Abdominal nodal metastasis from an unknown primary: A case report and review of literature

Abstract

BACKGROUND

Cancer of unknown primary (CUP) represents 1%-3% of malignant tumors with prominent biological heterogeneity. Abdominal lymph nodes are common metastatic sites for various tumors. However, the lack of a comprehensive comparison of potential tissue origins in routine practice leads to diagnostic biases, particularly when CUP is associated with abdominal lymph node metastasis. We aimed to enhance the clinicians’ awareness in differentiating and diagnosing complex metastatic tumors, and optimize the treatment strategy to reduce the risk of misdiagnosis.

CASE SUMMARY

A 77-year-old man was admitted with a 1-month history of a gastric body ulcer. A gastroscopy biopsy revealed high-grade intraepithelial neoplasia, and an abdominal computed tomography scan showed multiple enlarged lymph nodes. He underwent laparoscopic subtotal gastrectomy, which confirmed early gastric cancer with neuroendocrine differentiation. However, abdominal lymph node immunohistochemistry (IHC) results were inconsistent. Multidisciplinary consultation indicated that the enlarged lymph nodes were distributed in the retroperitoneum and the vicinity of the iliac vessels, indicating pelvic tumor lymphatic drainage. Supplementary tests showed a total prostate-specific antigen (PSA) level > 100 ng/mL, and lymph node tissue was positive for prostate cancer-specific immunohistochemical markers PSA and α-methylacyl-CoA racemase. A bone scan confirmed multiple bone metastases, leading to a diagnosis of gastric carcinoma in situ and advanced prostate cancer. The patient received endocrine therapy for prostate cancer and bone protection treatment, with no obvious adverse symptoms reported.

CONCLUSION

In CUP with abdominal lymphatic metastasis, understanding anatomy, pathology, drainage, markers, and IHC aids early management and accurate diagnosis.

Key Words: Gastric cancer; Prostate cancer; Lymphatic metastasis; Cancer of unknown primary; Immunohistochemistry; Case report

Core Tip: Cancer of unknown primary (CUP) is a metastatic cancer whose origin site remains undetermined after comprehensive examinations. Abdominal lymph node metastasis, a common clinical manifestation of CUP, is prone to diagnostic errors because the tissue of origin is often incompletely identified. We report a case where the initial diagnosis was early gastric cancer with abdominal lymph node metastasis. After relevant re-examination, the metastatic lymph nodes were determined to originate from prostate cancer. This emphasizes the importance of diagnostic awareness of suspicious metastatic lesions and the significance of multidisciplinary diagnosis and treatment.

INTRODUCTION

Cancer of unknown primary (CUP) refers to metastatic malignant tumors whose primary sites remain undetermined despite a standardized diagnostic process, including detailed medical history-taking, systematic physical examination, laboratory tests, and routine imaging evaluations. The challenge of determining the primary lesion in patients with CUP might stem from the limitations of the imaging technology’s sensitivity, the primary lesion being in a low metabolic state or having stem cell properties[1]. One of the common clinical manifestations of CUP is abdominal lymph node metastasis. Identifying the source of these metastases is particularly complex, as they can occur in the digestive, urinary, and reproductive systems. Meanwhile, not all tissue source comparisons have been conducted in routine clinical practice, leading to potential diagnostic errors.

Herein, we report a case of a dual primary tumor, initially diagnosed as gastric cancer with abdominal lymph node metastasis. However, subsequent evaluation confirmed that it originated from the prostate. The aim of this study was to raise awareness among clinicians about the importance of differentiating and diagnosing complex metastatic tumors, and to optimize the treatment strategy to reduce the risk of misdiagnosis.

CASE PRESENTATION

Chief complaints

The patient was a 77-year-old male. He was admitted to the hospital 1 month ago owing to the discovery of a gastric body ulcer.

History of present illness

The patient reported a loss of appetite without any clear cause 3 months prior, without experiencing abdominal pain or distension.

History of past illness

The patient reported no history of tumors or chronic diseases, including hypertension and diabetes.

Personal and family history

The patient denied having a family history of tumors.

Physical examination

The patient’s physical examination showed no obvious abdominal tenderness, muscle tension, or abdominal masses.

Laboratory examinations

The summary of the relevant laboratory tests conducted is as follows: The tumor markers indicated that alpha-fetoprotein was 3.4 ng/mL, carcinoembryonic antigen (CEA) was 0.5 ng/mL, carbohydrate antigen 125 was 8.4 U/mL, carbohydrate antigen 19-9 (CA19-9) was 15.68 U/mL, and the total prostate-specific antigen (PSA) for supplementary examination was > 100 ng/mL. The fecal occult blood test was positive. The liver and kidney functions of this patient were within normal limits.

Imaging examinations

The enhanced computed tomography (CT) scan of the patient’s chest and abdomen revealed a mass in the intestinal tract of the right lower abdomen and various enlarged lymph nodes in the abdominal cavity (Figure 1). Additionally, imaging manifestations of prostatic hyperplasia were also observed; however, no obvious occupying lesions were identified. A gastroscopy followed by a pathological examination indicated that the part of the glandular epithelium in the stomach body exhibited high-grade intraepithelial neoplasia. Colonoscopy revealed multiple polyps, with the pathological result indicating chronic inflammation and low-grade intraepithelial neoplasia. On December 26, 2024, the patient underwent a bone scan, which revealed multiple metastatic bone tumors throughout the body (skull, both shoulder joints, multiple ribs, multiple cervical vertebrae, thoracic vertebrae, lumbar vertebrae, and sacrum, multiple areas of the pelvis, and both hip joints).

Figure 1 Chest and abdominal computed tomography scan. A: No significant thickening of the stomach wall; B: Multiple enlarged lymph nodes beside the abdominal aorta; C: A mass in the intestinal cavity of the lower right abdomen; D: Enlarged lymph nodes on both sides of the pelvic cavity near the iliac vessels; E: Benign prostatic hyperplasia, without obvious space-occupying lesion; F: Abnormal calcification can be observed in the ilium beneath the bone window.

FINAL DIAGNOSIS

Given the patient’s symptoms, imaging results, and pathological findings, the preliminary diagnosis indicated a gastric body ulcer alongside multiple enlarged lymph nodes in the abdomen, which were possibly malignant (Figure 2). The postoperative pathology confirmed a clear diagnosis of early gastric cancer with neuroendocrine differentiation, while the abdominal lymph node biopsy indicated metastatic adenocarcinoma. However, the immunohistochemical staining for cytokeratin 20, villin, neural cell adhesion molecule, and synaptophysin was negative, which did not match the gastric cancer pathology. The patient declined to undergo positron emission tomography/CT due to financial constraints.

Figure 2 Postoperative pathology of laparoscopy. A: Gastric biopsy section, hematoxylin-eosin (HE) × 100; B: A typical “mesh-like” structure can be observed in the biopsy section of the abdominal lymph nodes, HE × 100; C and D: Immunohistochemical staining for (C) prostate-specific antigen (× 200), (D) α-methylacyl-CoA racemase (× 200) of abdominal lymph nodes. The immunohistochemical reagents used in the patient’s pathology were all provided by Fuzhou Maixin Biotechnology Development Co., Ltd.

Given the uncertainties regarding the patient’s diagnosis, the general surgery department organized a multidisciplinary consultation. After re-reviewing the CT images, we observed that the enlarged lymph nodes in the abdominal cavity were mainly located beside the iliac vessels and in the retroperitoneal area around the abdominal aorta, rather than around the stomach or the inguinal region. Considering the lymph node drainage patterns, the primary source may have been from the pelvic cavity, which means differentiation between prostate and urinary tract malignant tumors was necessary.

Adenocarcinoma is relatively rare among urethral malignancies, and no obvious suspicious lesions were detected in the bladder and urethra. Consequently, bladder and urethral malignant tumors were temporarily ruled out. We conducted a PSA test to investigate the possibility of prostate malignant tumors, and the pathology department conducted additional immunohistochemical PSA and α-methylacyl-CoA racemase tests on the lymph node biopsy tissue. The results were all positive, leading to the diagnosis of prostate cancer. Additionally, abnormal calcification foci were discovered in the patient's vertebrae and ilium, indicating bone metastasis of prostate cancer. Therefore, the final diagnosis of this patient was revised to gastric carcinoma in situ and advanced prostate cancer.

TREATMENT

The patient underwent “laparoscopic subtotal gastrectomy with gastroenterostomy and abdominal lymph node biopsy” on November 11, 2024. During the procedure, the gastric cancer was considered early-stage. After fully communicating with the patient’s family, the decision was to conduct “laparoscopic subtotal gastrectomy, gastrojejunostomy, and abdominal lymph node biopsy”.

After a clear diagnosis of advanced prostate cancer, the patient began endocrine therapy at the outpatient department on January 3, 2025. The specific treatment regimen included 10.8 mg of goserelin acetate (Nolutro) every 12 weeks, combined with 250 mg of flutamide taken three times daily. Additionally, the patient received subcutaneous denosumab injections every 4 weeks for bone protection. Owing to the local reimbursement procedures, the patient did not receive endocrine treatment at our hospital (Figure 3).

Figure 3 Clinical timeline. CT: Computed tomography; PSA: Prostate-specific antigen.

OUTCOME AND FOLLOW-UP

The treatment is ongoing, and the patient has reported no abnormal urination or local pain.

DISCUSSION

CUP is defined as metastatic malignant tumors for which, after comprehensive assessment, the originating site cannot be precisely identified. These tumors typically display low-grade or undifferentiated histological features, and their immunophenotypes often lack specificity, resulting in generally poor clinical outcomes (median overall survival of 3-16 months)[2-4]. The challenges associated with diagnosing and treating CUP stem from several factors. For instance, the primary lesion may be too small, spontaneously regress, or widely metastasize, thereby obscuring its origin[5]. Meanwhile, clinical practice faces limitations such as insufficient sensitivity of imaging examinations and limited representativeness of pathological sampling[3,6]. Therefore, establishing a systematic traceability strategy is essential for improving prognosis.

In the clinical phenotype of CUP, the proportion of lymph node metastasis ranges from 14.0% to 41.8%, and its anatomical distribution pattern can provide crucial clues for locating the primary lesion[7-9]. In this case, the patient exhibited primary abdominal and pelvic lymph node metastasis. The initial imaging results indicated a mass in the right lower abdomen; however, a thorough gastroscopy unexpectedly revealed a gastric ulcer accompanied by high-grade intraepithelial neoplasia. The intraoperative examination confirmed that the gastric lesion was an early adenocarcinoma. Nevertheless, the routine histopathological examination only classified the abdominal lymph node metastasis as malignant (with low-grade morphology). Moreover, the immunohistochemical results indicated focal positivity for cytokeratin 7 and negativity for cytokeratin 20, which did not match the immunohistochemical characteristics of tumors derived from the digestive tract[10]. Therefore, the primary lesion could not be clearly identified initially. This diagnostic dilemma highlights the limitations of the CUP standard diagnostic process, as a combination of routine imaging and basic immunohistochemistry (IHC) may prove insufficient in complex cases.

The anatomical location of metastatic lymph nodes provides significant indicative value. Based on the study of tumor metastasis patterns[11], the distribution of the enlarged lymph nodes in the abdominal cavity in this case aligns more closely with the metastatic characteristics of pelvic malignant tumors. The rectal and anal canal lesions were ruled out; nevertheless, no serum PSA test or focused prostate imaging assessment was conducted upon admission, leading to the omission of potential primary lesions during the initial diagnosis. The retrospective analysis revealed that no clear prostate lesion was observed on the patient’s CT scan; nonetheless, the osteogenic changes in the spine indicated the possibility of bone metastasis from prostate cancer. This discovery indicates the importance of conducting targeted re-evaluation of the imaging details in conjunction with clinical uncertainties. Through targeted detection of prostate cancer-specific antigen levels (serum PSA over 100 ng/mL) and IHC (strong positive results for PSA and α-methylacyl-CoA racemase), the primary site of the metastatic lymph nodes was eventually confirmed. Meanwhile, histopathology is the “gold standard” for diagnosing CUP[12]. The “sieve-like” structure observed in the pathological re-examination is a characteristic morphological marker of prostate cancer, highlighting the key role that a pathologist’s diagnostic experience plays in challenging cases.

Bone and lymph node metastasis are common in prostate cancer; however, atypical sites of metastasis have also been reported, including the liver, pancreas, reproductive tract, urinary tract, peritoneum, abdominal wall, and peripheral nervous system[13]. The patient was ultimately diagnosed with prostate cancer, with metastasis in abdominal lymph nodes and bones, as well as a concurrent double primary tumor of gastric cancer. Genetic diseases, such as Lynch syndrome[14], may lead to the simultaneous occurrence of gastric and prostate cancer; nonetheless, only a few cases have been reported[15,16]. Diagnosing double primary tumors requires strict exclusion of the possibility of metastasis. In this case, the gastric cancer tissue showed a typical glandular structure, while the metastatic lymph nodes presented as a prostate cancer-specific phenotype. No histological or immunophenotypic correlation was observed between the two tumors, supporting the diagnosis of dual primary cancer.

Prostate cancer metastasizing to the stomach is also a rare but important concern. It may occur many years after the initial diagnosis of prostate cancer and is associated with a poor prognosis[17]. In previously reported cases, patients typically present with non-specific clinical manifestations, including abdominal discomfort, nausea, vomiting, and anorexia[18-22]. In some cases, gastrointestinal bleeding (e.g., hematemesis and melena) may occur, often accompanied by systemic features such as fatigue and anemia[23-27]. Most prostate cancers that metastasize to the stomach are associated with high PSA levels, with some cases exceeding 1000 ng/mL.

However, some factors still contribute to the difficulty in diagnosis. Gastric metastasis of prostate cancer shows similar endoscopic manifestations to primary gastric cancer. In some cases, the serum PSA levels may be negative while the CEA/CA19-9 levels are elevated[17]. Moreover, some commonly used immunohistochemical markers for gastric cancer, such as cytokeratin 7, cytokeratin 20, and caudal type homeobox transcription factor 2, can also produce positive results in prostate cancer, which indicates that these markers lack sufficient specificity to distinguish the source of the tumors. Therefore, the identification of specific molecular markers, including α-methylacyl-CoA racemase, PSA, prostatic serum acid phosphatase, NK3 homeobox 1, Solute Carrier Family 45 Member A3, and Ets-related gene, is essential[17,21,28-30]. In this case, a strong positive PSA level of the metastatic lymph nodes may be related to a tumor that has not yet received endocrine therapy, indicating that the androgen receptor pathway of the tumor cells is still active. This phenomenon highlights the fact that a patient’s treatment history can influence the diagnostic value of biomarkers.

Currently, no standardized treatment strategy has been established for double primary cancers. Reports indicate that advanced gastric and prostate cancers could be controlled through sequential surgeries combined with adjuvant therapy[16]. In this case, endoscopic resection of early-stage gastric cancer might be the preferred treatment option. However, since the source of lymph node metastases at the initial diagnosis was unclear, choosing laparoscopic partial gastrectomy combined with lymph node biopsy aligned with the diagnostic and therapeutic guidelines. An early and accurate diagnosis is crucial for choosing a better treatment plan. Auxiliary departments, such as the imaging department and the pathology department, may make diagnostic errors due to their lack of a comprehensive understanding of the patient’s condition. This decision-making process underscores the core value of the multidisciplinary diagnosis and treatment model. Through the in-depth collaboration among the radiology department, the pathology department, and the clinical departments, the treatment path for complex cases can be optimized.

This case reminds us of the importance of having a clear diagnostic and treatment plan when faced with ambiguous results during clinical examinations. The diagnosing doctor needs to have relevant knowledge reserves in areas such as anatomy, imaging, and pathology. Achieving comprehensive management within a single department is difficult; therefore, a high-quality multidisciplinary team is required. Unfortunately, current challenges such as manpower, technology, and time can make the implementation of a multidisciplinary team difficult. In the future, this model may be optimized through an artificial intelligence-assisted decision-making system, ultimately achieving the goal of precision medicine.

CONCLUSION

CUP accompanied by abdominal lymph node metastasis is often misdiagnosed owing to the interference of multiple primary tumors and the limitations of routine examinations. In clinical practice, the examination scope can be expanded according to the anatomical drainage characteristics of lymph nodes to complete routine specific marker detection and targeted immunohistochemical staining. Additionally, multidisciplinary team collaboration should begin as early as possible to optimize the diagnostic process for complex metastatic cancers.

ACKNOWLEDGEMENTS

The authors express their gratitude to the patient for providing the relevant information and for cooperating with the follow-up process.