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W2080450770 abstract "Prostate cancer is the most commonly diagnosed malignancy and second leading cause of male cancer–related death in the Western world [1, 2]. With the widespread use of prostate–specific antigen (PSA) testing, there has been a dramatic increase in the number of newly diagnosed cases [3]. The mortality rate has also increased, though far less than the corresponding incidence rates. This wide discrepancy between incidence and mortality rates highlights the variable biologic behavior of this disease. Some tumors are small, of low histologic grade and unlikely to progress, the so–called ‘indolent’ cancers. The others are larger or of higher grade, the so–called ‘clinically important’ cancers that are much more likely to progress, metastasize and cause death [4]. Characterizing the clinical and biologic significance of early stage prostate cancer in an individual is highly desirable since it would provide valuable information in planning therapy and defining prognosis.Currently established prognostic markers include clinical stage, preoperative PSA level, histologic grade and extent of cancer in the needle biopsy specimen [5]. The prognostic value of these markers, however, becomes limited once tumors fall in their intermediate range when it becomes impossible to define with certainty the anticipated course of a given cancer. In recent years, a variety of tissue and biomarkers have been evaluated and show promise. Some of these include perineural invasion, lymphovascular invasion, DNA ploidy status, nuclear morphometry, microvascular density, markers of chromosomal anomalies, proliferative markers, peptide growth factors, cell–cell adhesion molecules, androgen receptor (AR) status, apoptotic index and tumor–suppressor genes [6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17]. While the early results are promising, these markers have not yet been established as independent prognostic factors.Neuroendocrine (NE) differentiation in prostate cancer has received increasing attention in recent years due to prognostic and therapeutic implications. The NE cells are widely distributed in the acini and ducts of the normal prostate gland and produce neurosecretory products, which affect growth, differentiation and regulation of secretory functions [18, 19, 20]. NE cells also constitute a variable component of most adenocarcinomas of prostate and recent evidence indicates their possible role in tumor proliferation, progression and development of androgen refractory state. Clinical studies have shown that prostate cancer with extensive NE differentiation behaves aggressively and is associated with poor prognosis [21, 22].Many studies have pointed out that NE differentiation has prognostic value independent of histological grade [22, 23]. Some investigators demonstrated a correlation with other known risk factors, such as grade and stage [21, 22]. The evidence, however, is conflicting since many studies found no correlation between NE differentiation and prognosis [24, 25].In this article, we review the current literature and assess the significance of NE differentiation in predicting the biological behavior of prostate cancer. This becomes particularly important for intermediate histologic grade tumors, which exhibit marked clinical disparity with regard to prognosis.NE cells in normal prostate constitute part of a diffuse multiorgan regulatory system also known as the amine precursor uptake and decarboxylation cell system. While NE cells are predominantly clustered in the lungs, gastrointestinal tract, C cells of the thyroid, and islet cells of the pancreas, they also occur in non–NE organs, like the prostate. These cells were originally considered to be of migratory neural crest origin but recent evidence suggests origin from the local endoderm [26]and from a single pluripotent stem cell [27].The NE cells are widely distributed in the ducts and acini of the prostate gland and in the urethral epithelium. Morphologically, they consist of two types: open and closed. While all NE cells have dendritic processes extending underneath and between adjacent epithelial cells, the open type also has apical processes extending to the lumen which are absent in the closed type. NE cells tend to vary quantitatively during the various phases in life. They are most abundant in the human prostate at birth, during fetal growth and at puberty. However, during quiescent growth intervals they are not readily observable [28]. NE cells in the peripheral prostate and utricle exhibit variation with age [29]indicating their hormone dependence, whereas those in the urethral region and prostatic urethra do not.Although NE cells secrete neuropeptides and biogenic amines, their exact function in the prostate remains unclear. By virtue of the secretory products it is highly likely that they regulate endocrine secretion and cellular growth and differentiation. These functions are mediated by autocrine, lumencrine, endocrine–neurocrine and paracrine mechanisms. Gershagen et al. [20]has proposed exocrine function for NE cells as well. Several lines of evidence suggest a significant role of NE cells in these functions: (1) autonomic afferent and efferent innervation raising the possibility of neurocrine secretions [18]; (2) localization of NE cells in the prostate [18], and (3) the presence of peptides involved in regulation of morphogenesis, and in an analogy to other well–established NE systems [18].Electron microscopy has revealed different types of secretory granules in NE cells, suggesting cellular heterogeneity [30]. Nearly all NE cells in the prostate secrete serotonin and other regulatory peptides like chromogranin (A, B), and the secretogranin family, calcitonin gene family (calcitonin, calcitonin gene–related peptide and katacalcin), parathyroid hormone–related protein, thyroid– stimulating hormone–like peptide, somatostatin and bombesin–like peptide [18, 31, 32]. Recent findings also suggest that neurotransmitters, including serotonin, play a facilitatory role in androgen action.The origin of NE cells in prostate cancer is controversial since in the normal prostate these cells are post–mitotic and terminally differentiated; there is no convincing evidence that neoplastic NE cells originate from transformed NE cells of a benign gland. Bonkhoff et al. [33]have shown by immunohistochemical studies that NE foci in prostate cancer have amphicrine cells, i.e. cells expressing both endocrine markers (chromogranin A) and exocrine markers (PSA). This strongly supports the concept that NE cells in prostate cancer originate from PSA–positive cell types during tumor progression.NE differentiation in prostatic adenocarcinoma is more frequently observed than any other genitourinary malignancy and occurs in three different forms: (1) small cell carcinoma [34]; (2) carcinoid and carcinoid–like tumors, and (3) focal NE differentiation in a conventional prostatic adenocarcinoma [35](table 1).Small cell carcinoma (SCC) of the prostate is a rare and extremely aggressive tumor. It frequently presents at an advanced stage with nodal or visceral metastasis and frequently has a rapidly fatal course. It was nearly 50 years after Barnard [34]described SCC in the lungs that Wenk et al. [36]in 1977 reported the first case of SCC of the prostate in a 62–year–old man. So far, less than 150 cases have been reported in the literature with an incidence of <1% of all prostatic neoplasm [37].Based on light microscopy, SCC is subdivided into oat cell, intermediate cell, and combined carcinoma types. In most cases, SCC is associated with prostatic adenocarcinoma. It usually grows in the form of nests and sheets of anaplastic cells with occasional formation of ribbons, rosettes or palisades. While routine histochemical studies with argentaffin and argyrophil stains are not very helpful, immunohistochemical studies are extremely useful in establishing the diagnosis [38]. SCC of the prostate expresses a variety of epithelial and neural markers, elaborate hormones, peptides and other bioactive substances, which can be assessed by immunohistochemistry (table 1). It rarely stains for PSA but usually shows immunoreactivity to two or more NE markers. Of particular use are neuron–specific enolase (NSE), chromogranin A and B, and synaptophysin. In questionable cases, ultrastructural studies are helpful in establishing the diagnosis and differentiating SCC from other tumors composed of small– and medium–sized cells.Primary prostatic SCC should be differentiated from other tumors composed of small– and intermediate–sized cells. These include lymphomas, malignant melanomas, neuroblastomas, embryonal rhabdomyosarcoma and Ewing’s sarcoma, carcinoid and secondaries from primary SCC.The vast majority of patients with locally advanced or metastatic disease, and the clinical picture could be complicated by an associated endocrinopathy or paraneoplastic syndrome. SCC of the prostate may be suspected if a tumor displays an unusually aggressive behavior and rapid progression despite conventional treatment. Multidrug combination chemotherapy is the cornerstone of treatment with surgery or radiation treatment as adjunctive. Amato et al. [39]reported 10% complete response and 52% partial response with a median survival of 9.4 months in 21 patients with SCC of the prostate treated with combination therapy. No difference exists in response to chemotherapy among various variants of SCC (pure or mixed). Oesterling et al. [40]reported a median survival of 17.1 months in 27 patients treated with radiotherapy and androgen ablation. Di Sant’Agnese [35]has also shown that SCC of the prostate frequently fails to respond to conventional androgen ablation therapy.Although carcinoids elsewhere in the body do not have an aggressive disposition [41], it is not true for the prostatic variant. Prostatic carcinoids are biologically aggressive, poorly differentiated tumors which display extensive NE differentiation.Focal NE differentiation, based on immunohistochemical studies, is far more common, reported in as may as 10–92% of cases with prostatic adenocarcinoma. The clinical and prognostic significance of these changes, however, remains unclear. Krijnen et al. [42]showed that NE–differentiated cells fail to express ARs suggesting that they may function independent of hormonal regulation. Many of the biogenic amines and peptides produced by NE cells, such as serotonin, calcitonin, calcitonin gene–related peptide, parathyroid hormone–related peptide and bombesin/gastrin–related peptide have shown growth–promoting properties [43]. Bonkhoff et al. [33]showed that the rate of proliferation of prostate cancer in the vicinity of NE differentiation is higher. Also, increased expression of antiapoptotic oncogenes (bcl 2) is shown in NE cells close to cancer foci.Cohen et al. [21]in 1991 suggested that NE cells take part in tumor progression and should be considered as an independent prognostic variable. In their clinical study, they showed a worse outcome in prostate cancer cases exhibiting higher NE differentiation than in those with a low percentage of NE differentiation. Since there were many compounding variables, the significance of these findings is questionable.NE–differentiated tumors, in general, are resistant to hormonal therapy. Krijen et al. [22]assessed the significance of NE differentiation using chromogranin A as a marker in patients with prostate cancer treated with palliative transurethral resection of the prostate (TURP) and androgen ablation. Their results strongly suggest that NE differentiation correlates with poor prognosis and disease progression. It was also noted that NE differentiation in prostate cancer is associated with an early failure of androgen ablation therapy. The authors noted that the prognostic significance of NE differentiation was independent of tumor grade.The correlation between tumor progression and NE differentiation is not uniformly noted. Many investigators have challenged the independent prognostic significance of NE differentiation in prostate cancer (table 2). An increasing NE differentiation is seen with worsening grade and tumor stage that could well be an epiphenomenon rather than actually conferring poor prognosis independently.McWilliam et al. [23]reported NE differentiation using chromogranin A and NSE in 52% of patients with prostate cancer undergoing TURP. They reported a significant correlation with worsening tumor differentiation, presence of bone metastases and worsening survival. They, however, found no independent effect of NE differentiation on survival. Speights et al. [44]correlated NE differentiation with indices of tumor proliferation and differentiation (MIB–1) in defining the prognosis of patients with prostatic adenocarcinoma undergoing TURP. They divided the patients into 2 groups: those with high–grade (≥7 Gleason sum) and high–stage (III and IV) tumors versus those with low–grade (≤6 Gleason sum) and low–stage tumors (IIa). NE differentiation and the proliferative index were determined by immunohistochemical staining using chromogranin A, synaptophysin, NSE and MIB–1, respectively. They found that the mean number of NE cells and mean proliferative index were statistically significantly greater in high–stage, high–grade tumors. However, they found no significant difference between the mean values of NE cells and proliferative index in high–grade/high–stage tumors that progressed and ones that did not. They failed to show an independent prognostic significance of NE differentiation.The variable prognostic significance of NE differentiation in different studies could be explained by: (1) methodlogical differences in determining the NE differentiation; (2) variance in interpretation of immunohistochemical results as methods presently employed are semiquantitative and require standardization; (3) the different cohorts of patients studied, and (4) if limited tissue samples are used there could be a serious sampling error as NE cells have unequal distribution in most tumors.Most studies have looked at NE differentiation in nonorgan–confined prostate cancer cases where the correlation with poor prognosis may be coincidental rather than causative. Some investigators have, however, evaluated the impact of NE differentiation on prognosis in organ–confined tumors.Van de Voorde et al. [45]studied morphologic and immunohistochemical changes in prostate cancer treated by radical prostatectomy after neo–adjuvant hormonal therapy. NE differentiation as indicated by chromogranin A expression was seen in 95% of tumors which was, however, restricted to certain areas only. A diffusely dispersed staining pattern was seen in fewer tumors. The authors noted an increased expression of chromogranin A with more advanced stage tumors, with increasing tumor volume, and increasing expression of proliferating cell nuclear antigen.Sheaff et al. [46]studied β–HCG expression in localized prostate cancer. Amongst 80 cases, 12 (9.6%) stained positively for β–HCG of which 9 (75%) developed metastases and 11 (92%) died within 18 months. Of the 68 (90.4%) β–HCG–negative cases, only 21 (31%) developed metastases and 25 (37%) died within 18 months. In the β–HCG–positive group, there was no correlation with grade, indicating its independent prognostic significance.Weinstein et al. [47]studied 104 patients with clinically organ–confined prostate cancer treated by radical prostatectomy. They found that histological grade (Gleason sum) and NE differentiation predicted progression in a multivariate analysis. NE differentiation provided prognostic information in addition to that provided by histological grade in cases of early prostate cancer. The authors found NE differentiation particularly useful in predicting prognosis for intermediate Gleason sum (5–6) tumors for which, at present, there is no definite prognostic indication.On the contrary, Cohen et al. [24]did not find NE differentiation useful in predicting tumor progression. Thirty–eight patients with stage–II prostate cancers were followed for 4 years beyond radical retropubic prostatectomy. While progression correlated well with the pathologic stage, NE positivity (chromogranin A and NSE) seen in more than 50% of radical prostatectomy specimens failed to predict tumor progression. In addition, the authors found no significant correlation in the staining between needle biopsy specimens and radical prostatectomy specimens.The androgen dependency of prostatic adenocarcinoma is well established, ever since the classical work of Huggins and Hodges [48]. Androgen ablation thus remains the mainstay in the treatment of (1) metastatic cancer, (2) recurrence following definitive treatment [49], and (3) as neo–adjuvant therapy prior to radiation therapy [50].The excellent initial response seen in most patients with metastatic cancer following androgen ablation is, in part, attributed to high AR content [51]. Poorly differentiated tumors are shown to respond poorly to androgen ablation [52], which could well be due to a diminished population of AR cells [53].Following the initial good response, most patients develop a hormone refractory state within 18–36 months. While the mechanisms leading to transformation of the hormone responsive to the refractory state remain unclear, many investigators have evaluated the role of NE differentiation in such cases [53, 54].Di Sant’Agnese and de Mesy Jensen [30]has attributed NE differentiation as one of the key factors leading to a lack of responsiveness of prostate cancer to androgen ablation. Krijnen et al. [42]by double immunofluorescent studies have shown that prostate cancer cells staining positive for chromogranin A fail to demonstrate ARs.Tetu et al. [54]observed that hormone insensitive, NE–differentiated, prostatic cancer, if endowed with the capacity to proliferative, eventually gives rise to a pure NE tumor. It is, however, a clinically infrequent phenomenon. On the contrary, Van der Kwast et al. [55]noted that 80% of hormone–insensitive prostate cancers following androgen ablation harbor a high proportion of AR–positive tumor cells.Since NE cells play a role in growth and differentiation, focal NE differentiation in prostatic adenocarcinoma is suggested to influence the proliferation of surrounding non–NE cells. A paracrine role of NE cells during the transition of androgen responsive to an androgen refractory prostatic adenocarcinoma has been proposed [53]. This paracrine effect is likely to continue despite androgen ablation therapy as these cells are AR–negative and continue to influence growth and proliferation of neighboring cells. Therefore, it is reasonable to suppose that even with continued androgen ablation, AR–negative cells and tumor cells exhibiting NE differentiation would increase in number. This is also supported by the observation of Abrahamson [53]that following androgen ablation therapy, tumor cells with NE differentiation increase.Koivisto et al. [56]recently reviewed the possible etiological factors in the development of hormone refractory prostate cancer (HRPC). Many of these involve the AR gene and its complex downstream signaling pathways. Several mutations of the AR gene in human prostate cancer have been found and many of these target the androgen–binding domain of the receptor. Furthermore, mutations are more frequent in distant metastases than in the primary tumor. However, the AR gene mutations are not uniformly observed. Taplin et al. [57]found that up to half of all HRPC had AR gene mutations whereas others noted a much lower incidence of only 0–3% [58, 59]. Current evidence indicates that not all HRPC have AR mutations as other factors such as AR amplification [60]and increased local bioavailability of androgens [61]are also involved.Many of the recent findings have future therapeutic implications for HRPC. NE–differentiated prostate cancer cells express a different set of hormones, which could be potential targets in the treatment of HRPC. Several of these have been evaluated in preliminary studies including antagonists of bombesin/gastrin–releasing peptides [62, 63], somatostatin [63]and serotonin [64].Pinski et al. [62]demonstrated that bombesin/gastrin–related peptide antagonist, RC–3095, enhances the inhibitory effects of LH–RH analogs on the growth of Dunnin R–33271 rat prostate cancer. While it is suggested that patients with advanced prostatic cancer could benefit from a combination of LH–RH analogs and bombesin/gastrin–related peptide antagonists, there are no human trials as yet. Somatostatin analogs have also been used to treat a variety of NE tumors. Their effect is complex and may be mediated through the inhibitory action of somatostatin on the pituitary growth hormones, by interference with local growth factors and by directly interacting with somatostatin receptors in prostate cancer cells.Hoosein et al. [64]showed that the serotonin antagonist Pindobind (5HTIA) inhibited proliferation of androgen–independent tumor cells lines in a dose–dependent manner.Serum PSA is extremely useful to assess disease progression, the efficacy of ongoing treatment (like androgen ablation) and recurrence after definitive treatment. Its value, however, becomes limited in the evaluation of stage D2 cancer and undifferentiated cancers that do not produce PSA reciprocal to the tumor burden [65]. These are usually hormone–refractory cancers and have a higher population of NE cells [56]. While it may be important to determine if a patient on androgen ablation has developed significant NE differentiation, its elucidation is not easy. Identification of NE cells in histological specimens may not be respresentative [66]because of its heterogeneous nature and localization to certain areas. This is particularly true for needle biopsy specimens [66]. Casella et al. [66]showed poor yield of core needle biopsies in determining NE differentiation and predicting prognosis. The detection of NE markers in the plasma may provide more comprehensive and quantifiable evidence of the degree of NE differentiation since the levels would correlate with both the primary tumor and associated metastases [67].NE cells release the neuropeptides by fusion of the granules with the cell membrane and exocytosis of the contents. Kadmon et al. [68]reported that plasma chromogranin A levels were elevated in almost half of 25 patients with D2 (metastatic) cancer. Angelsen et al. [69]found elevated serum chromogranin A levels in 75% of patients with skeletal metastasis and also noted a positive correlation between immunohistochemical findings and serum chromogranin A levels. Serum chromogranin A levels are also found to be increasingly elevated in a variety of other NE neoplasms, including medullary carcinoma of thyroid, pheochromocytoma, carcinoid, pancreatic islet cell tumor, etc. [70].It is hypothesized that prostate cancer stem cells differentiate along two lines: (1) exocrine cells producing PSA, and (2) NE cells producing chromogranin A, NSE, etc. The rate of differentiation is influenced by the hormonal milieu, i.e., in the androgen–depleted state NE differentiation is favored [68]. Kadmon et al. [68]also noted that in 33% of patients with elevated chromogranin A levels, both serum PSA and peroxidase–antiperoxidase were normal. This finding suggests that the elevated plasma NE marker level could be used as an indicator of HRPC. However, elevated levels of both NE factor and PSA would suggest the coexistence of mixed exocrine NE cell populations.Kimura et al. [71]found plasma chromogranin A levels useful for monitoring patients without elevated PSA levels. They showed no significant correlation between plasma chromogranin A and PSA since 80% of stage–C and D patients with very high plasma chromogranin A had normal PSA. Cussenot et al. [67]evaluated plasma neuropeptide levels before and after androgen ablation therapy in 135 patients with metastatic cancer. Significantly elevated plasma chromogranin A levels prior to therapy were seen in 15% of patients, which increased to 55% in hormone refractory progressive cancers. Contrary to other studies, 93% of patients with stage–D2 cancer had elevated PSA with elevated chromogranin A levels.The prognostic significance of NE differentiation in prostate cancer is controversial. However, many recent studies, employing tissue and serum markers show that NE differentiation correlates with disease progression, prognosis and development of androgen refractory states. In the absence of effective therapy for HRPC, there is an urgent need to develop newer therapeutic strategies based on current findings. As AR–negative NE cells are shown to play an important role in the development of HRPC, the several hormones expressed by NE cells could be potential targets for newer treatment strategies. Some of these include somatostatin, bombesin and serotonin. New therapeutic trials need to be developed." @default.
W2080450770 created "2016-06-24" @default.
W2080450770 creator A5033627307 @default.
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W2080450770 date "2000-01-01" @default.
W2080450770 modified "2023-09-26" @default.
W2080450770 title "Prognostic Significance of Neuroendocrine Differentiation in Prostate Cancer" @default.
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