Elevated serum progastrin-releasing peptide (31-98) level is a predictor of short response duration after hormonal therapy in metastatic prostate cancer

BACKGROUND: The neuroendocrine (NE) pathway has been attracting attention as a mechanism for the androgen-independent progression because the neuropeptide provokes tumor growth and inhibits apoptosis under androgen-deprived milieu in prostate cancer cells. On the basis that serum progastrin-releasing peptide (ProGRP) is elevated in patients with advanced disease stage, we examined the prognostic value of the neuropeptide. METHODS: Serum ProGRP status was determined with an enzyme-linked immunosorbent assay (ELISA) in 460 men with benign and malignant prostatic diseases, chronic renal failure, and healthy controls. Seventy patients with metastatic prostate cancer including four patients (5.7%) with NE carcinoma who underwent hormonal therapy were enrolled in the prognostic analyses by Cox proportional hazards model. RESULTS: The serum status steadily shifted toward predominant expression of ProGRP with the progression of prostate cancer into metastatic and androgen-independent stages. Univariate analysis revealed that the deteriorated performance status (PS) and extent of bony disease (EOD), and high serum alkaline phosphatase (ALP), serum ProGRP, and nadir prostate-specific antigen (PSA) levels were associated with a lower progression-free survival (PFS) rate (P < 0.005). Multivariate analysis demonstrated that PS, serum ProGRP, and nadir PSA held an independent predictive value for PFS (P < 0.05), and all correlated with bone-related factors. Serum ProGRP was the most significant predictor among pre-treatment factors in this model (P = 0.0094). CONCLUSIONS: The neuropeptide precursor ProGRP is a distinct serum marker that is useful to know the NE milieu and provides prognostic information in patients with advanced prostate cancer. Standard therapy for metastatic prostate cancer may make progress when further studies will clarify the causative link between serum ProGRP level and androgen-independent disease progression.     

Elevated serum progastrin-releasing peptide (31-98) in metastatic and androgen-independent prostate cancer patients

BACKGROUND: Increases in neuroendocrine phenotype and secretory products are closely correlated with tumor progression and androgen independence in prostate cancer. In this study, we explored this correlation using serum progastrin-releasing peptide (ProGRP), a carboxy-terminal region common to three subtypes of precursors for gastrin-releasing peptide (GRP), which is released from the neuroendocrine phenotype to act as a growth factor. METHODS: In 60 patients with benign prostatic hyperplasia (BPH) and 200 with prostate cancer, serum ProGRP levels were determined with an enzyme-linked immunosorbent assay (ELISA) kit and evaluated in relation to clinical stage, hormonal treatment, and prostate-specific antigen (PSA) values. Fourteen randomly selected patients were entered in the follow-up study. Additionally, expression of ProGRP as determined by immunohistochemical analysis was compared to that of chromogranin-A (CgA) in tissue samples from several subjects. RESULTS: We found a positive correlation between PSA and ProGRP in patients with untreated prostate cancer; no correlation was found in the treated groups. The increases in the ProGRP value and in the percentage of patients with higher than normal values were significant (P < 0.0001), especially in the androgen-independent group (P < 0.0001). A longitudinal study showed that, in a subset of patients, the ProGRP values tended to increase transiently when the cancer became androgen independent, but remained unchanged or decreased at the androgen-dependent stage. Positive staining for ProGRP occurred in a different distribution in neuroendocrine tissues than that of staining for CgA. CONCLUSIONS: The clinical results demonstrated the existence of a regulatory mechanism for GRP, which to date had only been observed in cell lines. These findings suggest that GRP is a growth factor potentially upregulated by androgen but that does not rely principally on androgen modulation. The large overlap in levels of ProGRP among the groups limits the use of this value as a monitoring tool. Measurement of ProGRP, however, does have potential as an independent parameter to evaluate androgen-independent progression and to facilitate a new therapeutic strategy that may compensate for current limitations of diagnosis based on PSA alone.     

Small cell carcinoma of the prostate: a case report

An 80-year-old man visited our hospital because of dysuria and pollakisuria. He had undergone anti-androgen therapy for prostate cancer for 8 months at another hospital. His serum prostate specific antigen (PSA) level was 14.4 ng/ml. We performed a prostate biopsy and identified poorly differentiated adenocarcinoma with Gleason score 4 + 5. After 4 months, his serum PSA level increased to 24.8 ng/ml, and we started maximum androgen blockade therapy using additional luteinizing hormone-releasing hormone (LH-RH) analogue. Subsequently, although his serum PSA level declined favorably, his condition worsened rapidly and he died at 16 months after the diagnosis. The autopsy pathology of his prostate revealed small cell carcinoma. We reviewed the initial biopsy specimens and found both small cell carcinoma and adenocarcinoma histologic types of prostate cancer.     

Atypical pulmonary carcinoid tumor with abnormal elevation of serum gastrin-releasing peptide precursor: report of a case

We report a rare case of atypical pulmonary carcinoid tumor accompanied by elevation of serum gastrin-releasing peptide precursor (ProGRP). A 55-year-old male presented to our hospital with a history of bloody sputum. The level of serum ProGRP was elevated to 781 pg/ml (normal < 46 pg/ml). Chest computed tomography (CT) revealed a solitary pulmonary tumor in the left lower lobe with sub-carinal lymph node enlargement. Transbronchial lung biopsy showed a pulmonary carcinoid, therefore left lower lobectomy with mediastinal lymph node dissection was performed. ProGRP decreased to normal level 1 month after operation. Histopathological diagnosis showed an atypical pulmonary carcinoid tumor.     

Prostate small cell carcinoma: report of two cases that differed in treatment responsiveness

Case 1 : A 76-year-old man with a chief complaint of dysuria had an elevated prostate specific antigen (PSA) level of 24.9. He underwent a transperineal needle biopsy of the prostate, and the histopathological diagnosis was prostatic small cell carcinoma. The cancer was clinically diagnosed as T3bN1M1 with multiple lung metastases. He started receiving hormonal therapy. After three months of hormonal therapy, the multiple lung metastases disappeared. Thereafter, the serum PSA level and the tumor volume increased and he died 12 months from the start of therapy. Case 2: A 79-year-old man was referred to our hospital with a chief complaint of dysuria. The serum level of PSA was elevated to 10.4. Transperineal prostate biopsy revealed prostatic small cell carcinoma. The cancer was clinically diagnosed as T3bN1M1, and hormonal therapy was started. Subsequently, although his serum PSA level declined, his condition worsened rapidly and he died five months after the start of therapy.     

Signet ring cell carcinoma of the prostate successfully treated with endocrine therapy: a case report

A 67-year-old man complained of dysuria. The prostate was enlarged and stony hard. The serum level of prostate specific antigen was abnormally high (46.2 ng/ml). Prostatic biopsy showed signet ring cells which were stained positive for prostate specific antigen and poorly differentiated adenocarcinoma. Computed tomographic scan revealed the enlargement of the para-aortic lymph nodes. Endocrine therapy with luteinizing hormone-releasing hormone agonist was started. After two months, the serum level of prostate specific antigen decreased to the normal range. The pathological findings and the good response to endocrine therapy in our case suggest that signet ring cell carcinoma of the prostate is only a morphologic variant of ordinary prostatic adenocarcinoma.     

Metastatic prostate cancer with normal level of serum prostate-specific antigen

The clinical and pathological features of metastatic prostate cancer with normal level of serum prostate-specific antigen (PSA) were investigated. Four patients with metastatic prostate cancer had serum PSA within the normal range at the diagnosis. All tumors were poorly-differentiated adenocarcinoma. Endocrine therapy was performed as the initial therapy in all patients. Despite subsequently treatment, all cases died of prostate cancer at 2, 8, 9 and 38 months. During disease progression, 3 of 4 patients had elevated serum markers such as carcinoembryonic antigen (CEA), CA19-9, CA15-3, CA125, neuron-specific enolase and pro-gastrin releasing peptide. Immunohistochemical examination of the initial biopsy specimens revealed that 4 and 3 cases were positive for CEA and chromogranin A, respectively. In advanced prostate cancer patients with low PSA level, those markers may aid in the follow up of disease.     

Small cell carcinoma of the prostate with hypercalcemia

We present a case of small cell prostate carcinoma with hypercalcemia in a 75-year-old man. He was diagnosed as having stage T3bN1M0 adenocarcinoma of the prostate. His serum prostate-specific antigen level was reduced to below the normal range after a combination treatment of a luteinizing hormone-releasing hormone agonist and flutamide for prostate carcinoma. He subsequently experienced increasing fatigue, poor appetite, short time loss of consciousness and pain in his lower abdomen. His serum calcium level and carcinoembryonic antigen were increased. He died 5 months from the start of treatment. The autopsy revealed small cell carcinoma of the prostate and multiple metastasis of the lung, liver, pancreas, lymph nodes and spine.     

Relapsed prostate cancer with neuroendocrine differentiation and high serum levels of carcinoembryonic antigen without elevation of prostrate-specific antigen: A case report

A 62-year-old man had been treated with combined androgen blockade due to cT2bN1M0 prostate cancer, and his serum prostate-specific antigen (PSA) levels decreased and remained under the level of 0.5 ng/mL during therapy. Approximately 40 months after the initial therapy, difficulty on urination and constipation developed gradually, and serum carcinoembryonic antigen (CEA) and pro-gastrin-releasing peptide (ProGRP) levels were high at this point. He underwent transrectal and transurethral biopsy of the prostate, which revealed adenocarcinoma positive for CEA and chromogranin A. He received palliative pelvic irradiation, and oral estramustine phosphate and etoposide combined therapy. Tumor markers decreased and clinical symptoms improved for several months. The patient died of encephalopathy of unknown etiology approximately 11 months after the relapse.     

Small cell carcinoma of the prostate: a case report

A 79-year-old man was admitted to our department with a chief complaint of urinary incontinence. The prostate was enlarged (145 cc), although the serum level of prostate specific antigen (PSA) was within the normal range (1.09 ng/ml). Digital rectal examination showed an enlarged, irregular prostate with stony hardness. We performed a prostate biopsy and histological examinations indicated poorly differentiated adenocarcinoma with a Gleason score of 5+5=10. A computed tomographic (CT) scan revealed a prostatic tumor invading the bladder, seminal vesicle and rectum. He was diagnosed with a stage T4N1M0 adenocarcinoma of the prostate. He was started-on hormonal therapy, but died one month from the start of treatment. Histological and immunohistological examinations were repeated; suggesting small cell neuroendocrine carcinoma of the prostate.     

Prostatic neuroendocrine carcinoma with priapism : a case report

An 84-year-old man presented with priapism in May, 2009. At 79 years old, he was diagnosed with stage C prostate cancer and then, was treated with hormonal therapy. The serum level of prostate-specific antigen (PSA) was within the normal range (0.02 ng/ml). Penile caverno-dorsal vein shunt (Barry shunt) and caverno-spongiosum shunt (Quackels shunt) were performed for the purpose of managing local symptoms. Following operation, the penile pain was mitigated. Postoperative computed tomography (CT) revealed the enlarged prostate and multiple metastases to lungs and multiple bone metastases. Histological examination of the prostatic needle biopsy revealed poorly differentiated neuroendocrine carcinoma of the prostate.     

Hormonal predictors of prostate cancer

INTRODUCTION: Androgens are necessary for the development and functioning of the prostate gland. The association of serum testosterone and pituitary hormone levels with prostate cancer development is not completely understood. In this clinical study, we evaluated the role of serum testosterone, free testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in predicting prostate cancer risk in patients who had transrectal ultrasonography-guided prostate biopsy with the suspicion of prostate cancer. MATERIAL AND METHODS: A total of 211 patients who were selected to undergo prostatic biopsy due to abnormal digital rectal examination and/or a serum prostate-specific antigen (PSA) level >2.5 ng/ml were included in the study. The patient characteristics of total PSA, free/total PSA ratio, serum total testosterone, free testosterone, free/total testosterone ratio, FSH and LH levels were compared according to the pathological diagnosis. RESULTS: The mean age was 63.91 years (range 44-83) and the mean PSA level was 9.23 ng/ml (range 0.13-50.41) in the whole group. Of 211 patients, 69 (32.7%) were positive for prostate cancer. The patients who were positive for prostate cancer had statistically lower levels of serum total testosterone compared with the patients who were diagnosed as having benign prostatic hyperplasia (BPH; 405 vs. 450.5 ng/dl, respectively; p = 0.013). The serum FSH level was significantly higher in men with prostatic cancer than in men with BPH (7.56 vs. 6.06 mIU/ml, respectively; p = 0.029). No significant differences between men with prostatic cancer and those with BPH were found for serum LH levels. When normal ranges for serum free and total testosterone levels were defined as 9 pg/ml and 300 ng/dl, respectively, patients who had low free testosterone and total testosterone levels had significantly higher cancer detection rates than patients with high serum androgen levels: 40.8% (40/98) versus 25.6% (29/113) (p = 0.021), and 48.6% (18/37) versus 29.3% (51/174), respectively (p = 0.023). After logistic regression analysis, none of the hormones showed a significant difference in predicting the risk of prostate cancer in patients undergoing prostate biopsy with suspicion of the disease. CONCLUSION: Our data suggest that patients diagnosed with prostate cancer have low levels of serum testosterone and high levels of serum FSH compared with the patients with BPH. No support was found for the theory that high levels of testosterone increase prostate cancer risk. Further studies are needed to clarify the relationship between hormones and prostate cancer etiology.     

Giant prostate carcinoma treated effectively with endocrine therapy: case report

An 87-year-old man visited our hospital, complaining of abdominal distention and inability to urinate. Computed tomography (CT) and magnetic resonance imaging revealed a giant prostate tumor. The patient underwent percutaneous tumor biopsies. The histologic diagnosis was moderately differentiated adenocarcinoma of prostate. The clinical stage according to the TNM classification system was T4N0M0, stage IV. Combined androgen blockade therapy was performed. Four months later, CT showed that the tumor had decreased markedly in size, and the serum prostate specific antigen level was within normal range. Hormone refractory prostate cancer was not found 1 year after the start of treatment.     

Scatter factor-hepatocyte growth factor elevation in the serum of patients with prostate cancer

PURPOSE: Scatter factor (SF), also known as hepatocyte growth factor (HGF), has been shown to induce proliferation, scattering and invasiveness in human prostate cancer cell lines. In this study we determined the serum level of SF-HGF in men with metastatic prostate cancer compared to those with localized prostate cancer and without prostate cancer. MATERIALS AND METHODS: Serum samples were obtained from men with biopsy proved adenocarcinoma of the prostate and radiographic evidence of metastatic disease, those with biopsy proved adenocarcinoma of the prostate and clinically localized disease, and those with negative sextant prostate biopsies. Serum SF-HGF was determined using a commercially available enzyme-linked immunosorbent assay kit. RESULTS: Of the 108 men enrolled in our study 52 had negative sextant biopsies, 36 had clinically localized cancer and 20 had metastatic disease. The serum level in men with metastatic disease was significantly elevated (mean 2,117 pg./ml., range 820 to 6,403) compared to that in men with localized cancer and without prostate cancer (mean 974 pg./ml., range 437 to 2,132 and 700, range 272 to 1,875, respectively, p = 9.5 x 10(-15)). Logistic regression analysis demonstrated that the association of ln (SF-HGF) with prostate cancer persisted after controlling for patient age and ln (prostate specific antigen) (p = 3.1 x 10(-4)). CONCLUSIONS: Serum SF-HGF is increased in men with metastatic prostate cancer. SF-HGF levels are associated with metastatic prostate cancer independent of the prostate specific antigen level and patient age. These data imply that SF-HGF may be an important serum marker for prostate cancer.     

Sharpin蛋白在前列腺癌中的表达及其与Gleason评分、t—PSA关系的研究

目的探讨Sharpin蛋白在人不同前列腺癌细胞株中与前列腺癌组织中的表达及其与Gleason评分、血清PSA的关系。方法采用实时荧光定量PCR法,检测Sharpin在DUl45、PC-3和LNCaP3种常见的前列腺癌细胞株和RWPE．1正常前列腺上皮细胞株中的表达。同时采用免疫组织化学方法检测Sharpin在前列腺增生及前列腺癌组织中的表达,并探讨与临床病理特征的关系。结果Sharpin在3种前列腺癌细胞株中的mRNA水平（1．62±0．31,1．36±0．23,2．1±0．1）要明显高于正常前列腺上皮细胞RWPE-1（0．6±0．11）。免疫组织化学结果示Sharpin在前列腺癌组织中高表达,前列腺癌中的阳性表达率远远高于前列腺增生组织,平均染色得分也要远远高于前列腺增生组织。另外,Sharpin在前列腺癌组织中的表达与患者的Gleason评分和术前血清的t-PSA密切相关,均呈正相关（P〈0．05）。结论Sharpin可能是前列腺癌的肿瘤相关抗原,sharpin的表达可能具有评估前列腺癌患者病情、指导临床治疗方案的指导及判断预后及复发的作用。     

Measurement of serum PSA values by DELFIA PSA and its clinical significance on diagnosis and follow-up of prostate cancer patients]

Serum prostate specific antigen (PSA) values detected by DELFIA PSA were evaluated for usefulness in the diagnosis and follow-up of patients with prostate cancer. The system is time-resolved fluoroimmunoassay using europium as a tracer, which has a detectable range of 0.10-500 ng/ml with a small sample volume (25 microliters) and reliable quality control data. Furthermore, serum PSA values detected by the assay were equivocal to those detected by Tandem-R PSA. From the mean +3 S.D. of serum PSA values obtained on 227 normal males, 1.98 ng/ml was decided as an upper normal level. Serum PSA values in benign prostatic hyperplasia (BPH) (n = 69) and prostate cancer (n = 86) patients were statistically higher than those in normal males. However, when 1.98 ng/ml was used as a cut-off value, the false positive rate in BPH cases elevated up to 80%. Therefore, in the differential diagnosis of prostate cancer and BPH, we recommend 11.7 ng/ml (mean + S.D. in BPH cases) as a cut-off value, in which sensitivity is 72.1%, 88.4% are true negative in BPH, and efficacy is 79.4%. Serially determined serum PSA values in following up the patients with prostate cancer were confirmed to be highly effective for diagnosing recurrence and evaluating treatment responses. These findings suggest that DELFIA PSA is a useful tool for determination of serum PSA values.     

Metastases to the penis from carcinoma of the prostate

A 58-year-old man presented with dysuria at the Osaka Medical College Hospital in November 1996. Laboratory examination revealed elevated serum prostate-specific antigen (PSA) to > 100 ng/mL. Adenocarcinoma of the prostate with metastasis to the bone was diagnosed after a biopsy of the prostate and bone scintigraphy; hormonal therapy was administered. Although bone metastasis was well controlled and the serum PSA level declined to within normal levels (2.0 ng/mL), several painless nodules were found on the penile glans. Biopsy of the nodules showed that the penile tumor was a metastasis from the prostate cancer. The patient underwent partial penectomy for relief from penile pain. The serum PSA level showed no elevation 3 months after the partial penectomy, suggesting that careful observation of prostate cancer patients is necessary, even when oseous metastasis is well controlled and serum PSA levels are kept within normal ranges by hormonal therapy. The case also indicates that urologists should consider the possibility of metastasis to the penis from prostate cancer.     

Small-cell neuroendocrine carcinoma as a variant form of prostate cancer recurrence: a case report and short literature review

BACKGROUND: Small-cell neuroendocrine carcinoma has been recognized as a rare histologic variant occurring in only 0.5% to 2% of prostatic primary tumors. However, recent autopsy studies suggest development to this phenotype in up to 10% to 20% of the cases with hormone-refractory disease. CASE PRESENTATION: A case of conventional adenocarcinoma before androgen-ablation therapy but showing progression to small-cell neuroendocrine carcinoma at the recurrence. The immunohistochemistry of the tumor showed strong positive staining for progastrin-releasing peptide (ProGRP), a carboxy terminal region common to 3 precursors for gastrin-releasing peptide, but almost negative staining for chromogranin-A and prostate-specific antigen. Combination chemotherapy based on cisplatin and etoposide was effective for controlling the tumor progression for 7 months, and the serum ProGRP level correlated well to the clinical course. Neither objective nor subjective responses were observed to somatostatin analogue therapy performed in the late stage of disease. CONCLUSIONS: The present case reminds the urologist that small-cell neuroendocrine carcinoma may be a variant form of disease recurrence during androgen ablation in advanced prostate cancer. A strategic approach for this phenotype evaluating serum neuroendocrine markers, such as ProGRP, should be taken when serum prostate-specific antigen does not reflect the disease state. This approach would allow one to choose alternative therapies targeting neuroendocrine cells other than androgen ablation.     

Progression from adenocarcinoma to small cell carcinoma of the prostate during endocrinotherapy: a case report

A 72-year-old man had undergone surgical castration for metastatic prostate cancer (stage D2, the PSA value was 4,300 ng/ml) in September, 1997. He was well clinically for 16 months with undetected level of PSA. However, he presented with general malaise and gross hematuria in May, 1999. After admission to our hospital his condition rapidly deteriorated and he died one week later with respiratory failure. Autopsy revealed extensive involvement of the prostate and bladder by solid tumor with multiple metastases in lungs, liver, spleen, kidneys and bone. Histological examination revealed pure small cell carcinoma of the prostate.     

Mass screening for prostate cancer in Tokushima City: the results of 2001

PURPOSE: Screening with prostate specific antigen (PSA) only to detect prostate cancer was started in Tokushima City from 2001 as one of health check lists. We evaluated the first year result. MATERIALS AND METHODS: Fifty-five years old or elder men living in Tokushima City who wants to measure serum PSA level to screen for prostate cancer were entered to screening program. The men whose PSA levels detected as over normal; range were recommended to visit to urologists for further examination to detect prostate cancer include prostate biopsy. The results of further examination were reported to Tokushima City and evaluated. RESULTS: The population of fifty-five or elder men in Tokushima City was 25,416 and 9,019 (35.5%) men were measured serum PSA levels. In 801 (8.9%) men, PSA levels were over normal range, and recommended further examination to detect prostate cancer. 451 (56.3%) men visited to urologists for further examination, and prostate biopsy was performed in 231 (51.2%) men. Finally, 121 men were diagnosed as prostate cancer, 52.1% of 231 men performed prostate biopsy, 26.7% of 451 men visited to urologist for further examination, 1.34% of 9,019 men measured serum PSA levels. Patient number for each clinical stages were 49 in B0, 16 in B1, 16 in B2, 29 in C, one in D1, and 10 in D2. Patients number in each age range were 3 in 55-59, 11 in 60-64, 22 in 65-69, 37 in 70-74, 33 in 75-79, 15 in 80 or elder. Patient number of Stage B and 74 years old or younger was 48 (39.7%). CONCLUSION: Prostate cancer was detected in 1.34% of 9,019 men who measured serum PSA levels, and early stage B was two thirds. PSA screening to detect prostate cancer as one of health check-lists in Tokushima City was useful to detect early prostate cancer.