Transperineal US-Guided Biopsy in Metastatic Prostate Cancer with Low Prostate Specific Antigen: A Case Report

Abstract

Prostate specific antigen (PSA) is a crucial tool for detecting and monitoring of prostate cancer, and elevated levels of PSA often indicate disease progression. Higher PSA levels are generally associated with more aggressive cancers and an increased risk of cancer-specific mortality. In this report, we present an unusual case of primary aggressive prostate cancer characterized by unexpectedly low PSA levels, despite the presence of multiple lumbar bone metastases at the time of diagnosis. It is extremely uncommon to have a low PSA level at the time of initial prostate cancer diagnosis, especially in cases that are non-recurrent, and even more so for adenocarcinomas without neuroendocrine differentiation. This report highlights the challenges in accurately diagnosing disease using CT and MRI findings when confronted with atypically low PSA patterns, necessitating invasive diagnostic approaches such as transperineal biopsy following abdominoperineal resection in a patient with a colostomy.

INTRODUCTION

Prostate cancer is the most commonly diagnosed cancer in men worldwide and the second leading cause of cancer-related deaths in men in the USA (1,2). According to the National Cancer Information Center report released in 2023, prostate cancer ranked 4th among cancers occurring in men in Korea in 2021. Prostatespecific antigen (PSA) plays a pivotal role in prostate cancer detection and monitoring, often indicating disease progression when its levels are elevated (1). PSA testing is widely employed for screening because of its simplicity and affordability. Traditionally, a PSA threshold of >4 ng/mL has been recommended as an indication for biopsy (2). However, it is important to note that PSA levels may not consistently reflect the severity of prostate cancer. Some patients may present with high-grade or metastatic prostate cancer despite having low PSA values (2). Wang et al. (1) reported that 2.8% of patients diagnosed with high-grade metastatic prostate cancer had PSA levels of <4 ng/mL. Neuroendocrine prostate cancer is a rare and highly aggressive disease that accounts for only 1% of all newly diagnosed prostate cancer. Patients with metastatic prostate cancer are confronted with a discouraging 5-year survival rate of 29% (1,2). Low serum PSA levels have been associated with neuroendocrine tumors or treatment-induced small-cell neuroendocrine prostate cancer (2). However, it should be noted that 17% of patients with metastatic castration-resistant prostate cancer may develop histological changes resembling primary neuroendocrine prostate cancer characteristics after androgen deprivation therapy. Wang et al. (1) showed that low serum PSA levels predict poor outcomes in patients with primary neuroendocrine prostate cancer.

It is exceedingly rare to have a low PSA level at the initial diagnosis of prostate cancer, particularly for non-recurrent cancer and in cases of adenocarcinoma, rather than neuroendocrine cancer. Here, we present a unique case of primary aggressive prostate cancer characterized by unexpectedly low PSA levels, despite the presence of multiple lumbar bone metastases at diagnosis. This report highlights the challenges in accurately diagnosing disease based on CT and MRI findings when confronted with atypically low PSA patterns, necessitating invasive diagnostic approaches such as transperineal biopsy following abdominoperineal resection in a patient with a colostomy.

CASE REPORT

We present the case of a 68-year-old male who underwent abdominoperineal resection and colostomy 26 years previously for rectal cancer. The patient presented with persistent lower back pain for one month. Initial thoraco-lumbar MRI revealed multiple metastases in the lumbar and pelvic bones. An enhanced CT scan of the abdomen and pelvis, performed to evaluate the primary tumor, revealed multiple metastatic lymphadenopathies in the para-aortic, aortocaval, right internal iliac, and both inguinal areas (Fig. 1A). Additionally, the prostate gland showed diffuse irregular enlargement and enhancement, suspicious of prostate cancer (Fig. 1A). Further assessment with prostate MRI revealed an irregular margined mass measuring approximately 3.0 × 3.0 × 3.4 cm, exhibiting low signal intensity on T2-weighted images (Fig. 1B). In the high b-value dffusion weighted image (DWI) (Fig. 1C), high signal intensity was observed throughout the prostate gland, while low signal intensity was demonstrated in the apparent diffusion coefficient (ADC) map (Fig. 1D), indicating diffusion restriction. The prostate imaging reporting and data system (PI-RADS) score was determined to be 5, as the lesion was larger than 1.5 cm and had invaded the bladder base. Despite the suspicious findings on CT and MRI, the patient’s PSA level measured at 2.7 ng/mL, which was lower than expected, considering his age and the aggressive nature of the disease.

Fig. 1. A 68-year-old male with a history of rectal cancer and subsequent metastatic prostate cancer.

A. Left image: Axial CT demonstrates metastasis of lymph nodes (white arrow) at the paraaortic space and osterosclerotic bony metastasis (black arrow) at L3 vertebra body. Right image: Axial CT at the pelvic level reveals metastatic lymph nodes (white arrow) in the left inguinal area and diffuse irregular enlargement of prostate gland (arrowheads), suggestive of prostate cancer.

B. Axial T2-weighted MRI displays approximately 3.0 × 3.0 × 3.4 cm, slightly high signal intensity lesion (arrowheads) in the prostate gland and also displays the left inguinal lymph nodes (yellow arrow).

C. DWI (b = 1000 s/mm²) demonstrates hyperintense area (arrowheads) in nearly the entire prostate gland and inguinal lymph nodes (arrow).

D. ADC map in the prostate gland (arrowheads) and inguinal lymph nodes (yellow arrow) show reduced signal intensity.

E. Transperineal ultrasonography using convex probe reveals irregularity and heterogeneity of the prostate gland (arrowheads).

F. Left image: Microscopic finding (H&E stain, ×400) shows diffusely infiltrating atypical cells, and the atypical cells show a sheet-like growth pattern with hyperchromasia and a clear cytoplasm. Middle image: Immunohistochemical staining for P504S is strongly positive (×400). Right image: Immunohistochemical staining for prostate specific antigen shows focal weak positivity (×400).

ADC = apparent diffusion coefficient, DWI = diffusion weighted image

To obtain histopathological confirmation, a biopsy of the inguinal lymph nodes was performed, which revealed a poorly differentiated metastatic carcinoma. Given the patient’s history of abdominoperineal resection, a transrectal biopsy was not feasible because of anatomical alterations. Therefore, a transperineal biopsy using a 3–5 MHz convex probe was performed (Fig. 1E). Biopsy confirmed the diagnosis of poorly differentiated prostate adenocarcinoma with a Gleason score of 10 (5 + 5) without evidence of neuroendocrine differentiation.

Microscopic findings (Fig. 1F, left image) showed diffusely infiltrating atypical cells and immunohistochemical staining revealed focalweek positivity for PSA (Fig. 1F, middle image), whereas P504S (Fig. 1F, right image) was strong positive. However, the cells were negative for synaptophysin, chromogranin-A, and CD56, indicating the absence of neuroendocrine differentiation.

This retrospective study was approved by the Institutional Review Board of our hospital (IRB No. 2023-07-001-001), and the requirement for informed consent was waived.

DISCUSSION

PSA levels are closely linked to tumor burden and strongly associated with the prognosis of prostate cancer. Generally, high PSA levels indicate more aggressive cancers and increased risk of cancer-specific mortality (2). However, some studies have reported poorer survival outcomes in patients with high-grade prostate cancer and lower PSA levels (3,4). Low PSA levels are often associated with recurrent cancer; in such cases, 18F-choline PET/CT imaging can be beneficial for detection, even in cases with low PSA levels (<1 ng/mL) (4).

The effect of low PSA levels on high-grade (Gleason 8–10) prostate cancer remains unclear. A correlation has been observed between substantially low PSA levels and increased rates of metastasis and mortality in patients with biopsy Gleason scores of 8–10. Wang et al. (2) reported that low PSA levels in high-grade metastatic prostate cancer are associated with advanced disease, visceral metastasis, and poor cancer-specific outcomes. Only 2.8% of high-grade metastatic prostate cancer has a PSA level ≤4 ng/mL at diagnosis. High-grade metastatic prostate cancer with low PSA levels manifests aggressive clinical features and yields poorer cancer-specific outcomes, requiring increased attentionto disease management (1,2). In Chung et al.’s study (5), it was observed that approximately 25% of prostate biopsies conducted at PSA levels of 2.5 to 4.0 ng/mL led to the diagnosis of prostate cancer, with clinically significant cancer detected in 18.5% of these cases. Furthermore, prostate cancer was identified in more than 20.0% of the patients with PSA levels <4.0 ng/mL, indicating the potential necessity to lower the PSA cutoff level from 4.0 ng/mL. However, at a PSA cutoff level of 4.0 ng/mL, the detection specificity for prostate cancer is 21%, while the sensitivity is 91%. Low serum PSA levels are associated with a poorer prognosis in patients with both neuroendocrine prostate cancer and neuroendocrine differentiation (2). Mahal et al. (6) collected clinical and transcriptomic data from two national cohorts and a large transcriptome database that included 626057 patients with N0M0 prostate cancer. Low PSA levels and high-grade prostate cancer represent distinct entities with a significantly elevated risk of prostate cancer-specific mortality and poor response to androgen deprivation therapy. These cancers are associated with neuroendocrine genomic characteristics (6).

Our case represents a rare instance of low PSA levels during the initial diagnosis of prostate cancer, which is an anomaly in non-recurrent cancer, particularly adenocarcinoma, rather than in neuroendocrine cancer. Lowering the PSA cutoff value based on isolated cases such as ours could lead to an increase in unnecessary tissue biopsies, which carries a risk of complications such as bleeding, prostate infection, or sepsis. Furthermore, overdiagnosis without clinical significance can result in significant psychological stress for patients. In challenging cases where transrectal probe insertion is not feasible due to the absence of the rectum or severe anal fistula, the transabdominal approach becomes complicated because of obstructed visibility caused by the bladder. However, in such situations, the transperineal approach using a convex probe can serve as an alternative method for conducting tissue biopsies. It is crucial to carefully consider the need for tissue biopsy in cases of suspected prostate cancer based on imaging findings or the presence of metastatic features.

Recent studies have highlighted the effectiveness of MRI-targeted prostate biopsy (TBx) in detecting clinically significant prostate cancer, even in men with low PSA levels. MRI-TBx has shown improved detection rates for prostate cancer in men with low PSA levels, including clinically significant cases, similar to men with high PSA levels (7). Therefore, when prostate cancer is suspected based on imaging findings or the presence of metastatic features, conducting a tissue biopsy, such as MRI-TBx, becomes imperative.

In conclusion, the diagnosis of prostate cancer in patients with low PSA levels highlights the significance of a meticulous evaluation of CT/MRI findings. When suspicion arises, consideration of a tissue biopsy is essential for an accurate prostate cancer diagnosis. It is paramount to be mindful of anatomical variations resulting from previous surgeries and choose an appropriate biopsy approach, such as transabdominal or transperineal methods, to ensure accurate diagnosis and proper management of prostate cancer cases with low PSA levels.