The biological potential of prostate cancer is extremely variable [1]. It is perhaps the only cancer, which could be managed by, deferred treatment in its early course for selected cancers [2]. To define the biological potential of prostate cancer, prognostic markers are employed. There are numerous markers for assessing the biological aggressiveness of the prostate cancer [3]. However, large studies have shown that they lack sensitivity and specificity due primarily to their expression in normal prostatic epithelium as well. This justifies a recent surge in interest in markers specific to malignant prostatic tissue [4]. Recent studies have shown the potential of neuro-endocrine differentiation in adenocarcinoma of the prostate and its role in ascertaining the biological aggressiveness of the tumor [3]. Wang et al [5] has recently noted that the expression of the pS2 protein is implicated in the pathogenesis and progression of some neuro-endocrine tumors.

Maisakowski et al. first described the pS2 gene in the MCF-7 human breast cancer cell line [6]. The pS2 is a cysteine rich secretory protein, containing 84 amino acids and a molecular weight of 6.45 k-Da. The pS2 gene is highly expressed in estrogen-receptor positive breast cancer, and high levels of pS2 protein correlate with responsiveness to primary endocrine therapy and better patient survival in breast cancer. However, in prostate cancer it is linked with NE differentiation and poorer outcome [7].

In the present study, we have investigated the expression of pS2 in malignant primary prostatic tissue in specimens obtained from transurethral, open prostatectomy, and correlated this with neuro-endocrine differentiation and clinical stage and grade. This is a preliminary report on pS2 expression in prostate cancer, a larger study will better define the correlation between stage, grade of cancer with pS2 and CgA expression.

The cancerous lesion composed of 35% (n = 29) stage T1, 32% (n = 27) stage T2, 25% (n = 21) stage T3 and 6% (n = 5) stage T4 disease according to the TNM classification. Based upon the stage of the disease patients were divided into three groups i.e. organ confined (T1-2), locally invasive (T3-4 and N1) and metastatic (M1) cancer.

In 95-cancer specimen from transurethral resection (n = 69) for urinary obstruction and radical retropubic prostatectomy for organ-confined cancers (n = 15), pS2 reactivity was detected in the adjoining normal or hyperplastic acini in only 4.2%. The pS2 expression in cancer was found in 10% (figure 1). The immuno-histochemical reactivity of pS2 in malignant epithelial cells was confined to the cytoplasm of with a tendency to a perinuclear accentuation.

Expression of pS2 was correlated with the stage of disease in Figure 1. Staining for NE marker (CgA) was seen in 31% (figure 1); correlation between the pS2 and CgA expression is summarized in table 1, it showed that 2/3rd of pS2 also showed CgA expression.

	n (%)	CgA +ve	CgA -ve	Mean GS
pS2 +ve.	9(10)	67%	33%	7.5
pS2 -ve.	86(90)	28%	72%	6.2

+ve. Expression positive

-ve. Expression negative

CgA Chromogranin A

GS Gleeson sum

Worsening histological grade was associated with greater expression of pS2. In Gleason sum groups 2–4 and 5–6, expression of pS2 was noted in 6 and 8% respectively whereas in Gleason sum group 8–10 the expression was observed in 30% (p < 0.001). The expression of pS2 [figure 4(a) and 4(b)] in various prognostically and therapeutically distinct groups based upon the grade of cancer is described in figure 2.

In the present study, we investigated the expression of pS2 protein in the adenocarcinoma of prostate and in the surrounding normal prostate tissue. We used a standard immunohistochemical method to assess pS2 expression in tissue sections of adenocarcinoma prostate instead of instead of biochemical or immuno-radiometric assay. The immuno-histochemical method for detection of pS2 expression has drawbacks in comparison to biochemical and immunoradiometric assay on tissue extracts. Both of the later methods allow precise quantification of levels of expression for a better correlation with other parameters studied.

However, as we are interested in the clinical utility of pS2 expression in our prostate cancer population, we used immunohistochemistry, which allows appreciation of intra-tumoral heterogeneity of expression and of both cancerous and non-cancerous cells. pS2 protein expression has been demonstrated in a range of malignant and benign pathologies. It is highly expressed in receptor positive human breast cancer [5] but expression in other cancers like ovarian [7], cervical [8], gastrointestinal [9], thyroid [10] and bladder [11] is variable.

A significant implication of pS2 in prostate cancer is the close association of this marker with Neuroendocrine (NE) differentiation. There is increasing evidence that focal NE differentiation frequently occurs in prostatic adenocarcinoma and it may have significant prognostic implications [12–14]. NE differentiation is also described in hormone refractory prostate cancer; Krijnen et al [14] noted that androgen receptors are not present in prostatic adenocarcinoma staining positive for CgA. While Higashiyama noted 17% expression of pS2 in all pulmonary cancers, Wang et al [5] noted 45% expression in small cell cancers of the lung (a neuroendocrine carcinoma). Recent evidence has suggested that expression of pS2 is closely associated with neuroendocrine differentiation in prostate cancer [15]. Colombel et al from in an RT-PCR study found a high expression of pS2 in prostate cancer; however, they found no correlation between with tumour stage or Gleason grade. Our present work [15] indicates that NE differentiation not only correlates with other prognostic markers like grade of the cancer but also has independent prognostic value. Bonkhoff et al [15] noted that pS2 expression was consistently confined to NE differentiation in untreated tumors and in carcinomas that relapsed after hormonal therapy. Our results have similarly shown that 6 out of 9 cancers that have expressed pS2 were also positive for CgA.

Our results demonstrate that although the expression of pS2 protein was noted in only 1/10th of prostate cancers, it significantly correlates with the histological grade and NE differentiation; both have independent and interdependent prognostic value. There is dearth of data exploring the correlation of pS2 expression and aggressiveness of prostate cancer cell behavior. Limited literature available at present show significant association of pS2 expression with prognosis in prostate cancer, however more work is required to explore the utility of this marker in defining the biological potential of prostate cancer.