Research ArticleClinical Studies

Clinical Features of Treatment-related Neuroendocrine Prostate Cancer: A Case Series

KOTARO SUZUKI, TOMOAKI TERAKAWA, NAOE JIMBO, RENA INABA, YUZO NAKANO and MASATO FUJISAWA
Anticancer Research June 2020, 40 (6) 3519-3526; DOI: https://doi.org/10.21873/anticanres.14340

Abstract

Background/Aim: The development of treatment-related neuroendocrine prostate cancer (t-NEPC) is an increasing clinical concern. The objectives were to clarify the clinical features of t-NEPC. Patients and Methods: A total of 9 patients with histologically confirmed t-NEPC were reviewed. Results: Of these 9 patients, 2 patients were diagnosed with t-NEPC by a histological examination without elevation in blood tumor marker levels. Immunohistochemistry revealed an acquired Rb loss in 5 patients. All patients were treated with platinum-based chemotherapy as first-line treatment and 6 patients received concurrent radiation therapy (RT). The median cancer-specific survival was 14.4 months, and 7 patients achieved an objective response. Patients with tumor-infiltrating CD8+ lymphocyte (CD8+-TILs) showed better response than those without CD8+-TILs. Conclusion: We described the clinical features of histologically confirmed t-NEPC. In addition to the importance of biopsy, we showed that platinum-based chemotherapy plus RT had a favorable cytoreductive effect. Further clinical recognition and studies are needed.

In recent treatment strategies for prostate cancer, androgen receptor axis-targeted (ARAT) agents have been a mainstay in all stages (1, 2). However, with the increased frequency of using potent ARAT agents, the emergence of neuroendocrine (NE) differentiation in the late stage of castration-resistant prostate cancer (CRPC), hereafter referred to as treatment-related neuroendocrine prostate cancer (t-NEPC), has received focus as a new clinical problem (3). t-NEPC is characterized by a small cell morphology as a consequence of lineage plasticity, secretion of neuroendocrine serum tumor markers, such as neuron-specific enolase (NSE) and chromogranin A (CgA), and resistance to ARAT agents due to their development in an AR-independent manner (4). In addition, t-NEPC patients often show aggressive disease with visceral metastasis and have a poor prognosis (5). However, the clinical features of t-NEPC are still unclear.

To improve the prognosis of t-NEPC, establishment of the standard treatment for t-NEPC is an urgent necessity. Based on the treatment of small-cell NE cancer of other organs (6, 7), t-NEPC has often been treated with platinum-based regimens. However, although histological classification is generally essential for the effective treatment of malignancies, previous studies that described the efficacy of platinum-based chemotherapy for t-NEPC did not necessarily require a histological confirmation (8, 9). Thus, the true treatment efficacy of platinum-based regimens for t-NEPC remains unknown.

In the present study, we describe a case series of 9 patients with histologically confirmed t-NEPC. We show the clinical characteristics of t-NEPC and the therapeutic outcomes of our multimodality treatment, which is based on the management of small cell lung cancer (SCLC) in t-NEPC patients.

Patients and Methods

Patients. A total of 9 patients histologically diagnosed with t-NEPC at Kobe University Hospital between May 2015 and July 2019 were enrolled in the present study. The study design was approved by the Research Ethics Committee of our institution (No. B190096) and conducted in accordance with the Declaration of Helsinki.

Treatment strategy and study design. In our management strategy for t-NEPC, when patients initially diagnosed with prostate adenocarcinoma (AC) are clinically suspected of developing NEPC, including rapid disease progression with elevated serum NE tumor markers but no increase in the prostate specific antigen (PSA) level, a pretreatment biopsy is generally performed. After histological confirmation of NEPC morphology, EP therapy is adopted as 1st-line regimen (etoposide: 100 mg/m2 on days 1 to 3 every 3 weeks and cisplatin: 80 mg/m2 on day 1). In elderly patients or patients with renal deterioration, we use EC therapy [etoposide and carboplatin: area under the blood concentration time curve (AUC)=5] instead of EP therapy. The doses of each regimen are reduced as appropriate. According to the treatment strategy for platinum refractory SCLC, amrubicin and nogitecan are sequentially administered as subsequent regimens for tolerable patients after the failure of a platinum-based regimen (10, 11). In addition, concurrent local radiation therapy (RT) is used to treat progressive and symptomatic disease sites, considering the efficiency of chemoradiotherapy in SCLC patients (12).

View this table:
Table I.

Patient characteristics and prior treatment course.

The treatment response was initially evaluated based on the blood levels of tumor markers, including NSE and gastrin releasing peptide (Pro-GRP) in each cycle of treatment, and then evaluated by computed tomography or bone scintigraphy at least once every 12 weeks and classified according to the response evaluation criteria in solid tumours (RECIST) 1.1. Adverse events were evaluated based on the Common Terminology Criteria for Adverse Events (CTCAE) ver.4.0.

Histopathological analyses. The histological diagnosis of NEPC was made based on the criteria of the World Health Organization (2015) for SCLC, relying on hematoxylin and eosin staining: small-sized neoplastic cells showing nuclear molding with scant cytoplasm and round to oval nuclei with dispersed granular chromatin without nucleoli (13).

NE differentiation was confirmed by positive immunostaining for ≥1 of the three NE markers, including synaptophysin, CgA and neural cell adhesion molecule (NCAM). For further characterization of t-NEPC, we performed immunostaining of insulinoma-associated protein 1 (INSM1), thyroid transcription factor 1 (TTF-1), PSA, AR, p53, Rb, programmed death-ligand 1 (PD-L1) and CD8. As reported in a previous study, diffuse positivity or complete negativity for p53 was considered to indicate the presence of a TP53 mutation (14).

Statistical analyses. We investigated the changes in the blood tumor markers, progression-free survival (PFS) of platinum-based chemotherapy, and cancer specific survival (CSS) in patients with t-NEPC. The change in the blood levels of tumor markers was evaluated at ≥4 weeks after the initiation of treatment. To estimate the PFS and CSS using the Kaplan–Meier method, we employed EZR, which is a graphical user interface for R (15).

Results

Characteristics prior to NE differentiation. The patient characteristics, tumor activity of prostate cancer and therapeutic course prior to the diagnosis of t-NEPC are shown in Table I. The median age was 71 years old (range=60-83 years old). The median PSA level at the first visit was 11 ng/ml (range=4.2-323 ng/ml), and 8 of 9 patients showed AC with Gleason score (GS)≥8 at the initial prostate biopsy. Six patients were diagnosed with clinical T stage≥T3b of TNM classification, and 6 had metastasis at the diagnosis with prostate AC. All patients had a treatment history of medical or surgical castration prior to NE differentiation. In addition, ARAT drugs, including abiraterone and enzalutamide, were administered to 3 patients.

Tumor activity of t-NEPC. Table II shows the tumor characteristics of t-NEPC. The median interval between AC and the t-NEPC diagnosis was 29.4 months (range=4.5-74.5 months). The PSA levels were relatively low and were not detected at all in 3 patients. While NSE was elevated in 7 patients, Pro-GRP was elevated in 3 patients. In addition, 3 had liver metastasis, and 5 showed urinary retention due to a bulky prostate mass. In the histological examination, 6 showed a pure small-cell morphology pattern and the remaining 3 showed a mixed pattern [small cell carcinoma (SCC) combined with AC], in which SCC was mainly observed. Two patients (case 3, 7) who showed normal NE differentiation marker values were diagnosed with t-NEPC based solely on the morphological criteria.

View this table:
Table II.

Tumor characteristics of neuroendocrine prostate carcinoma.

Histological analyses of t-NEPC. The results of the immunohistochemical (IHC) analysis of t-NEPC are summarized in Table III. With the exception of case 2, in which the patient was diagnosed with t-NEPC based on aspiration cytology, all cases were positive for synaptophysin and NCAM, while 2 of 8 patients were negative for CgA. In addition, an acquired TP53 mutation was indicated in 2 cases (case 6: hetero positive→loss and case 8: hetero→diffuse positive) and an acquired loss of Rb was observed in 5 cases (case 1, 3, 6, 8, and 9). Regarding cancer immunity, a small number of PD-L1-positive cells were observed in 2 patients (case 5 and 9), and 6 of 8 cases showed some amount of tumor infiltration by CD8-positive lymphocytes (CD8+-TILs) in the tumor nest. Notably, patients without CD8+-TILs (Cases 1 and 4) had relatively poor treatment responses to chemotherapy in comparison to those with CD8+-TILs (Table IV).

Treatment and clinical outcomes of t-NEPC. The clinical outcomes of t-NEPC are shown in Table IV. While 8 patients were treated with EP therapy, case 9 was started with EC therapy in consideration of his advanced age. Six patients underwent concurrent RT combined with chemotherapy. Amrubicin and subsequent nogitecan after the failure of 1st-line platinum-based regimen were introduced in 3 patients (case 2, 3 and 6). In these 3 patients, the OS after 1st-line failure tended to be longer in comparison to the remaining 3 patients (Case 1, 4 and 5) who received the best supportive care after platinum-based therapy. Regarding the treatment response of the 1st-line treatment in the imaging examinations, 7 (77.8%) patients showed the objective response [complete response (CR): 1 and partial response (PR): 6]. Notably, most of the symptoms, including urinary retention and cancer pain, were immediately improved. During the median observation period of 11.5 months (range=4.0-21.2 months), 3 patients died from t-NEPC, 4 were alive with disease, and 1 died from other causes.

The changes in the NSE levels are shown in Figure 1A. Although case 4 showed progression disease in the imaging examinations, all 7 patients achieved an NSE decline of ≥60%. In addition, the median PFS of 1st-line platinum-based chemotherapy was 10.1 months [Figure 1B, 95% confidence interval (CI)=3.2-not reached] and CSS of t-NEPC was 14.4 months (Figure 1C, 95%CI=3.9-not reached).

The therapeutic course of case 5, for whom EP therapy was most effective among the 9 patients, is shown in Figure 2. In this case, the NSE level reflected the treatment response to EP well and the therapy was effective for approximately 10 months (10 courses) (Figure 2A). The multiple lymph node metastases were shown to have achieved CR, in addition to the primary site of the prostate (Figure 2B). His symptoms due to paraneoplastic dermatomyositis also improved in accordance with the therapeutic response.

View this table:
Table III.

Immunohistological analysis of t-NEPC.

View this table:
Table IV.

Clinical outcomes of neuroendocrine prostate carcinoma.

Figure 1.
Figure 1.

Clinical outcomes of treatment-related neuroendocrine prostate cancer (t-NEPC). (A) Waterfall plot representing the percentage of the best response in neuron specific enolase (NSE). (B) The Kaplan–Meier curve for the progression-free survival of platinum-based chemotherapy. (c) The Kaplan–Meier curve for the cancer-specific survival in patients with t-NEPC.

Discussion

In the present study, we described the clinical features of 9 cases with histologically confirmed t-NEPC who were treated based on the management of SCLC.

Although, a previous review suggested that the incidence of t-NEPC has been rising rapidly as a result of the increasing use of potent ARAT agents for CRPC (3), the incidence rate of t-NEPC remains unclear. Recently, Aggarwal et al. showed that NE differentiation occurred in 17% of mCRPC patients in their prospective study (16). However, Aggarwal's study, in which biopsy could be performed for mCRPC patients with any stage of disease, included patients with high PSA levels or without elevated NE marker levels (16). In these patients, the disease may still have been AR-dependent; we should distinguish this condition from t-NEPC disease. Clearer diagnostic criteria and further clinical recognition will likely lead to the collection of more precise data.

According to pathologic classification of NE differentiation in prostate carcinoma, SCC, large-cell neuroendocrine carcinoma (LCNEC) and mixed (small- or large-cell) NE carcinoma-acinar AC have been shown to be aggressive malignancies, and differentiation into these types from conventional CRPC has been termed t-NEPC (17, 18). In our cohort, all 9 patients who underwent a histological examination showed SCC morphology and no cases showed LCNEC. Notably, in the present study, 2 of 9 patients showed normal levels of both NSE and Pro-GRP and were histologically diagnosed with t-NEPC. Similarly, a systematic review also reported that 22.8% of t-NEPC cases are diagnosed by morphological criteria alone (5). These findings suggest that a biopsy may be required for an immediate, precise diagnosis and the prompt initiation of appropriate therapy, at least in patients with aggressive disease. The current NCCN guideline of prostate cancer recommends performing a biopsy of accessible metastatic lesions in patients with visceral metastases.

For further characterization of t-NEPC, molecular analyses of NE differentiation in prostate cancer have been performed (19, 20). Aberrations in the p53 and Rb signaling pathway have been shown to be associated with NEPC, which is also observed in SCLC (3). Consistent with this, our IHC analysis also showed differences in the p53 and Rb expression patterns between primary AC tissue and t-NEPC tissue in some cases. Although we could not demonstrate a correlation between these results and the prognosis of t-NEPC because functional mutations are generally not evaluated by IHC, a genomic sequential analysis may clarify whether such a correlation exists.

Regarding the treatment strategy of t-NEPC there are obvious genomic differences in developmental process between t-NEPC and SCC of other organs (19), but chemotherapy with a platinum-based regimen, based on the standard treatment of SCLC, has been reported to show a certain degree of therapeutic efficacy in t-NEPC (3). In our study, platinum-based chemotherapy drastically reduced the elevated NSE levels in NSE-positive patients, and had a favorable cytoreductive effect. Interestingly, IHC analyses suggested that CD8+-TILs in tumor nests may be a predictor of the efficacy of the treatment, as shown in previous reports of other malignancies (21, 22). In addition, the median CSS was 14.4 months, which was comparable to that of t-NEPC in previous reports (3). Notably, the quality of life (QOL) of most patients was improved; most of the symptoms, including urinary retention and cancer pain, were immediately improved in our cohort. Our data suggest that it is worth trying platinum-based chemotherapy, at least in t-NEPC patients whose QOL has rapidly worsened. In addition, when appropriate, we actively use amrubicin and nogitecan, which are standard therapeutic agents for relapsed SCLC after the failure of a platinum-based regimen (11, 12). However, even in histologically confirmed t-NEPC, limited cases could receive 2nd-line treatment (23) and most remaining patients might change to best supportive care in clinical practice. Although the present study included a small number of cases with short observation periods, our three cases showed a favorable response to subsequent therapy after a platinum-based regimen, indicating the possibility that systemic sequential treatment based on the management of SCLC may be beneficial for t-NEPC patients. Of further note, SCLC is generally sensitive to RT, and concurrent chemoradiation therapy has become the standard of care for limited-stage SCLC (24). This approach has also been implemented for the palliation of individual sites in cases of metastatic t-NEPC in previous reports (5, 8) as well as in our present study. These findings suggest that multimodality management based on the histology of SCC may be beneficial for patients with t-NEPC.

Figure 2.
Figure 2.

Treatment and clinical outcome of case 5. (A) Treatment course of etoposide plus cisplatin (EP) therapy and changes in prostate specific antigen (PSA) and neuron specific enolase (NSE) levels. (B) Computed tomography (CT) images of para-aorta lymph node (left panels), pervic lymph node (middle panels) and prostate (right panels). Upper images were taken at the induction of EP therapy and lower images were taken after 2 courses of it. Arrows (white) indicate disease site.

One concern is whether treatment with a platinum-based regimen would be better than AR targeted therapy for patients with mixed-type (SCC combined with AC) t-NEPC. To assess this point, we should evaluate the tumor marker levels, especially the serum PSA levels, in addition to the histology. While patients with progressive disease who have low or no change in their PSA levels should be treated according to the treatment strategy for SCC, those who show elevating PSA levels, indicating AR-dependent progression, may receive benefit from AR targeted therapy. In addition, the NCCN guidelines recommend that combined SCLC, which has an SCC component with a non-SCC component should be treated as SCLC (25, 26). Thus, in our treatment strategy, t-NEPC patients, even those with mixed-type disease, with low or no change in their PSA levels, are generally treated according to the treatment strategy for pure SCC.

The development of novel agents for t-NEPC has become more crucial than ever for the further improvement of the overall prognosis of prostate cancer. A phase II trial of alisertib, an inhibitor of the allosteric interaction between the Aurora kinase A gene (AURKA) and N-myc gene (MYCN), which has been studied as a biomarker of t-NEPC (17, 20), was performed in NEPC patients. However, although a subset of patients showed a favorable response to alisertib, the overall clinical benefit of this agent has yet to be demonstrated (27), suggesting that further investigation of an additional key gene to MYCN/AURKA may be warranted. Recently, immune-checkpoint inhibitors (ICIs) received approval as a treatment option for patients with advanced SCLC (28, 29). Although ICIs did not dramatically improve the prognosis of SCLC, it is possible that increasing the therapeutic options may result in improvements in the prognosis of t-NEPC if ICI therapy becomes an approved treatment strategy for t-NEPC in the future.

Several limitations associated with the present study warrant mention. The study was a single-arm study containing a small number of patients with a relatively short follow-up duration. Therefore, it is difficult to identify prognostic markers of t-NEPC and which subgroups of patients are likely to benefit from our multimodality therapy. Although such studies may be difficult to carry out due to the rarity of t-NEPC, further prospective, large-scale studies will be needed in order to validate our results.

In conclusion, we here described the clinical features and therapeutic outcomes of histologically confirmed t-NEPC. In addition to the importance of biopsy, we showed a favorable cytoreductive effect of our multimodality treatment based on the SCC morphology in t-NEPC patients. Further molecular and genomic analyses may lead to the advent of novel therapeutic agents and to the improvement of the prognosis in patients with t-NEPC.

Footnotes

  • Authors' Contributions

    KS, TT, YN and MF designed the study. KS and TT acquired and analyzed the data. NJ and RI performed immunohistochemical analyses. KS and TT drafted the manuscript, and YN and MF revised it critically for important intellectual content. All Authors gave final approval of the version to be published.

  • Conflicts of Interest

    The Authors declare no conflicts of interest regarding this study.

  • Received April 19, 2020.
  • Revision received April 29, 2020.
  • Accepted April 30, 2020.

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Clinical Features of Treatment-related Neuroendocrine Prostate Cancer: A Case Series
KOTARO SUZUKI, TOMOAKI TERAKAWA, NAOE JIMBO, RENA INABA, YUZO NAKANO, MASATO FUJISAWA
Anticancer Research Jun 2020, 40 (6) 3519-3526; DOI: 10.21873/anticanres.14340
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