prostate carcinoma is a consideration. A panel of markers, including proPSA, should be performed when metastatic prostate carcinoma is in the differential diagnosis.     

The role of P501S and PSA in the diagnosis of metastatic adenocarcinoma of the prostate

BACKGROUND: Adenocarcinoma of the prostate can present as metastatic carcinoma with no known primary. Prostatic origin can be confirmed in most of these cases by immunohistochemistry for prostate-specific antigen (PSA) and prostate-specific acid phosphatase. In a small subset of high-grade prostate carcinomas, both markers are negative and therefore are not helpful for confirming prostatic origin. Recently, novel marker proteins that are preferentially expressed in prostate tissue were identified. One such marker is P501S or prostein, a 553-amino acid protein that is localized to the Golgi complex. It is expressed in both benign and neoplastic prostate tissues, but not in any other normal or malignant tissue examined to date. Owing to its apparent specificity, prostein may be a good marker to demonstrate prostatic origin in metastatic prostate cancer. DESIGN: Five-micron sections of a tissue microarray were subjected to immunohistochemistry with a monoclonal mouse anti-P501S (clone 10E3, Dako, Carpintera, CA) antibody and a monoclonal mouse anti-PSA (clone ER-PR8, Dako, Carpintera, CA) antibody. The tissue microarray contains 78 cases of metastatic prostatic adenocarcinoma, 20 cases of primary prostatic adenocarcinoma, and 20 cases of benign prostate tissue from the peripheral zone as well as samples of benign brain, pancreas, kidney, thyroid, testis, skeletal muscle, and fibroconnective tissue. RESULTS: Similar staining (intensity and extent) was identified for both markers in the majority of metastatic tumors (11 distant sites, 42 pelvic lymph nodes), in all 20 primary tumors and in all benign prostate and nonprostate tissues. The P501S stain had perinuclear cytoplasmic (Golgi) distribution even in poorly differentiated tumors and metastases. Two distant metastases were negative for PSA but retained focal weak positivity for P501S. Two other distant metastases were weakly PSA positive, but strongly P501S positive. Metastases in the pelvic lymph nodes were positive for both markers in 53 cases and 1 lymph node metastasis was strongly PSA positive but P501S negative. In summary, 67 of the 69 cases (97%) of metastatic prostate carcinomas were PSA positive, whereas 68 of the 69 cases showed at least focal weak reactivity for P501S (99%). None of the tumors were negative for both markers. CONCLUSIONS: Immunohistochemistry for P501S is a sensitive and highly specific marker for identifying prostate tissue. The large majority of metastatic prostatic adenocarcinomas are P501S positive (99%). A small subset of metastatic prostatic adenocarcinoma shows significant differences in staining intensity and extent for PSA and P501S and, therefore, combined use of these markers may result in increased sensitivity for detecting prostatic origin.     

Changes in immunohistochemical staining in prostatic adenocarcinoma following diethylstilbestrol therapy

Twenty-eight pretreatment and posttreatment biopsies from 11 cases of prostatic adenocarcinoma were stained for prostate-specific acid phosphatase (PAP), prostate-specific antigen (PSA), and keratin to determine the effect of hormonal (diethylstilbestrol) therapy on these immunological markers. Treatment intervals ranged from 2 to 63 months. All pretreatment tumors were strongly positive for PAP, and nine were strongly positive for PSA. Two were weakly positive for PSA, and all were negative for keratin. In five of the 11 posttreatment group cases, staining with both PAP and PSA was reduced. In three posttreatment cases, the malignant epithelium showed a squamoid appearance, and in these areas the keratin gave a positive reaction. These findings indicate that immunohistochemical staining with PAP and PSA may change in response to hormonal therapy. These alterations may lead to false-negative results when using these techniques to identify the primary tumor source of metastatic deposits of prostatic carcinoma.     

Immunopathology of tissue markers in prostate cancer

Summary Prostatic acid phosphatase (PAP) and prostate specific antigen (PSA) are markers for tumors of prostatic origin. The immunoperoxidase staining for these substances is described for both benign prostates and prostatic carcinomas, including several less frequent subtypes. A list is presented of several non prostatic tissues, which can occassionally cross-react with antibodies to PAP and PSA. PSA is found to be the antigen of choice with PAP a valuable adjunct in differential diagnosis of difficult bladder neck lesions and of metastatic tumors. The usefulness of these markers in diagnosis of fine needle aspiration cytology is also examined.     

Expression of androgen receptor and prostatic specific markers in salivary duct carcinoma: an immunohistochemical analysis of 13 cases and review of the literature

Salivary duct carcinoma (SDC) is an uncommon, pathologically distinct entity characterized by its morphologic resemblance to ductal carcinoma of the breast and highly aggressive behavior. Approximately two thirds of patients die within 4 years of initial diagnosis despite aggressive, combined surgical resection and radiotherapy. Review of the literature indicates that androgen receptor (AR), a marker frequently detected in prostatic carcinoma, is expressed in over 90% of SDCs, whereas two common breast carcinoma markers, estrogen and progesterone receptors (ER and PR), are expressed in only 1.3% and 6% of the tumors, respectively, by immunohistochemistry. This hormonal profile suggests that SDC, in contrast to its histiologic similarity to ductal carcinoma of the breast, is immunophenotypically more related to prostatic carcinoma. To substantiate this hypothesis, we performed immunohistochemical staining of 13 cases of SDC for the presence of AR and two prostatic markers, prostate specific antigen (PSA) and prostatic acid phosphatase (PAP). Our results showed multifocal, scattered, moderate immunostaining for PAP and diffuse, moderate immunostaining for PSA in seven (58.3%) and two (16.7%) cases, respectively. These results create a potential diagnostic challenge to surgical pathologists who are dealing with a metastatic adenocarcinoma of AR+/PSA+/-/PAP+/- phenotype, particularly in male patients of unknown primary. Metastatic salivary duct carcinoma should be given serious thought if clinical investigation fails to reveal a prostatic primary. The immunophenotypic homology that exists between SDC and prostatic carcinoma also suggests that antiandrogen therapy as used in the treatment of prostatic carcinoma might be beneficial in patients with metastatic SDC when all other conventional modalities fail.     

Carcinoembryonic antigen and carbohydrate antigen 19-9-producing adenocarcinoma of the prostate: report of an autopsy case

Prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) are well known as specific tumor markers of prostate cancer, but carcinoembryonic antigen (CEA)- and carbohydrate antigen 19-9 (CA19-9)-producing adenocarcinoma originating in the prostate is rare. We report here a case of prostatic adenocarcinoma positive for these 4 tumor markers in a 50-year-old man who had initially complained about chest pain due to metastatic bone tumor. In spite of the extensive treatment involving hormone and radiation therapy, the patient died of rapid tumor extension only 4 months after initial diagnosis. Autopsy revealed multiple metastases to the bone, liver, lungs and lymph nodes. Histologically, two types of adenocarcinoma were involved in both primary prostate and metastatic sites: one was a poorly differentiated adenocarcinoma positive for PSA and PAP but not CEA or CA19-9, and the other one was a less differentiated adenocarcinoma partially positive for CEA and CA19-9 but not for PSA or PAP. Based on this case and previous cases by review of the literature, CEA- and CA19-9-producing adenocarcinoma of the prostate was suggested to rapidly progress with multiple metastases and to show poor prognosis with strong resistance to any treatment.     

Immunohistochemical diagnosis of a case of metastatic prostate cancer to breast

Bilateral breast mass was found in a 71-year-old male who had been placed on estrogen therapy for stage D2 prostatic adenocarcinoma. Microscopically the mass contained adenocarcinoma morphologically similar to that of the prostate, but the differential diagnosis was impossible between metastatic prostatic carcinoma and primary breast carcinoma. Formalin-paraffin sections of both tumors were stained positively by PSA (prostatic specific antigen) and PAP (prostatic acid phosphatase) using B-SA (biotin-streptavidin) system technique and prostatic origin of the breast mass was confirmed. Prostatic origin for metastatic carcinoma in the breast is are with only 30 reported cases in the literature including 5 Japanese cases. In most of them the diagnosis of the breast lesion as prostatic carcinoma has been made on morphologic and clinical grounds only. Accurate diagnosis is important for the prognosis of the patient, and immunohistochemical method is useful for he diagnosis of breast carcinoma metastasized from prostatic origin.     

Prostatic carcinosarcoma: case report and review of literature

True carcinosarcoma of the prostate is a rare neoplasm, with only 9 cases well documented by immunocytochemistry and ultrastructural examination. We report a case of an unresectable pelvic tumor studied at autopsy. The primary prostatic neoplasm and pulmonary metastases were composed of well differentiated adenocarcinoma admixed with foci of leiomyosarcoma and osteosarcoma. The sarcomatous components showed reactivity with vimentin and desmin, did not express prostatic acid phosphatase (PAP) and prostate specific antigen (PSA), and contained myofilaments on electron microscopic examination. Positive staining of the carcinomatous component for PAP and PSA was noted. These findings confirm the mixed epithelial and mesenchymal components in primary and metastatic sites, and support the diagnosis of true prostatic carcinosarcoma.     

Changes of phenotypic expression of prostatic antigen in secondary transitional cell carcinoma of the prostate: evidence for induction phenomenon as a mechanism for acquisition of prostatic antigens in prostatic transitional cell carcinoma

BACKGROUND: In vitro and experimental studies of mesenchymal-epithelial interaction for the prostatic stroma have demonstrated that the prostatic stroma is capable of inducing the nonprostatic epithelium to acquire many features of prostatic epithelium. We investigated whether this phenomenon could be observed in vivo in human prostatic stroma. MATERIALS AND METHODS Sixty transitional cell carcinoma (TCC) of the urinary bladder: (a) 20 with glandular lumen; (b) 20 without glandular lumen: (c) 10 mixed TCC-adenocarcinoma (ACA); and (d) 10 with synchronous or metachronous TCC of the prostate; and three primary TCC of the prostate were examined and submitted for immunostaining for prostatic acid phosphatase (PAP) and prostatic specific antigen (PSA). RESULTS: There was a spectrum of immunostaining for PSA ranging from negative reactivity in TCC without glandular lumen of the urinary bladder, to focal and weak reactivity in single cells with varying degrees of nonmucinous glandular differentiation and to strong reactivity in groups of cells in primary and synchronous or metachronous TCC in the prostate. The areas of carcinoma geographically closest to the prostate and with the most extensive nonmucinous glandular differentiation displayed the most frequent and strongest immunoreactivity for PSA. The immunoreactivity for PAP was usually stronger than for PSA. Four cases of TCC and mixed TCC-ACA were immunoreactive only for PAP. Furthermore, there was a change in the phenotype of TCC in the urinary bladder as it spread into the prostate. For 10 TCC in the urinary bladder with synchronous or metachronous tumor in the prostate, all TCC in the urinary bladder were negative for PAP and PSA, whereas six TCC in the prostate were focally positive. CONCLUSIONS: The spectrum of immunoreactivity for PAP and PSA and the change in immunoreactivity of TCC of the urinary bladder as it spreads into the prostate are likely induced by the prostatic stroma through the mechanism of mesenchymal-epithelial interaction. Prostate 47:172-182, 2001.     

PAP and PSA in prostatic carcinoma cell lines and aspiration biopsies: relation to hormone sensitivity and to cytological grading

Because a change from hormone-sensitive to hormone-resistant carcinoma of the prostate often occurs concomitantly with genetic changes or as a result of the latter, the markers specific for prostatic tissues might also be affected. We therefore first studied the presence of prostatic acid phosphatase (PAP) and prostate-specific antigen (PSA) in LNCaP and LNCaP-r human prostatic carcinoma cell lines. Since both markers were found in these cell lines, we proceeded to quantitate PAP and PSA in aspiration biopsies from patients with prostate tumors. The amounts of these markers were compared with cytological findings. PAP and PSA were analyzed in the biopsy material from 120 patients using commercial radioimmunoassay (RIA) kits. DNA was determined using Riedel H33258 stain. Cytological grading was performed according to the Uropathological Study Group of Prostatic Carcinoma. Significant correlations were found between PAP/DNA or PSA/DNA values and grade of differentiation of the prostate tumor. In view of earlier reports and the results presented here, the amounts of markers or the protein pattern of tumor tissue may be a useful complement to the morphological findings and for selecting optimal therapy for patients with prostatic tumors.     

Naturally occurring prostate cancer antigen-specific T cell responses of a Th1 phenotype can be detected in patients with prostate cancer

BACKGROUND: Cytotoxic T cells (CTL) are considered one of the primary effector cell populations in antitumor immunity. Recent studies, however, have demonstrated the critical importance of helper T cells (Th), specifically interferon gamma (IFN gamma)-secreting Th1 cells, either by supporting an appropriate CTL environment or by recruiting other effector cells. We evaluated whether patients with prostate cancer have naturally occurring Th-cell responses specific for two prostate cancer-associated antigens, prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP), and whether Th1-type responses to these antigens could be detected. METHODS: Peripheral blood mononuclear cells (PBMC) were collected from 80 patients with prostate cancer and 20 male controls without prostate disease. Th-cell responses were evaluated by measuring antigen-specific proliferation. IFN gamma and IL-5 secretion in response to antigen stimulation was determined by enzyme-linked immunosorbent assay. RESULTS: T cell proliferative responses specific for PSA and PAP could be detected in patients with prostate cancer. Six percent (5/80) of patients had T cell responses specific for PSA and 11% (9/80) for PAP. T cell responses specific for PSA were more prevalent in patients with metastatic disease (P = 0.02), whereas responses specific for PAP could be detected in patients irrespective of disease stage. IFN gamma-producing Th cells, specific for both PSA and PAP, could be identified in patients with prostate cancer. CONCLUSIONS: Patients with prostate cancer can have detectable Th-cell responses specific for the prostate cancer-associated proteins PSA and PAP. The presence of antigen-specific Th1 immune responses in prostate cancer patients suggests that an immune environment capable of supporting antigen-specific CTL may exist in vivo. Prostate 47:222-229, 2001.     

Evaluation of commercial immunoperoxidase kits in diagnosis of prostate carcinoma

Comparison of one commercial immunoperoxidase kit for prostate specific acid phosphatase (PSAP) and two for prostate specific antigen (PA) with an unlabelled antibody peroxidase-antiperoxidase (PAP) technique using rabbit antihuman PSAP revealed generally good reproducibility of results on formalin fixed, paraffin-embedded sections of primary and metastatic prostatic carcinoma. Frequency of positivity was 92 per cent with both our noncommercial PAP and the kit method for PSAP, and 82 per cent and 89 per cent with kits for PA. Thus, sensitivity, with the PA kits was less than with our noncommercial PAP and the kit PSAP, with less intense immunostain and occasional false negatives. Specificity was good with all three kits, and no false positive results were obtained. Commercial immunoperoxidase kits provide a relatively easy and inexpensive means for practicing pathologists in a service-oriented setting to make more precise diagnoses in cases of poorly differentiated or metastatic carcinoma of prostatic origin.     

Immunoreactive prostatic specific antigen in male periurethral glands.

Prostatic specific antigen (PSA) is considered an antigen unique to benign and malignant prostatic tissue. Recent evidence in the literature has raised serious doubts about the specificity of this antigen. In this study twenty male urethral specimens were evaluated for PSA and prostatic acid phosphatase (PAP) from patients without evidence of prostatic cancer. Eight of these 20 urethral specimens exhibited strong immunostaining for both PSA and PAP, localized in the periurethral glands. Five of the 17 urethral biopsies were positive for both antigens, while all three of the whole mount autopsy specimens stained positive for PSA and PAP. Within the autopsy series, there was heterogenous staining of the periurethral glands within the same specimen. This evidence disproves the fact that PSA and PAP are organ specific as previously described. More than likely any tissue of cloacal origin has potential for staining positive for prostatic specific antigen and prostatic acid phosphatase.     

Immunohistochemical diagnosis of the metastasizing prostatic carcinoma

Metastases of 47 known prostatic carcinomas were subjected to the unlabeled immunoperoxidase procedure to localize prostate acid phosphatase (PAP) and prostate-specific antigen (PSA). PAP was found in 64% and PSA in 78% of bone marrow, lymph node, lung and liver metastases investigated. There was no significant difference between the intensity of staining in primary and metastatic neoplasms. Staining of PAP and PSA was found to be less intense in poorly differentiated metastases of prostatic adenocarcinomas. The data suggest that the demonstration of PAP and PSA is a practical and sensitive test for determining the prostatic origin of a clinically and histologically unclassifiable metastasis.     

Daily variability in human serum prostate-specific antigen and prostatic acid phosphatase: a comparative evaluation

The daily variation of serum levels of prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) was investigated simultaneously in 10 patients with osseous metastatic prostatic cancer, 10 patients with benign prostatic hyperplasia, and 10 volunteers without prostatic disease. Duplicate serum samples were obtained from all patients on the same day at 8 AM, 12 PM, 4 PM, and 8 PM. Statistical analysis (two-factor analysis of variance comparing time period to disease group) of the mean PSA and PAP levels at the four sampling times on all patient groups demonstrated no evidence of circadian rhythmic variation or any other distinct pattern for the observed sample times. Overall, the variability in PSA levels was significantly less than that observed for PAP. There was no significant difference in mean percent variation between patient groups (cancer, benign, and normal prostate glands) for both the PSA and PAP assays. Our data reveal that serum PSA measurements fluctuate unpredictably over the course of a day in patients with and without prostatic disease, but to a lesser extent than that seen for serum PAP values. These findings illustrate the potential inaccuracy of single determinations of serum PAP or PSA levels for monitoring disease recurrence and treatment response in patients with prostate cancer.     

Comparative study of the clinical usefulness of prostate specific antigen and prostatic acid phosphatase in prostatic disease

The clinical usefulness of prostate specific antigen (PSA) and prostatic acid phosphatase (PAP) activity measurements has been compared in 45 patients with benign prostatic hyperplasia (BPH) and 132 patients with prostatic carcinoma (PC), 21 of whom had metastatic disease (MPC) and 111 of whom had intracapsular cancer. No BPH patient had increased PAP but 47% had increased PSA. Of the PC patients only 27% had increased PAP and 70% increased PSA. All of the MPC patients had increased PSA but only 62% had increased PAP. Increased PAP was found only in MPC but increased PSA was also found in BPH. In identifying PC, the predictive value of an increased PSA concentration is 83% and an increased PAP activity is 100%. On the other hand, the predictive value of a normal PSA concentration is 51% and of a normal PAP activity only 34%. As the PAP test is much less efficient than the PSA test, it should be discontinued.     

Changes in tumor markers following cryosurgery of prostate carcinoma

Cryosurgery is performed in poor risk cases of prostate carcinoma with dysuria. This modality has been reported to reduce the metastatic lesion postoperatively in cases of prostate carcinoma accompanied by metastasis and is employed as an adjuvant therapy of prostate carcinoma. However, many cases are already at an advanced stage and have undergone other therapeutic modalities and as a result the exact role of cryosurgery in prostate carcinoma is not clear. The present investigation was undertaken to clarify the effectiveness of cryosurgery in prostate carcinoma. The patients consisted of 21 untreated cases of histologically confirmed prostate carcinoma admitted our hospital during the 5-year period from December, 1982 to December, 1987, in all of whom treatment by cryosurgery alone was indicated, i.e., up stage B, and in whom changes in prostate carcinoma tumor markers, alkaline phosphatase (ALP), acid phosphatase (ACP), prostatic ACP detected enzymatically (PACP), and by radioimmunoassay (PAP), gamma-seminoprotein (gamma-Sm), and prostate specific antigen (PSA) were measured. During the same period, changes in tumor makers in 11 cases of prostate hypertrophy treated by transurethral resection of prostate (TUR-P) were also examined. The tumor markers were measured prior to cryosurgery and 1, 3, 7 and 14 days postoperatively as well as at 1, 3 and 6 months. Following TUR-P, in the cases of prostate hypertrophy, no postoperative changes in ALP, ACP or PACP were observed but there was elevation of PAP and gamma-Sm at day 1 and elevation of PSA until day 3, but none of these were statistically significant differences.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adenocarcinoma of the prostate involving 2 cell types (prostate specific antigen producing and carcinoembryonic antigen producing) with selective metastatic spread.

Of 3 patients with clinically localized adenocarcinoma of the prostate 2 were treated by radical prostatectomy and 1 was treated with radiation therapy. Serum prostate specific antigen (PSA) values were elevated before therapy. After treatment the PSA levels were decreased to zero. All 3 patients later had evidence of metastatic tumor spread to the liver with elevation of serum carcinoembryonic antigen but not PSA. Immunohistochemical staining of the 2 primary tumors from the prostatectomy specimens identified 2 cell clones, one immunoreactive to PSA and prostatic acid phosphatase (PAP) and nonimmunoreactive to carcinoembryonic antigen, and the other immunoreactive to carcinoembryonic antigen but not PSA or PAP. Biopsy of a hepatic metastasis in 2 patients confirmed anaplastic carcinoma of the carcinoembryonic antigen-producing cell type. Immunohistochemical staining of a lymph node metastasis identified the PSA-producing cell type only. Such results suggest selective metastatic spread of each cell type to its own organ tropic site. Occasional carcinoembryonic antigen-producing prostate cancers may metastasize to the liver. Serum carcinoembryonic antigen measurements occasionally may be useful in the management of certain prostate adenocarcinoma patients.     

Prostate tumour markers and differentiation grade in prostatic cancer.

Serum acid phosphatase activity, prostate specific phosphatase and prostate specific antigen were measured in 100 patients with prostatic cancer. The patients were divided according to the differentiation grade into 3 groups: G1 (well), G2 (moderately) and G3 (poorly differentiated) carcinoma. Bone metastases were identified by scintigraphy. Among the 76 M0 patients the mean levels of all 3 markers were slightly higher in patients with moderately differentiated prostatic carcinoma. Among the 24 M1 patients the primary tumour was either G2 (18 patients) or G3 (6 patients); none had G1 lesions. Significantly higher serum ACP and PAP levels were found in patients with G2 tumours than in those with G3 lesions. It was concluded that the histological differentiation grade of prostatic carcinoma did affect serum levels of prostatic tumour markers; the tendency towards higher levels in the G2 group was noticeable in both non-metastatic and metastatic cases despite the limited number of patients in the latter category. In clinical practice this information may be an important additional tool in staging prostatic cancer.     

Influence of luteinizing hormone-releasing hormone analogues on serum levels of prostatic acid phosphatase and prostatic specific antigen in patients with metastatic carcinoma of the prostate

Serum concentrations of luteinizing hormone (LH), testosterone, prostatic acid phosphatase (PAP) and prostatic specific antigen (PSA) were measured in 16 patients with advanced prostatic cancer before and after treatment with luteinizing hormone-releasing hormone (LHRH) analogue. An initial rise of serum LH and testosterone levels was observed on day 2 of the treatment. Subsequently, serum concentrations of PAP and PSA showed a transient increase on day 5 of the treatment. This indicates that LHRH analogues had better be given in combination with antiandrogens in patients with metastatic carcinoma of the prostate.