Neuroendocrine Carcinoma of the Prostate – a Case Report

1. Introduction

Neuroendocrine differentiation of prostate cancers has gained recent interest because of their relationship to castration resistant disease. The 2016 WHO classification of prostate cancers with neuroendocrine differentiation incorporates four different morphological subtypes, one of them being small cell neuroendocrine carcinoma (1). This particular subtype is rare; clinically it is characterized by an aggressive evolution and rapid spread. Herein, we present the case of a patient with de novo small cell neuroendocrine, poorly differentiated carcinoma, with multiple metastases.

2. Case presentation

A 67-year-old male was investigated for constipation, loss of appetite and pelvicperineal pain in August 2021. The patient had no significant family history, was only under treatment for arterial hypertension grade II, was a never-smoker and was an occasional alcohol consumer. The laboratory findings showed only an elevated creatinine level at the initial presentation. A colonoscopy was performed that did not show any evidence of a mass. The abdominal and pelvic CT scan revealed the prostate with irregular margins and 57/60/55 mm in size. A coralliform calculus was described in the left kidney and a renal scintigraphy showed a diminished renal function. The patient was admitted to the Urology Clinic in November 2021 where he underwent a series of investigations – urinary tract ultrasound, urethrocystoscopy and proctoscopy. The transrectal prostatic ultrasound revealed a large prostatic mass, which invaded the seminal vesicles bilaterally and compressed the anal canal. Several biopsies were performed. Moreover, PSA, CEA and CA 19-9 values were elevated. A thoracic CT scan was performed and pulmonary metastases and several osteolytic lesions were also described.

At this point, the patient was referred to the Oncology department for constipation, fatigue and pain management. He was complaining of severe pain in the perineal area, which was insufficiently controlled with tramadol and paracetamol. The physical examination revealed pallor and mild pain on palpation in the hypogastric region. Mild anemia with iron deficiency and slight elevation of the creatinine level was also found. The treatment for pain management was initiated with fentanyl patches and anti-inflammatory medication. Additionally, prokinetics and laxatives were prescribed.

The histopathologic report of the prostatic biopsy revealed neuroendocrine morphology with small cells, foci of necrosis and high mitotic rate, suggestive of a poorly differentiated carcinoma with small cells (Fig. 1). Immunohistochemically, the tumor cells showed a high ki67 of 75-80%, NKX3.1 negative and TTF-1 positive (Fig. 2); the neuroendocrine markers (synaptophysin, CD56, chromogranin A) were intensely positive (Fig. 3). Therefore, the final diagnosis was poorly differentiated neuroendocrine carcinoma of the prostate stage IV with pulmonary and bone metastases.

Figure 1. A: HE staining 20X; B: HE staining 40X (Courtesy of Mihaela Mihai MD, Fundeni Clinical Institute)

Figure 2. From left to right: Ki-67 10X – 75-80%, NKX3.1 10X – negative, TTF-1 40X positive; (Courtesy of Mihaela Mihai MD, Fundeni Clinical Institute)

Figure 3. A: CD56 40X- positive; B: SYN 40X – positive; C: CG-A 40 X – positive. (Courtesy of Mihaela Mihai MD, Fundeni Clinical Institute)

The multidisciplinary team assessed the case of this patient and it decided on the prompt initiation of palliative chemotherapy. Accounting for the aggressive nature of the tumor, an abdominal and pelvic CT was repeated. Multiple bilateral liver metastases (the largest in the VI th segment with a maximum diameter of 68/47 mm) and a large celio-mesenteric lymphadenopathy were also described. At this point, the pelvic tumor measuring up to 10/9 cm invaded the posteriorinferior bladder wall and the anterior rectal wall and multiple pelvic lymph nodes (maximum diameter of 50/30 mm encompassing the left iliac vein) and osteolytic lesions were identified.

The patient started chemotherapy at the beginning of December 2021 with cisplatin 80 mg/ m2 on day one and etoposide 100 mg/m2 on days 1-3, every 21 days, planned for 4-6 cycles. The treatment was generally well tolerated. The adverse events were anemia (grade 1/ 2), asthenia (grade 1) and elevation of the creatinine level (grade 1/ 2). Cisplatin pre-and post-hydration protocols were followed to reduce nephrotoxicity. Still, at the end of the 6th chemotherapy cycle, the creatinine level was 1.9 mg/dL and creatinine clearance was 32 mL/min. Thus, the administration of cisplatin was discontinued.

In March 2022, the patient was evaluated with a CT scan (thoracic, abdominal and pelvic) which revealed partial response according to RECIST v1.1.

There was no evidence of pulmonary metastases, or abnormal lymph nodes in the celio-mesenteric area. The hepatic lesions showed at least a 50% reduction in diameter compared to baseline (e.g. the lesion in segment VI was 25/15 mm versus 68/47 mm at baseline). The prostatic tumor had a maximum diameter of 58/56 mm versus 100/90 mm at baseline (Fig. 4).

Figure 4. Prostatic tumor – on the left side in November 2021 (max. diameter 100/90 mm); on the right side in March 2022 (max. diameter 58/56 mm)

The patient was discharged in April 2022 with recommended follow-up after three months, and with symptomatic treatment.

After 3 months, the patient was evaluated with a CT scan of the thorax, abdomen and pelvis. The scan revealed stable disease according to RECIST v1.1. A month later, in august 2022, the patient was brought in for dizziness, confusion and headaches. An emergency CT was performed a few days prior, which described multiple brain metastases. He underwent whole brain palliative radiotherapy and palliative chemotherapy with Irinotecan, leucovorin and 5-fluorouracil (FOLFIRI) starting in September 2022.

3. Discussion

Large/small cell poorly differentiated neuroendocrine carcinomas are aggressive tumors with high mitotic rates and high Ki-67 index, which most of the time require combined treatment. Neuroendocrine carcinomas are rarely associated with carcinoid syndrome and are most of the time found as pulmonary masses – according to the SEER database, while only 9% of NECs are extrapulmonary (2). Of all cases of prostate cancer, only 0,5-2% are small cell carcinomas (3).

Two mechanisms are incriminated in the pathogenesis of neuroendocrine prostatic tumors. Most frequently, the neuroendocrine features appear as a result of an acinar adenocarcinoma undergoing transformation following long-term hormone therapy, with the loss of androgen receptors. The second mechanism involves the malignant transformation of the neuroendocrine cells usually present in the prostate (4). De novo small cell carcinoma of the prostate is a rare occurrence; in one single-center study conducted by Spiess et al, two-thirds of the patients included developed SCC after being diagnosed and treated previously for prostatic adenocarcinoma (5).

The 2016 WHO classification of prostatic cancers acknowledges four different types of prostatic cancers with neuroendocrine differentiation: adenocarcinoma with neuroendocrine differentiation, well-differentiated neuroendocrine tumor/carcinoid and large or small cell neuroendocrine carcinomas of the prostate (6). A small cell neuroendocrine carcinoma diagnosis can be made by microscopic examination of tumor morphology on H&E stain. The tumor cells show characteristic neuroendocrine morphology, with scant cytoplasm, hyperchromatic nuclei without conspicuous nucleoli, frequent mitosis, nuclear molding, rosette-like structures, and prominent necrosis. Immunohistochemically, these tumors are positive for at least one of the neuroendocrine markers – synaptophysin, chromogranin and CD56 (7, 8).

Several differential diagnoses were considered regarding the anatomic site of origin for this tumor. A pulmonary or pancreatic neuroendocrine carcinoma metastatic to the prostate were considered, as well as neuroendocrine differentiation of a primary prostatic adenocarcinoma. The immunohistochemical report excluded a diagnostic of prostatic adenocarcinoma because NKX3.1, a marker highly specific for prostatic adenocarcinoma, was negative. Regarding TTF-1 positivity, as seen in our patient, different studies highlighted the possibility of this occurrence in de novo small cell neuroendocrine carcinomas of the prostate, in over 50% of cases (9).

A literature review conducted by Palmgren et al reviewed articles published from 1983 until 2005 regarding small cell carcinomas of the prostate. Patients with small cell carcinoma of the prostate had different clinical presentations – voiding symptoms, neurologic and constitutional symptoms were among the most frequent (3). The case described by Bhandari et al presented with biochemical modifications of the PSA level, without any other clinical symptoms. Unfortunately, the disease quickly progressed and therapeutic interventions focused on symptom control and palliative care, highlighting once again the aggressive nature of this tumor (10).

Metastases were present in most of the patients in these studies at the time of diagnosis, with liver, lung and bone metastases being the most frequent. Most patients included in these studies had more than one metastatic site (3, 5, 11). Conteduca et al reported 82,8 % of patients with metastases at the time of neuroendocrine small cell carcinoma of the prostate diagnosis, all of which had liver metastases (12).

A population-based study conducted by Deorah et. al regarding the survival of patients diagnosed with small cell carcinoma of the prostate included 191 cases reported in the SEER database from 1973 until 2003. The oneyear overall survival rate was 50,9%, with progressively lower rates at two and five years (27,5 and 14,3% respectively), with median survival being just 19 months (11).

Small cell carcinomas resemble other small cell primaries. Being such rare tumors, treatment paradigms are extrapolated from small cell lung cancer. Currently, systemic therapy regimens for the metastatic setting rely on cisplatin and etoposide, with carboplatin being a good replacement if needed. FOLFOX or FOLFIRI can also be used (2). Although remission has been reported in different studies after aggressive systemic therapy, these responses are short-lived. Some studies reported progression free survival at just six months in (5). The Impower133 study brought improvements in OS and PFS in small cell lung cancer with the PD-L1 inhibitor atezolizumab in combination with standard chemotherapy, becoming standard of care. Based on this, it was hypothesized that checkpoint inhibitors might offer a new therapeutic option in small cell carcinoma of the prostate. Wee et al identified patients that received chemotherapy+atezolizumab in the firstline setting of a metastatic prostatic small cell carcinoma. This study did not show any benefit from the addition of immunotherapy in this setting, with a median PFS of 3,4 months and OS of 8,4 months (median follow-up of 6,5 months) (13). On the other hand, a case report published in 2018 reported a sustained response with pembrolizumab in a 78-year old male with platinum-refractory metastatic small cell carcinoma of the prostate with a history of high-grade adenocarcinoma (14).

4. Conclusion

Small cell neuroendocrine carcinoma of the prostate is an infrequent entity, with a highly aggressive evolution. The histopathologic and immunohistochemical diagnoses were challenging and highly disputed in this case.

A multidisciplinary approach involving a pathologist subspecialized in genitourinary pathology was necessary for the appropriate diagnosis and treatment strategy. Clinically, the patient had an improved performance status and a good response to platinum-based chemotherapy, as seen in other reported cases. These responses seem to be shortlived, and the overall prognosis of these patients is poor. The optimal management is not well defined, given that the clinical experience is scarce at this moment and there is a constant need of new data and new treatment options in order to improve the outcomes of these patients.

Abbreviations

CT – computed tomography

PSA – prostate specific antigen

CEA – carcinoembryonic antigen

CA19-9 – carbohydrate antigen 19-9

H&E – hematoxylin and eosin

SYN – synaptophysin

ChA – chromogranin A

NEC – neuroendocrine carcinoma

SCC – small cell carcinoma

SEER – the surveillance, epidemiology and end results program

PD-L1 – programmed death-ligand 1

OS – overall survival

PFS – progression free survival

Statements:

Authors’ contributions: MN wrote the manuscript, IG & MM revised the text.

Consent for publication: As the corresponding author, I confirm that the manuscript has been read and approved for submission by all co-authors.

Conflict of interest: All authors declare having no competing interests associated with this publication.

Funding Sources: This case report did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.

Informed consent: The informed consent was obtained from the patient for publication and any accompanying images.

Ethical Approval: The treatment strategy was approved by the institutional tumor board (Fundeni Clinical Institute, Bucharest, Romania).

References:

1. Humphrey, P.A., et al., The 2016 WHO classification of tumours of the urinary system and male genital organs—part B: prostate and bladder tumours. 2016. 70(1): p. 106-119.
2. Shah, M.H., et al., Neuroendocrine and adrenal tumors, version 2.2021, NCCN Clinical Practice Guidelines in Oncology. 2021. 19(7): p. 839-868.
3. Palmgren, J.S., S.S. Karavadia, and M.R. Wakefield, Unusual and underappreciated: small cell carcinoma of the prostate. Semin Oncol, 2007. 34(1): p. 22-9.
4. Sleiman, W., et al., Large-cell neuroendocrine tumor of the prostate: a case report and review of the literature. 2021. 15(1): p. 1-5.
5. Spiess, P.E., et al., Treatment outcomes of small cell carcinoma of the prostate: a single-center study. Cancer, 2007. 110(8): p. 1729-37.
6. Spetsieris, N., et al., Neuroendocrine and aggressive-variant prostate cancer. 2020. 12(12): p. 3792.
7. Inamura, K.J.O., Prostatic cancers: Understanding their molecular pathology and the 2016 WHO classification. 2018. 9(18): p. 14723.
8. Epstein, J.I., et al., Proposed morphologic classification of prostate cancer with neuroendocrine differentiation. 2014. 38(6): p. 756.
9. Nadal, R., et al., Small cell carcinoma of the prostate. Nat Rev Urol, 2014. 11(4): p. 213-9.
10. Bhandari, R., et al., Small Cell Carcinoma of the Prostate: A Case Report and Review of the Literature. Cureus, 2020. 12(2): p. e7074.
11. Deorah, S., et al., Survival of patients with small cell carcinoma of the prostate during 1973-2003: a population-based study. BJU Int, 2012. 109(6): p. 824-30.
12. Conteduca, V., et al., Clinical features of neuroendocrine prostate cancer. Eur J Cancer, 2019. 121: p. 7-18.
13. Wee, C.E., et al., Chemotherapy with atezolizumab for small cell or neuroendocrine carcinoma of the prostate: A single institution experience. Prostate, 2021. 81(13): p. 938-943.
14. Salhab M, D.M., Walsh W, Pembrolizumab for platinum refractory small cell carcinoma of the prostate, a case report. Hematology and Medical Oncology, 2018(3): p. 1-3.