Prostate cancer presenting as brain metastasis with concurrent elevation of carcinoembryonic antigen and carbohydrate antigen 19-9 levels: illustrative case

Abstract

BACKGROUND

Prostate cancer is a common malignancy in men and usually presents with elevated prostate-specific antigen (PSA) levels and metastases to the bones or lymph nodes. Brain metastases are rare, occurring in less than 1% of cases. Concurrent elevation of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) is also uncommon.

OBSERVATIONS

A 61-year-old man presented with left hemiparesis and cognitive decline. Laboratory tests revealed elevated PSA, CEA, and CA19-9 levels. Imaging revealed a cystic frontal lobe mass, lung nodules, pelvic lymphadenopathy, and a prostatic lesion. MRI confirmed a 5-cm right frontal mass with heterogeneous enhancement and edema. A prostate biopsy revealed adenocarcinoma positive for CEA and CA19-9. Endoscopy revealed no gastrointestinal malignancies. Craniotomy and histopathological examination confirmed the diagnosis of adenocarcinoma. Immunohistochemical analysis revealed CEA positivity, partial CA19-9 positivity, strong NKX3.1 positivity, and PSA negativity. Postoperatively, the patient received androgen deprivation therapy with leuprorelin acetate and darolutamide, along with 5 cycles of docetaxel chemotherapy. At the 24-month follow-up, he remains neurologically stable without recurrence.

LESSONS

Brain metastases from prostate cancer with elevated CEA and CA19-9 are rare. Although these markers often indicate a poor prognosis, this patient achieved a favorable outcome with multimodal treatment.

https://thejns.org/doi/10.3171/CASE25735

Prostate cancer is one of the most common malignancies affecting men globally, with approximately 1.4 million new cases diagnosed annually. Although metastases typically involve the bones and lymph nodes, involvement of the CNS, particularly brain metastases, is rare.^1–6 The concomitant elevation of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) in these cases is also unusual.^7–9 Herein, we report the case of a brain metastasis from prostate cancer in a 61-year-old man who presented with simultaneously elevated CEA and CA19-9 levels and discuss the associated diagnostic and therapeutic challenges.

Illustrative Case

A 61-year-old man presented to the emergency department with complaints of unsteady gait and progressive cognitive decline. CT of the brain revealed a large, cystic, intra-axial mass in the right frontal lobe, with significant perilesional edema and midline shift (Fig. 1A), prompting an urgent referral to the neurosurgery department. The patient’s initial Glasgow Coma Scale score was E4V5M6. Although the patient was initially ambulatory and was able to visit the outpatient clinic, his left hemiparesis progressively worsened over the course of approximately 1 month, and he soon required a wheelchair and assistance with daily activities. The patient’s medical history included type 2 diabetes mellitus and hyperlipidemia, both of which were controlled with oral medications.

FIG. 1.

Radiological findings of the brain tumor and systemic metastatic tumors. A: Noncontrast head CT scan showing a cystic lesion with surrounding edema in the right frontal lobe. B: Axial T1-weighted contrast-enhanced MR image showing a ring-enhancing cystic mass in the right frontal lobe. C: Postoperative contrast-enhanced MR image showing gross-total resection of the lesion. D: Chest CT scan revealing multiple small pulmonary nodules in both lungs (yellow arrows), suggestive of potential metastatic lesions. E: Abdominal CT scan showing enlarged retroperitoneal lymph nodes (yellow arrow). F: Pelvic CT scan showing an abnormal prostatic lesion (yellow square), consistent with prostatic malignancy.

MRI of the brain revealed a 5-cm cystic mass with heterogeneous contrast enhancement, mural nodules, and peritumoral edema in the right frontal lobe, suggestive of a metastatic tumor (Fig. 1B).¹⁰ Although the imaging characteristics were atypical for common brain metastases, the nodular enhancement pattern and associated edema prompted the consideration of a metastatic lesion in the differential diagnosis. Systemic CT evaluation revealed multiple small peripheral pulmonary nodules (Fig. 1D), asymmetric contrast enhancement in the left lobe of the prostate (Fig. 1F) and enlarged pelvic lymph nodes (Fig. 1E).

Laboratory tests showed elevated levels of prostate-specific antigen (PSA; 7.234 ng/mL), CEA (43.1 ng/mL), and CA19-9 (63.3 U/mL). Transrectal ultrasound-guided prostate biopsy confirmed acinar adenocarcinoma (Fig. 2A) with a Gleason score of 4 + 4. H&E staining of the biopsy specimen revealed adenocarcinoma. Immunohistochemical analysis demonstrated positivity for CEA (Fig. 2B) and CA19-9 (Fig. 2C), while staining for PSA was negative (Fig. 2D).

FIG. 2.

Immunohistochemical staining of the prostate biopsy specimen. A: H&E staining revealing adenocarcinoma. B: Immunohistochemical staining for CEA showing strong positivity. C: Immunohistochemical staining for CA19-9 showing partial positivity. D:Immunohistochemical staining for PSA showing negativity. Original magnification ×40.

Upper and lower gastrointestinal endoscopies revealed only benign polyps with no evidence of malignancy.

Because a comprehensive systemic workup was required to identify the primary lesion and an urgent surgical slot could not be accommodated under our institutional scheduling constraints, the patient had to wait approximately 1 month before tumor resection. During this interval, his motor function progressively deteriorated, ultimately necessitating craniotomy. Intraoperatively, the cystic component was yellowish, and cytological examination of the fluid revealed malignant cells. Gross-total resection of the tumor was achieved by focusing on the nodular solid components.

Histopathological examination of the brain tumor revealed an adenocarcinoma of prostate origin (Fig. 3A and B). Immunohistochemical analysis showed negativity for PSA (Fig. 3C), diffuse cytoplasmic positivity for cytokeratin (Fig. 3D), positivity for CEA (Fig. 3E), partial positivity for CA19-9 (Fig. 3F), and strong nuclear positivity for NKX3.1 (Fig. 3G and H), a prostate-specific transcription factor, confirming its prostatic origin and leading to a diagnosis of brain metastasis from prostate adenocarcinoma.

FIG. 3.

Histopathological and immunohistochemical findings of the brain tumor. A: H&E staining showing metastatic adenocarcinoma with glandular formation. B:)A high-power view of the H&E staining showing crowded atypical glands with hyperchromatic nuclei. C: Immunohistochemical staining for PSA showing negative staining. D: Immunohistochemical staining for cytokeratin showing diffuse cytoplasmic positivity. E: Immunohistochemical staining for CEA showing strong positivity. F: Immunohistochemical staining for CA19-9 showing partial positivity. G: Immunohistochemical staining for NKX3.1 showing strong nuclear positivity, consistent with a prostate origin. H: High-power NKX3.1 staining demonstrating diffuse nuclear expression in the tumor cells. Original magnification ×40 (A–G); ×100 (H).

Postoperative contrast-enhanced MRI showed no evidence of residual tumor and resolution of the mass effect (Fig. 1C). The patient’s neurological symptoms gradually improved, and he was discharged. Postoperatively, the patient received androgen deprivation therapy with leuprorelin acetate in combination with darolutamide, along with 5 cycles of docetaxel chemotherapy.^11–14 At 24 months after the surgery, the patient remained neurologically stable with no radiological evidence of recurrence. Radiotherapy has not yet been administered but is reserved as a salvage option in case of future radiographic progression. This decision was based on the patient’s favorable postoperative recovery, absence of recurrence on follow-up imaging, and a multidisciplinary assessment prioritizing stepwise escalation of therapy.

Informed Consent

The necessary informed consent was obtained in this study.

Discussion

Observations

Brain metastases from prostate cancer are a rare clinical entity, typically occurring during the late stages of systemic disease progression.^1,2,5 In the present case, neurological symptoms prompted early imaging, which led to the identification of a solitary cystic lesion in the right frontal lobe. Immunohistochemical analysis confirmed the lesion as metastatic prostate adenocarcinoma, despite the absence of PSA expression. Notably, the tumor displayed an atypical serum tumor marker profile—elevated CEA and CA19-9 levels with negative PSA—suggesting a rare and atypical biological subtype that may warrant further clinical and molecular investigation.

Although CEA and CA19-9 are generally not associated with prostate adenocarcinoma, a few prior reports have documented such aberrant marker profiles in advanced disease with visceral dissemination. Kodama et al. described a patient with widespread metastases to the bone, liver, lungs, and lymph nodes, who presented with high CEA and CA19-9 but no elevation in PSA. Despite hormone and radiation therapy, the patient died within 4 months of diagnosis.⁷ Similarly, Shindo et al. reported a PSA-negative prostate cancer case with high CEA and CA19-9 levels and extensive visceral metastases, including to the liver and lungs. That patient experienced rapid disease progression and died within two months.⁹ These cases collectively support the notion that CEA- and CA19-9–positive prostate adenocarcinomas in the absence of PSA expression may be associated with aggressive disease behavior and poor clinical prognosis.

To our knowledge, no previous reports have described a case of brain metastasis from prostate cancer with this tumor marker profile. Our case is therefore unique not only in its clinical presentation but also in its relatively favorable outcome. Unlike the previously reported cases, this patient exhibited isolated neurological symptoms, which facilitated early imaging and surgical intervention. Histological examination confirmed the diagnosis, and NKX3.1 immunostaining—a prostate-specific marker with high sensitivity and specificity—proved critical in establishing the prostatic origin, particularly in the absence of PSA expression.

The NKX gene family plays crucial roles in embryonic development, tissue differentiation, and organogenesis by regulating cellular differentiation and function. Among them, NKX3.1 (also known as NKX3A) is a prostate-specific gene essential for prostate development and maturation.^15,16 It is predominantly expressed in prostate tissue, making it highly specific for prostate cancer diagnosis. Therefore, NKX3.1 staining facilitates the differentiation between prostate and other tumor origins. Although PSA was negative in both the brain and prostate specimens, the strong positivity for NKX3.1, a prostate-specific marker with high sensitivity and specificity, supported the diagnosis of prostate origin. This finding aligns with previous studies showing that NKX3.1 retains diagnostic accuracy even in PSA-negative or poorly differentiated prostate cancer.^17,18

Despite elevated serum PSA levels, immunohistochemical staining for PSA was negative in both brain and prostate tissue. Previous studies have documented that PSA expression can be lost or markedly reduced in poorly differentiated or aggressive metastatic prostate cancer, even when circulating PSA remains detectable. In this context, NKX3.1—a highly sensitive and specific prostate marker—was instrumental in confirming the tumor’s prostatic origin.¹⁹

Preoperative imaging also revealed multiple small pulmonary nodules, raising the suspicion of systemic dissemination. Although biopsy of these nodules was considered, their peripheral location and radiological stability precluded safe sampling. Given the likelihood of systemic disease, the multidisciplinary tumor board opted for systemic therapy. Despite the presence of suspected multiple metastases, the patient responded favorably to treatment and remains neurologically stable without radiological or clinical evidence of recurrence at 24 months after diagnosis.

One of the most remarkable aspects of this case is the discrepancy in prognosis compared to previously reported cases with similar tumor marker profiles. Several factors may have contributed to this outcome: 1) early detection of the brain lesion due to isolated neurological symptoms; 2) immediate resection, which enabled a definitive pathological diagnosis; and 3) early initiation of systemic therapy guided by the accurate identification of the primary tumor. In contrast, the previous reports involved patients with extensive disease at presentation and no local control of dominant lesions, which may have contributed to rapid deterioration.

Limitations

This case report is inherently limited by its nature as a single case report, restricting the generalizability of the findings. Moreover, genomic and molecular profiling were not conducted, precluding a deeper understanding of the tumor’s biological characteristics and potential therapeutic targets. Comprehensive molecular analyses of future cases are warranted to better elucidate the pathogenesis and clinical behavior of such atypical prostate cancer presentations.

Lessons

This case highlights several important clinical considerations. Brain metastases from prostate adenocarcinoma are uncommon and infrequently reported in the literature. In such cases, relying solely on PSA levels may lead to misdiagnosis. NKX3.1, due to its high specificity and sensitivity for prostate origin, should be considered as a part of the immunohistochemical panel.^17,18

Elevation of CEA and CA19-9 in prostate cancer is rare but has been previously documented.^7–9 It might represent a distinct molecular subtype characterized by divergent differentiation. Although it is often linked to aggressive behavior and visceral metastasis, early multimodal intervention—as in our case—can lead to favorable outcomes.

This case supports the utility of resection in patients with isolated brain metastases from prostate cancer. Although brain involvement is generally a poor prognostic indicator, particularly in hormone-sensitive diseases, combining resection with systemic therapy can preserve function and extend survival.^2,8

In conclusion, this case highlights the diagnostic challenges of atypical metastatic prostate cancer, particularly in the absence of conventional markers such as PSA. The application of prostate-specific immunohistochemical markers, especially NKX3.1, is essential for the accurate identification of the tumor’s origin. Moreover, early diagnosis combined with a coordinated, multimodal treatment approach leads to favorable clinical outcomes, despite the presence of high-risk molecular features. This case underscores the importance of integrating thorough pathological evaluation with personalized therapeutic strategies for managing rare and atypical presentations of prostate cancer.

Acknowledgments

We thank Diptanu and Eleanor H. for their valuable assistance with English language editing.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Sumiyoshi, Oda. Acquisition of data: Sumiyoshi, Fujii, Kasashima. Analysis and interpretation of data: Sumiyoshi, Kasashima, Oda. Drafting the article: Sumiyoshi. Critically revising the article: Sumiyoshi, Oda. Reviewed submitted version of manuscript: Sumiyoshi, Oda. Approved the final version of the manuscript on behalf of all authors: Sumiyoshi. Study supervision: Saiki.

Correspondence

Sosuke Sumiyoshi: Otsu Red Cross Hospital, Otsu, Shiga, Japan. sosuke.sumi@gmail.com.