An 82-year-old male patient presented to the emergency department of our hospital on May 14, 2023, with a primary complaint of diarrhea lasting more than 10 days accompanied by fatigue. A diagnosis of gastrointestinal dysfunction was made, and treatment was initiated with Cefoperazone sodium, Levofloxacin sodium chloride for infection, and Esomeprazole sodium for acid suppression and gastric protection, along with other symptomatic therapies. Despite these interventions, the patient reported no improvement in symptoms. Subsequently, the patient visited Jinyang Community Health Hospital, where a fecal occult blood test returned negative. For further evaluation and treatment, the patient was referred to our hospital and admitted with an outpatient diagnosis of diarrhea. On May 20, 2023, serological examination revealed reduced levels of erythrocytes (2.91×10^12/L), albumin (34 g/L), cholinesterase (2781 U/L), and potassium (1.7 mmol/L). Additionally, urinalysis showed elevated microscopic erythrocytes, urinary occult blood (4+), and a positive fecal occult blood test (using the colloidal gold method). Laboratory and imaging studies upon admission are summarized in Supplementary Table 1 .On May 23, 2023, the patient tested positive for the COVID-19 nucleic acid. Given the positive result and the clinical presentation, it was considered that the diarrhea might have been induced by COVID-19. The patient exhibited positive fecal occult blood, attributed to local mucosal shedding in the intestines, likely caused by frequent diarrhea (more than 10 episodes daily) over the past two weeks. The patient was prescribed oral Nirmatrelvir for antiviral treatment and Montelukast for symptomatic antidiarrheal management, along with other supportive therapies. On May 24, 2023, a routine urological examination revealed potential benign prostatic hyperplasia with calcification, a left renal cyst, mild left hydronephrosis, dilatation of the upper left ureter, mild separation of the right renal pelvis, and possible urinary retention. Subsequently, the patient developed urinary retention and bilateral lower limb edema. An indwelling urinary catheter was inserted, and diuretics, along with other symptomatic treatments, were administered. The patient has a history of gout and is routinely prescribed oral Febuxostat or Benzbromarone (1 tablet daily). Thirty years ago, the patient underwent an appendectomy, although the details of the procedure remain unclear. The patient denies any family history of hereditary diseases. On May 25, 2023, enhanced abdominal CT imaging revealed asymmetrical thickening of the lower rectal wall, along with enlarged lymph nodes around the rectum and adjacent to the right iliac vessels. The borders of the prostate and left seminal vesicle were indistinct, with benign prostatic hyperplasia and calcification noted ( Figure 1A ). On June 1, 2023, an electronic colonoscopy identified a 0.8 cm subpedunculated polyp in the transverse colon, which was subsequently excised via endoscopic mucosal resection (EMR). Additionally, an ulcer was observed in the sigmoid colon. Symptomatic treatment was provided, and the patient’s condition improved, with no abdominal pain, distention, hematemesis, or melena. The patient was deemed fit for discharge. On August 29, 2023, the patient presented with complaints of difficulty defecating, abdominal distension, and exacerbated abdominal pain over the past two days. For further diagnosis and treatment, the patient was re-admitted with clinical suspicion of intestinal obstruction. On physical examination, the abdomen was soft, with a visible, healed surgical scar, but no palpable masses or bowel sounds. There was no tenderness, rebound tenderness, or muscle rigidity. McBurney’s point was non-tender, and bowel sounds were not hyperactive. No shifting dullness was observed. Examination of the anus, rectum, and external genitalia was not performed. A follow-up lower abdominal CT scan (64-slice, non-contrast) in September 2023 revealed rectal stent placement, with the remaining diagnostic findings consistent with the enhanced CT from May ( Figure 1B ). On September 7, 2023, colonoscopy revealed rectal edema, pinpoint stenosis, obstruction of the intestinal lumen, and proximal intestinal extension. These findings were observed despite the colonoscope barely passing through the colon ( Figures 1C, D ). Consequently, a colonoscopic diagnosis of perirectal circumferential stenosis with obstruction was made, followed by endoscopic stenting and biopsy.

Histopathology revealed that the intrinsic glandular epithelium did not exhibit evidence of heterogeneous hyperplasia or migration in conjunction with the tumor cells. The tumor cells exhibited invasive growth and were characterized by signet-ring cell morphology. The initial pathological diagnosis was poorly differentiated adenocarcinoma. Since signet-ring cells are not exclusive to gastric and intestinal adenocarcinomas, and imaging revealed that the prostate gland lacked clear demarcation from the surrounding structures, immunohistochemistry was performed. The immunohistochemical analysis results were as follows: CK (+), PSA (+), NKX3.1 (+), CK7 (–), CK20 (–), CDX-2 (–), GATA3 (–), and Ki-67 (+, approximately 10%) ( Figure 2 ). The final pathological diagnosis was prostate cancer with rectal involvement, a Gleason score of 5 + 5 = 10, and ISUP grouping 5. Based on the pathological diagnostic results, the patient underwent further testing for tumor markers, namely PSA (282.00 ng/ml), NSE (17.4 ng/ml), and CA24-2 (12 IU/ml).

The results of the imaging examination were consistent with the expected findings. The prostate gland exhibited abnormal signal intensity with poorly defined borders, presenting as low T1WI, mixed T2WI, and a high signal shadow in DWI. Additionally, the gland displayed markedly inhomogeneous enhancement after contrast administration. ( Figures 1E, F ) revealed high signal shadows in DWI on both sides of the seminal vesicle glands, irregular thickening of the rectal wall, and a swollen, enlarged lymph node-bearing pelvic region. Radiologic diagnosis: Prostate lesion, prostate cancer highly suspected, bilateral involvement of the seminal vesicle glands, rectal involvement, and pelvic lymph node metastasis.

To explore the key molecular events leading to the malignant biological behavior of prostate cancer, second-generation DNA sequencing on tissue samples was performed at the Nanjing Shihe Medical Testing Laboratory. The aim was to identify rare variants associated with the metastasis and progression of Signet ring-like cell prostate cancer. The results identified two significant mutations linked to tumorigenesis in the tested samples: the V600E mutation in BRAF and the F133L mutation in SPOP. The BRAF mutation is located in exon 15. This missense mutation is characterized by a change from T to A at nucleotide position 1799, resulting in an amino acid change at position 600 from valine to glutamate (V600E). The SPOP gene mutation, located in exon 5, is characterized by a change from T to C at nucleotide position 397, resulting in the alteration of phenylalanine to leucine (F133L) at the amino acid level.

To clarify the impact of BRAF and SPOP mutations on prostate cancer patients’ survival time, the Sangerbox data platform (http://sangerbox.com/home.html) was used to download the mRNA expression matrix and clinical survival data of prostate cancer samples. After excluding cases with missing clinical information, 495 samples were retained for further analysis. The SPOP expression, divided by the median, was used to categorize the samples into high and low -expression groups. Subsequently, Kaplan-Meier survival curves were generated using the R survival package ( Figure 3A ). The results showed that the survival rate was diminished in the SPOP high-expression cohort, with a statistically significant difference between the two groups (p=0.043).

Transcriptome data were then downloaded from the TCGA database, and the expression profiles of prostate cancer tumor samples (n=483) were divided into two groups (group 1 and group 2, consensus matrix k=2) based on SPOP and BRAF gene expression using the consistency clustering algorithm ( Figure 3B ). The ConsensusClusterPlus software package was used to generate a consensus clustering heatmap analysis ( Figure 3C ), showing the degree of similarity between samples. The results showed notable differences between the two groups, with a high degree of consistency.

Finally, samples of masked somatic mutations (MSM) in single nucleotide variation (SNV, n=501) were downloaded from the TCGA database for further analysis alongside the sequencing results. The results show that in prostate cancer, mutations are more likely to occur in SPOP, TP53, and TTN, with the SPOP gene being more prone to missense mutations than other mutation types ( Figures 3D-F ). Unfortunately, the patient has not undergone surgical treatment at our institution due to personal reasons. We will continue to monitor the patient through regular follow-up visits and have advised the patient to routinely monitor serum PSA, NSA, creatinine, hemoglobin, liver function, and testosterone levels, as well as undergo CTC, DRE, sexual function/urinary control evaluations every 2–6 months. Additionally, abdominal and pelvic CT or MRI should be performed at least annually.