A case report of small-cell carcinoma of the prostate with ectopic adrenocorticotropic-hormone (ACTH) syndrome and hypokalemia

Introduction

Currently, prostate cancer ranks second in global incidence among malignant tumors in males and fifth in mortality (1). Neuroendocrine prostate cancer (NEPC) represents a rare and highly aggressive histological subtype of prostate cancer, typically manifesting after hormonal therapy for prostate cancer and often associated with anti-androgen therapy. Approximately 17% of men diagnosed with adenocarcinoma of the prostate may undergo complete or partial neuroendocrine differentiation following androgen deprivation therapy (ADT), leading to a condition known as treatment-related neuroendocrine prostate cancer (t-NEPC). Remarkably, only one percent of NEPC cases are an initial diagnosis (2). The pathological types of t-NEPC encompass small cell carcinoma, large cell carcinoma, and mixed neuroendocrine carcinoma, with small-cell prostate cancer being the most prevalent (3). Small-cell prostate cancer exhibits a heightened propensity for multi-organ metastasis and secretes various hormones capable of inducing paraneoplastic syndromes, such as pro-adrenocorticotropic and antidiuretic (4). The production of ectopic adrenocorticotropic hormone by prostate cancer is a rare phenomenon, with fewer than 50 documented cases to date (5). This paper presents a case study involving a patient who developed ectopic adrenocorticotropic-hormone (ACTH) syndrome (EAS) following ADT, endocrine therapy, and chemotherapy, culminating in a pathological transformation to small-cell prostate cancer. Notably, the patient presented primarily with intractable hypokalemia and hypertension and did not have typical Cushing-like symptoms. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-271/rc).

Case presentation

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

A 56-year-old male patient was diagnosed with prostate adenocarcinoma in November 2021. His initial PSA was 208.000 ng/mL, with a Gleason score of 4+4=8 [the World Health Organization/International Society of Urological Pathology (WHO/ISUP) grading subgroup Gradegroup4]. He had multiple metastases in both lungs, bilateral pleura, pelvic lymph nodes, and bones throughout the body, at a clinical stage of T4N1M1c. After 8 months of endocrine and docetaxel chemotherapy, he progressed, with new lesions appearing in the penis. Biopsies of the prostate, lung, and penile lesions confirmed metastatic small cell neuroendocrine carcinoma of the prostate. At this point, his prostate-specific antigen (PSA) was 0.72 ng/mL, and neuron-specific enolase (NSE) was 165.8 ng/mL, indicating a diagnosis of treatment-associated neuroendocrine prostate cancer (t-NEPC). He underwent two cycles of etoposide + cisplatin (EP) regimen and four cycles of irinotecan + cisplatin (IP) regimen chemotherapy on the basis of endocrine therapy, all of which showed progression. He then switched to backline therapeutic agents such as sorafenib, olaparib, temozolomide, and topotecan, and finally passed away in May 2023 due to disease progression.

From Dec 2022 to Jan 2023, patient had recurring low potassium, normalized with supplementation. On Feb 21, 2023, admitted for routine electrolyte check—potassium 2.8 mmol/L ↓, mild blood pressure elevation (130/85 to 160/100 mmHg). Immediate potassium supplementation. On Feb 22, recheck—potassium 2.9 mmol/L ↓ (Figure 1). Suspected abiraterone side effects halted treatment on Feb 23. Despite IV potassium on Feb 23–24, levels persisted at 2.8 mmol/L. Endocrinology recommended intensified potassium supplementation and tests for aldosterone, renin, cortisol, ACTH and related exams. On Feb 27, test results revealed cortisol levels at 0 a.m.: 328.12 nmol/L ↑ (normal range, 12.8–82.5 nmol/L), 8 a.m.: 308.36 nmol/L (normal range, 124.2–662.4 nmol/L), 4 p.m.: 390.65 nmol/L ↑ (normal range, 49.68–179.40 nmol/L), ACTH 167.02 pg/mL (normal range, 7.0–65.0 pg/mL), aldosterone 22.80 pg/mL ↓, renin: 0.50 ulU/mL ↓, considered ectopic ACTH secretion causing cortisol elevation. Following the small-dose suppression dexamethasone test and enhanced magnetic resonance imaging (MRI) of the head, EAS was diagnosed.

Figure 1 Changes in the patient’s blood potassium after admission to the hospital.

Starting Mar 8, 2023, the patient received 250 mg quater in die of the adrenal steroidogenesis inhibitor metyrapone. Cortisol normalized the next day (Figure 2) swiftly. Post-potassium supplementation, blood levels gradually stabilized. ACTH and cortisol decreased with metyrapone, olaparib and temozolomide for the tumor, and potassium supplementation. Neuroendocrine tumor marker NSE was significantly decreased, symptoms improved, and normal blood potassium was maintained with oral potassium chloride 1.5 g times daily. Effective anti-tumor and adrenal block therapy led to the patient’s successful discharge on Mar 31, without further hypokalemia.

Figure 2 Changes in cortisol and ACTH in the patients. ACTH, adrenocorticotropic hormone.

Discussion

Possible triggers of small-cell prostate cancer transformation

Small-cell prostate cancer, a rare pathological type among prostate cancers, may be induced by therapeutic drugs like ADT drugs, docetaxel, abiraterone, enzalutamide, etc., causing neuroendocrine differentiation. This leads to a lack of androgen receptor (AR) and PSA expression in tumor cells, making them treatment-resistant. Additionally, radiotherapy can also induce this transformation (6). Treatment-associated small cell neuroendocrine prostate cancer (t-SCNC) was observed in 17% of patients with advanced metastatic desmoplasia-resistant prostate cancer (mCRPC) in a multi-institutional prospective study of patients with small cell neuroendocrine carcinoma of the prostate, and it was associated with shorter survival (2).

Tumor markers in small-cell prostate cancer

In small-cell prostate cancer, AR and PSA levels are generally within normal range or slightly elevated, while neural-related markers like carcinoembryonic antigen (CEA), NSE, and chromogranin A (CgA) show increased expression (7), serving as crucial indicators for NEPC. Among t-NEPC patients, the average monthly PSA elevation prior to biopsy diagnosis is 16%. Elevated serum levels of CgA and lactate dehydrogenase (LDH) are observed in 48.3% (14/29) and 62.5% (20/32) of NEPC cases, respectively (8). In our patient, PSA levels remained normal for several months after confirming small-cell prostate cancer through prostate lesion aspiration. Conversely, NSE levels were significantly elevated post-confirmation. Clinically, a considerable proportion of treated end-stage prostate cancer patients exhibit characteristics of small-cell neurosecretory cell carcinoma, often displaying aggressive behavior and visceral metastases (9). A systematic review analyzing 123 NEPC patients revealed that the median time between initial prostate cancer diagnosis and NEPC development was 20 months [hazard ratio (HR), 1.66; P=0.032]. A high Gleason score (≥8) at diagnosis emerged as an independent risk factor for early NEPC development (10). Therefore, prostate cancer patients, especially those with a high Gleason score following prolonged endocrine therapy, should be vigilant for small-cell NEPC if they experience rapid multi-organ and extensive metastases with normal or slightly elevated PSA levels. During this period, monitoring neuroendocrine tumor markers like NSE, CgA, and others becomes critical.

Imaging examination of small-cell prostate cancer

Imaging plays a pivotal role in localizing and diagnosing tumors; however, accurately local neuroendocrine tumors (NETs) remains challenging. These tumors often exhibit reduced expression of prostate-specific membrane antigen (PSMA) and AR, making their detection via PSMA-positron emission tomography (PET)-computed tomography (CT) challenging (10). Moreover, routine 18F-fluorodeoxyglucose (FDG)-PET-CT encounters limitations in detecting NETs, especially those that are well-differentiated and exhibit slow growth rates. Nonetheless, radiolabeled somatostatin (SST) analogues can effectively localize most NETs since they typically overexpress SST receptors. Recent studies have demonstrated the superiority of 68Ga-DOTA-TATE PET-CT in providing higher spatial resolution and more detailed anatomical information, significantly aiding in the identification of smaller tumors in NET patients (11). Patients demonstrating positivity in 68Ga-DOTA-NOC scans generally exhibit a more favorable prognosis than those with positive FDG-PET scans, suggesting higher proliferation rates in FDG-PET-positive patients (12). In our specific case, imaging was not employed to locate NETs due to existing pathological evidence confirming the diagnosis of small-cell neuroendocrine carcinoma of the prostate. Instead, imaging primarily focused on assessing the tumor’s extent, invasion, and monitoring the progress of therapy.

Management of small-cell prostate cancer treatment

In accordance with guidelines from the Neuroendocrine Tumor Society of North America for extrapulmonary small cell carcinoma, treatment aligns with the small cell lung carcinoma (SCLC) regimen (13). Upon confirming the patient’s tumor pathology, the initial plan transitioned to the EP regimen, a primary small-cell lung cancer treatment. After two cycles, tumor progression mandated a shift to the IP regimen. Despite four cycles, progression persisted, leading to the identification of brain metastasis. Treatment then switched to surufatinib, a third-line small-cell lung cancer treatment. A subsequent imaging review revealed significant progression of lung lesions and brain metastases after two weeks. Consequently, the patient commenced the backline small-cell lung cancer regimen, OT (olaparib + temozolomide). Studies suggest OT’s efficacy, with an overall response rate (ORR) of 41.7% and a median progression-free survival (mPFS) of 4.2 months in 50 patients with recurrent SCLC. Common side effects include grade 1–2 thrombocytopenia, anemia, and neutropenia. Exhaustion, nausea, and vomiting are less frequent, while drug-induced pneumonia is rare, occurring in only two cases (14). During the above treatment process, we found that the patient still experienced rapid progression after receiving different chemotherapy regimens targeting small-cell tumors. We speculate that this is related to the biological characteristics of small cell prostate cancer, such as fast cell proliferation, strong invasiveness, and a tendency to metastasize. Additionally, the upregulation of driver genes and proliferative marker genes (such as PBK/TOPK), neuroendocrine marker genes (such as CTNNA2), receptor tyrosine kinases (e.g., FGFR3), mitotic genes (including UBE2C), and the downregulation of cell adhesion molecule genes (including CLDN10, COL4A5, and MMP7), as well as gene mutations and abnormal signaling pathways, are also factors contributing to the higher invasiveness and poorer chemotherapy response of small cell prostate cancer compared to adenocarcinoma (15).

Clinical manifestations of small-cell prostate cancer combined with EAS

Cushing’s syndrome (CS) from EAS is rare, constituting 9–18% of CS cases (16). Patients usually display symptoms like primary tumor foci, intractable hypokalemia, edema, hypertension, hyperglycemia, and malaise. However, classic Cushing’s signs such as a full-moon face, buffalo back, and purple striae are rare due to the swift cortisol surge, so the absence of obvious physical signs. In this case, the patient’s focus was on intractable hypokalemia, mild hypertension, and edema, with no elevated blood glucose or typical Cushing’s signs. Hypokalemia may be linked to abiraterone, a prostate cancer drug, causing delayed diagnosis and treatment, implying that we must emphasize vigilance for paraneoplastic syndromes in tumor patients with electrolyte disorders, hypertension, and edema, as it is crucial. Diagnosing EAS is challenging; patients usually lack typical Cushing’s manifestations. Initial symptoms often include severe hypokalemia and hypertension, which are usually associated with oncologic drug reactions, causing diagnosis and treatment delays.

Diagnosis of small-cell prostate cancer combined with EAS

EAS is commonly diagnosed through a comprehensive approach, combining lab investigations and imaging studies. Patients should undergo initial assessments, including 24-hour urine free cortisol, plasma cortisol, and cortisol circadian rhythm monitoring. Typically, patients show markedly elevated levels of urine-free cortisol, plasma cortisol, and ACTH concentrations, along with circadian rhythm disruption. Further, ACTH suppression failure is observed in both small and large dose dexamethasone suppression tests, and corticotropin-releasing hormone (CRH) stimulating test results indicate unresponsiveness. Pituitary MRI serves to exclude pituitary tumor-induced ACTH elevation, while chest, abdomen, and pelvis imaging identifies primary tumor sites, localizes ACTH-secreting tumors, and determines the condition’s underlying etiology (16).

Treatment of CS due to EAS

The treatment of EAS can be categorized into three scenarios: (I) if the tumor is small, limited, or concealed, and hormonal risks dominate, the therapeutic objective should be to manage CS while surgically resecting visible tumor tissues; (II) if the tumor poses a significant risk, often characterized by high invasiveness or metastasis, prompt initiation of chemotherapy (typically EP) is recommended. Concurrent pharmacological treatment for hypercortisolism can be added, or bilateral adrenalectomy can be performed; (III) in cases with a high hormonal risk and a metastatic tumor causing severe CS, measures to control hypercortisolism are imperative (16). In our case, the patient falls into the third category. The tumor had widely metastasized and had been ineffective in the first-line treatment plan for small-cell carcinoma. At this point, severe CS had resulted in evident intractable hypokalemia, making the priority controlling cortisol elevation. Considering the patient’s tumor progression and physical condition, bilateral adrenalectomy should not be considered for now, and pharmacological treatment is the preferred choice. Due to their rapid onset of action, efficacy, and high safety profile, adrenal steroidogenesis inhibitors are favored for pharmacologic treatment. They are often the first-line choice for patients with severe adrenocorticotropic hypercortisolism. However, caution should be exercised for potential adrenocortical insufficiency as a side effect (17). In accordance with guidelines and considering pharmacological accessibility, Metyrapone was chosen as the therapy medicine for our patient.

Prognosis

Prostate small cell carcinoma is highly malignant and prone to multiple organ metastases. The median survival time after NEPC diagnosis is seven months, and the involvement of more than three metastatic organs is associated with a shorter survival time (HR, 3.31; P=0.001) (10). Patients with small-cell prostate carcinoma (SCPC)-related CS face an even graver prognosis, surviving a median of only two months in reported cases. Sepsis, potentially due to hypercortisolism, predominates as the cause of death, highlighting the urgent need to control hypercortisolism. Patients who receive both adrenal blockade and chemotherapy have a longer median survival time compared to those who receive only adrenal blockade (including bilateral adrenalectomy) or no specific treatment (18).

Conclusions

In recent years, prostate cancer incidence has risen. Endocrine therapy is vital for its treatment. Patients in standard treatment display extended survival. In the late stage of treatment, patients are prone to being resistant to endocrine therapeutic drugs and to develop castration-resistant. Prostate cancer transforming into small-cell neuroendocrine carcinoma is one of the mechanisms behind this resistance. After transformation, patients usually have normal or slightly elevated PSA and AR levels. Despite stable markers, the disease rapidly progresses, with new metastatic foci emerging in multiple organs. In this phase, elevation of neuroendocrine markers like CEA, NSE, and glycosaminoglycan (Gag) occurs. Choosing suitable pathology for qualitative assessment, imaging localization, and quantification is crucial for confirming tumor diagnosis, informed treatment decisions, and prognosis prediction. The approach to treating prostate cancer with small-cell neuroendocrine transformation is parallel small-cell lung cancer, but prognosis is generally poor. Small-cell neuroendocrine carcinoma of the prostate may lead to rare EAS. During this time, besides tumor-induced symptoms, patients may also show CS features, including edema, hypertension, and hypokalemia. The symptoms’ specificity is limited, posing challenges for accurate diagnosis; however, timely and precise diagnosis is crucial for the patient. Patient mortality is often linked not only to tumor invasion but also to elevated cortisol levels, causing intractable hypokalemia, sepsis, and related complications. Therefore, simultaneous tumor treatment with adrenal gland blocking therapy significantly extends survival. In summary, small-cell carcinoma of the prostate is rare, and EAS occurrence is even rarer. Clinicians face challenges in timely, precise diagnoses and treatment planning. More experience is critical to enhance management protocols for this uncommon ailment.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-271/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-271/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-271/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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