Abstract
Metastatic carcinoma prostate with low serum prostate-specific antigen (PSA < 10 ng/ml) is usually poorly differentiated and has poor overall survival. This study aims to compare the clinicopathological profile and oncological outcomes between treatment-naïve metastatic carcinoma prostate with low PSA (< 10 ng/ml) and high PSA (> 10 ng/ml) at presentation. Data were collected retrospectively from the hospital’s database from January 2005 to December 2017. All treatment-naïve metastatic adenocarcinoma prostate cases with PSA < 10 ng/dl were included (n = 27), excluding one patient with prostatic rhabdomyosarcoma. Age-matched controls (± 2 years) in a 1 case:2 controls ratio were selected (n = 54). Patients were followed with PSA at 3, 6, and 12 months, and at the last follow-up. Most patients in both groups presented with lower urinary tract symptoms (LUTS). Neuroendocrine differentiation was more common in the low PSA group. The pattern of bone metastasis was similar in both groups. A higher percentage of patients (79.6%) in the high PSA group progressed to castration-resistant prostate cancer (CRPC) compared to 50% in the low PSA group, though the median time to CRPC was similar. In conclusion, the mode of presentation and pattern of metastasis were similar in both groups. Neuroendocrine histology was higher in the low PSA group (18.5% vs. 1.85%). No difference was observed in the time to CRPC between the two groups, though this interpretation should be cautious due to limited follow-up cross-sectional imaging.
Supplementary Information
The online version contains supplementary material available at 10.1007/s13193-024-02157-9.
Keywords: Low PSA, Metastatic carcinoma prostate, Castration-resistant prostate cancer, Neuroendocrine differentiation
Introduction
Prostate cancer is the second most common malignancy in men worldwide [1]. Serum prostate-specific antigen (PSA) has been used in the diagnosis and management of patients with prostate carcinoma since 1984 [2].The level of PSA usually correlates with the volume of metastasis of disease. PSA levels > 58 ng/ml are highly indicative of spread to the skeleton, even in the absence of radiological or scintigraphic evidence of metastases [3]. Less than 1% of patients with cancer prostate present with low PSA (< 10 ng/ml) [4, 5]. Low PSA metastatic prostate cancer is often poorly differentiated and associated with a poor prognosis, having an overall 3-year survival rate of 33% [5]. Our study aimed to compare the clinicopathological profile and oncological outcomes (including disease progression to castration-resistant prostate cancer, CRPC) between patients with low PSA (< 10 ng/ml) and high PSA (> 10 ng/ml) at presentation.
Material and Method
This retrospective comparative cohort study was conducted with IRB clearance (IRB No. 13766). Data were collected from the hospital’s electronic database covering January 2005 to December 2017. We included all treatment-naïve metastatic adenocarcinoma prostate cases with PSA < 10 ng/dl (n = 27), excluding patients with prior treatment, non-adenocarcinoma histopathology, or incomplete data. Age-matched controls (± 2 years) were selected in a 1 case:2 controls ratio (n = 54) (Fig. 1).
Fig. 1.
Strobe diagram
The primary outcome was to compare the clinicopathological profile, and the secondary outcome was to compare disease progression between the two groups (group A: low PSA < 10 ng/ml, group B: high PSA > 10 ng/ml). The high-volume disease was defined according to CHAARTED criteria [6]. Disease progression and CRPC were defined as biochemical progression and/or radiological progression on imaging, with or without symptomatic progression [7].
Results
From January 2005 to December 2017, a total of 511 patients were diagnosed with metastatic prostate carcinoma, based on data from the hospital’s electronic inpatient database. Out of 511, 28 patients were diagnosed with low PSA (< 10 ng/ml). One case with rhabdomyosarcoma in histopathology and low PSA was excluded from our study. Age matched (± 2 years) controls in 1 case/2 controls ratio were selected from the same period (Strobe diagram 1). The mean age of the low PSA group and the high PSA group was 68 ± 8.82 years (range 50–81 years) and 67 ± 8.4 years (range 50–81 years), respectively. The baseline glomerular filtration rate (GFR) was similar between both groups, with mean values of 62.12± 20.7 ml/min/1.72 m2 for the low PSA group and 75.23±20.23 ml/min/1.72 m2 for the high PSA group. Physical status, as assessed by the American Society of Anesthesiologists (ASA) classification, showed no significant differences, with the majority of patients in both groups classified as ASA 2. The median PSA in the low vs. high PSA arm was 4.83 ng/ml (IQR 2.74–8.74) and 315 ng/ml (IQR 61.13–352), respectively. The median Gleason score was the same in both groups (Gleason score 9). Basic demographics are summarized in Table 1.
Table 1.
Baseline demographic characteristics
| Variables | Low PSA (n = 27) | High PSA (n = 54) |
|---|---|---|
| Age | ||
| Range (years) | 50–81 | 50–81 |
| Mean (SD) | 68.4 ± 8.82 | 67 ± 8.4 |
| PSA at diagnosis(ng/ml) | ||
| Median (IQR) | 4.83 (2.74–8.74) | 315(61.13–352) |
| Alkaline phosphatase (U/L) | ||
| Mean (SD) | 290.5 ± 509.5 | 313.5 ± 429.5 |
| Baseline eGFR (ml/min/1.72 m2) | ||
| Mean (SD) | 62.12 ± 20.7 | 75.23 ± 20.23 |
| Haemoglobin (gm/dl) | ||
| Mean (SD) | 12.07 ± 2.01 | 12.08 ± 1.88 |
| Serum calcium (mg/dl), Mean (SD) | 8.97 ± 0.48 | 8.93 ± 0.83 |
| Gleason score | ||
| Median (IQR) | 9 (8–9) | 9 (8–9) |
| 7 | 2(7.4) | 7(12.9) |
| 8–10 | 25 (92.6) | 47 (87.1) |
| Physical status (ASA) | ||
| 1 | 3 | 8 |
| 2 | 24 | 44 |
| 3 | 0 | 2 |
PSA prostate-specific antigen, eGFR glomerular filtration rate, ASA American Society of Anaesthesiologist
Most of the patients in both groups presented with lower urinary tract symptoms with or without bony pain (Supplementary Table 1). Bone scan was performed in all cases in both groups whereas cross-sectional imaging (CECT/MRI abdomen and pelvis) was more commonly done in the low PSA group (62.9% vs 16.7%). The pattern of bone metastasis was similar in both groups (high volume 74% in the low PSA group, 75.9% in the high PSA group). In our study, we observed similar bony metastasis in high and low PSA metastatic prostate cancer groups (92.6% in the low, 94.44% in the high PSA group). Cross-sectional imaging revealed that non-axial bone metastases were more frequent in the high PSA group, correlating with higher alkaline phosphatase levels, indicative of a greater overall tumour burden.
Histopathological confirmation of disease was done in all the cases by expert uropathologists. Immunohistochemistry markers (PSA, HMWCK, chromogranin A, synaptophysin, pancytokeratin, PSAD, CK7, CK20, CD56, NSE) were used in nearly half of the low PSA group biopsies (48.14%) compared to only 14.8% in the high PSA group. On histopathology, neuroendocrine differentiation was found to be significantly higher in the low PSA group (18.5% low vs. 1.85% in the high PSA group; single patient with PSA of 21 ng/ml) whereas cribriform and comedonecrosis pattern was observed to be higher in the high PSA group (40.7 vs 22.2% and 5.55 vs 3.7% respectively). Immunohistochemistry showed significantly higher expression of neuroendocrine markers (chromogranin A and synaptophysin) in the low PSA group, supporting the histopathological findings of neuroendocrine differentiation. Other markers such as PSA, HMWCK, pancytokeratin, PSAD, CK7, CK20, CD56, and NSE were used to confirm the diagnosis and further characterize the tumour biology.
Patients in both groups received androgen deprivation therapy (Supplementary Table 2). Chemotherapy was received by 47.6% of patients in the low PSA group and 38% in the high PSA group. Chemotherapy regimens varied slightly between groups, with a higher percentage of low PSA group patients receiving multi-agent chemotherapy regimens post-2015, potentially reflecting a shift towards more aggressive treatment strategies in response to neuroendocrine differentiation.
Follow-up data showed that 33.3% of the low PSA group and 9.3% of the high PSA group were lost to follow-up. PSA was followed at 3, 6, and 12 months and at the last follow-up. The median follow-up in the low and high PSA groups was 27 months (IQR 7, 55.75) and 29 months (IQR 9.25, 46.25) respectively. In Our study, 33.3% of the low PSA group and 9.3% of the high PSA group were lost to follow-up.
The median PSA at 6 months was 0.44 ng/ml (IQR 0.13–1.01) and 2.76 ng/ml (IQR 2.13–55.65) in low and high PSA groups respectively. In the high PSA group, 79% of patients progressed to CRPC, compared to 50% in the low PSA group. However, this has to be interpreted carefully in light of challenges in following up low PSA metastatic carcinoma prostate with PSA; not all patients have follow-up bone scan and/or cross-sectional imaging. Forty (49.4%) and 19 (23.4%) patients had CECT/MRI at presentation and at follow-up respectively, and diagnosis of CRPC was primarily based on PSA progression. Median time to CRPC was 12 months (range, 6–29 months) in low and 11 months (range, 5–15 months) in high PSA groups, respectively. No significant differences were noted in terms of receiving chemotherapy (47.6% in low, 38% in high PSA arm) in both groups. It was noted that the patients diagnosed with CRPC after 2015 received more chemotherapy compared to those diagnosed before 2015. Thirty per cent of cases from low PSA and 28.6% of cases from high PSA arm required palliative radiation therapy which was similar. In our study, we found that the overall survival was similar in both groups (Fig. 2) though the follow-up data was limited.
Fig. 2.
Kaplan–Meier curve for overall mortality
Discussion
Metastatic adenocarcinoma prostate with low PSA (< 10 ng/ml) is unusual and less studied [4, 5]. Birtle et al. [8] retrospectively studied 33 men with low PSA (< 10 ng/ml) and found the median age of presentation to be 67 years and a median PSA of 3.5 ng/ml, similar to our findings. The most common presentation was lower urinary symptoms with or without bone pain (85% current study vs. 51% Birtel et al.).
Higher PSA levels are more predictive of bony metastasis [9]. In our study, the incidence of bony metastasis was similar across PSA groups; however, the volume of bony metastasis (axial and non-axial) was higher in the high PSA group (83.3% vs. 59.3%), correlating with higher alkaline phosphatase levels in this group. In a retrospective study by Sella et al. [10] on metastatic carcinoma prostate with low PSA (< 10 ng/ml), out of 18 patients, 11 had bony metastasis (61.1%), 8 had lymph node metastasis (44.4%), 10 had liver metastasis (55.5%), and 6 had lung metastasis (33.3%). In comparison, our patients with low PSA had 92.6%, 82.3%, and 17.6% bone, lymph node, and visceral metastasis, respectively. However, 37.1% of our low PSA patients did not undergo cross-sectional imaging (CECT/MRI) at initial assessment, and those who did not have cross-sectional imaging had bony metastasis diagnosed by bone scan.
Adenocarcinoma with neuroendocrine differentiation was present in one patient in the high PSA group (PSA = 21 ng/ml) and in five patients in the low PSA group. Prostatic architectural distortion due to neuroendocrine differentiation may lead to lower PSA production, resulting in low serum PSA levels [9]. Apart from this, the volume of bony metastasis in the low PSA group was relatively less (59.3%) compared to the high PSA group (83.3%). These factors could explain the lower PSA levels in metastatic adenocarcinoma at presentation. The higher incidence of neuroendocrine differentiation observed in the low PSA group (18.5%) not only suggests a distinct biological behaviour but also highlights the need for consideration of alternative therapeutic strategies beyond standard androgen deprivation therapy, which may be less effective in such cases. This observation aligns with research by Sun et al. [11] which highlighted that neuroendocrine differentiation in prostate cancer is predictive of aggressive disease behaviour and poor clinical outcomes This could partially explain why a significant portion of the low PSA group also progresses to CRPC, despite the lower initial PSA levels. Surekha et al. [12] reviewed 223 cases of metastatic carcinoma prostate and found that the median time to CRPC after ADT was 10–16 months, and PSA at presentation per se did not predict the time to CRPC. These findings were in concordance with our study which showed no difference in the time to CRPC between the two groups with median time to CRPC being 11 and 12 months in high and low PSA groups respectively. The possibility of missing out on some CRPCs cannot be ruled out as our study lacked cross-sectional imaging in a significant number of patients both at the time of diagnosis and follow-up. Therefore, CRPC was mainly defined based on PSA progression, and we found that patients with higher PSA at presentation were more likely to progress to CRPC based on PSA progression criteria. The clinical progression in prostate cancer is complex and may be influenced by underrecognized histopathological variants, as evidenced by Surekha et al.’s study [12], which indicated that traditional markers such as PSA could be inadequate in predicting disease progression. Furthermore, the similar time to CRPC between the two groups suggests that factors other than initial PSA levels, such as tumour biology and genetic mutations, might play a crucial role in disease progression. Recent studies suggest that molecular alterations, including TP53 mutations and PTEN loss, are common in neuroendocrine prostate cancer and contribute to its aggressive behaviour and treatment resistance [13, 14]. Further research is needed to investigate the molecular characteristics of these tumours and develop targeted therapies.
Smith C et al. [15] found that hypercalcaemia in prostate cancer was associated with unusual histopathology like neuroendocrine tumour and small cell tumour. We could not confirm the same, as all our patients were normocalcaemic irrespective of histopathology which could be due to the small sample size of our study. Chromogranin A and synaptophysin are highly sensitive and specific for neuroendocrine differentiation [11]. All metastatic Ca prostate patients with neuroendocrine differentiation showed chromogranin and synaptophysin positivity in their biopsy.
The histopathological analysis showed significant neuroendocrine differentiation in patients with low PSA metastatic prostate carcinoma. Prostatic tissue contains scattered neuroendocrine cells among ductal/acinar cells, with fewer than 50 cells showing de novo positivity for neuroendocrine markers in prostatic adenocarcinoma [16]. Neuroendocrine differentiation can be classified into small-cell neuroendocrine carcinoma (SCNEC), large-cell neuroendocrine carcinoma (LCNEC), mixed neuroendocrine neoplasms, and treatment-related neuroendocrine prostatic carcinomas (t-NEPCs). These t-NEPCs are the most common and are usually castration-resistant, with pathogenesis primarily attributed to transdifferentiation and lineage plasticity during treatment [17, 18]. Histomorphological features often show a mixed adenocarcinoma and SCNEC component, with an abrupt transition from poorly differentiated adenocarcinoma (Gleason 5). Immunohistochemistry for synaptophysin and chromogranin confirmed the neuroendocrine component [16–18]. Figures 3 and 4 illustrate these histopathological findings. In Fig. 3, sections from case 1 show prostatic core biopsy findings with Gleason patterns 4 and 5, including small cells with an increased nuclear-to-cytoplasmic (N) ratio, salt-and-pepper chromatin, and granular eosinophilic cytoplasm (Fig. 3A–E). Figure 4 shows a tumour from case 2, with a cribriform pattern and partial neuroendocrine differentiation, confirmed by positive staining for synaptophysin and chromogranin (Fig. 4A–C).
Fig. 3.
Histopathological images from case 1
Fig. 4.
Histopathological images from case 2
Figure 2 illustrates the Kaplan–Meier survival curves, showing no significant difference in overall survival between the low and high PSA groups. This suggests that despite differences in histopathology and initial PSA levels, survival outcomes were similar, highlighting the complexity of metastatic prostate cancer prognosis. Similar findings have been reported in other studies, indicating that while higher PSA levels are associated with a greater tumour burden, they do not necessarily predict worse survival outcomes. Studies have shown that patients with PSA levels < 4 ng/mL have varied survival outcomes, significantly influenced by other factors like tumour stage and Gleason score, emphasizing the need to consider multiple factors for accurate prognosis [19, 20].
Our study has certain limitations. The retrospective collection of clinical data resulted in poor follow-up and limited cross-sectional imaging. The retrospective nature also led to the incomplete retrieval of some information.
Conclusion
Our study demonstrates that the mode of presentation and pattern of metastasis are similar between the low and high PSA groups. Neuroendocrine histology was significantly higher in the low PSA group (18.5% vs. 1.85%). No significant difference in the time to CRPC was observed between the two groups. However, this conclusion should be interpreted with caution due to the limited availability of cross-sectional imaging in our study.
Supplementary Information
Below is the link to the electronic supplementary material.
Abbreviations
- PSA
Prostate-specific antigen
- LUTS
Lower urinary tract symptoms
- CRPC
Castration-resistant prostate cancer
- IRB
Institutional Review Board
- EAU
European Association of Urology
- HMWCK
High molecular weight cytokeratin
- CK
Cytokeratin
- NSE
Neuron-specific enolase
- IQR
Interquartile range
- SD
Standard deviation
- CECT
Contrast-enhanced computed tomogram
- MRI
Magnetic resonance imaging
- ADT
Androgen deprivation therapy
- GnRH
Gonadotropin-releasing hormone
- GFR
Glomerular filtration rate (by Chronic Kidney Disease Epidemiology equation (CKD-EPI))
Author Contribution
Ujjwal Kumar (Principal author): project development, data collection, manuscript writing.
Mudasir Farooq: manuscript writing, data analysis.
Shivashangari: pathology-related input and images.
Santhosh Nagasubramanian: project development, data collection, manuscript writing.
Lakshmanan Jeyaseelan: data analysis.
Arun Jacob Philip George: manuscript editing, data analysis.
Nirmal Thampi John: project development, data analysis, manuscript editing.
Santosh Kumar: data analysis, manuscript editing.
Data Availability
The authors declare full transparency of the data submitted and is available if requested for.
Declarations
Ethical Approval and Consent to Participate
This study was approved by the institutional review board (IRB Min no: 13766(retro) dated 27.01.2021).
Consent for Publication
All authors consent for publication of the manuscript.
Competing Interests
The authors declare no competing interests.
Disclaimer
All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.
Footnotes
Publisher's Note
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Supplementary Materials
Data Availability Statement
The authors declare full transparency of the data submitted and is available if requested for.