A rare case of prostate cancer initially presented by disseminated intravascular coagulation‐related subdural hemorrhage

Abstract Background Disseminated intravascular coagulation (DIC) has been reported in various solid malignancies and is a common coagulation‐related complication in prostate cancer. However, DIC has been rarely reported as the initial presentation of prostate cancer. Herein, we reported a patient referring with subdural hemorrhage (SDH) and DIC with an unexplained cause who was later diagnosed with prostate cancer. Case Presentation We presented a 68‐year‐old man who was referred to the hospital with a gradual deterioration of consciousness, dyspnea, and edema in the genitalia and lower limbs. His primary laboratory tests showed elevated prothrombin time (PT) and partial thromboplastin time (PTT) and a decreased fibrinogen level of 47 mg/dL [200–400 mg/dL]. The DIC score was 7, which was suggestive of DIC. Moreover, cranial imaging showed SDH. Further work‐up revealed elevated prostate‐specific antigen and prostate enlargement with a mass effect on the bladder with a bone lesion, which was suggestive of metastatic prostate cancer. Conclusion This report highlights DIC as a possible initial presentation of an underlying malignancy, as well as the importance of treatment of underlying disease in the management of DIC. A comprehensive and systematic work‐up is essential for early diagnosis in patients with DIC to avoid further complications and mortality.


| INTRODUCTION
Disseminated intravascular coagulation (DIC) is a life-threatening coagulation disorder that may occur in a wide range of clinical conditions. A comprehensive exploration should be performed for any underlying medical disorder, including sepsis, trauma, solid and hematological malignancies, obstetrical complications, and vascular disorders after confirmation of the DIC diagnosis. 1 DIC has been reported in different solid malignancies and is a coagulation-related complication of prostate cancer. 2 The incidence of DIC in patients with prostate cancer is estimated between 13% and 30%. 2 Although DIC is a coagulopathy that often complicates prostate cancer, it has been rarely reported as the initial presentation of prostate cancer. [3][4][5] Herein, we reported a 68-year-old man who presented with a gradual deterioration of consciousness, dyspnea, and lower limb edema who later was discovered to have DIC and subdural hemorrhage (SDH) as an uncommon initial presentation of prostate cancer. This report highlights DIC as it could be a primary manifestation of an underlying malignancy, as well as the importance of early diagnosis and treatment of underlying disease in the management of DIC. Due to the high mortality of DIC in a patient with an underlying malignancy, a comprehensive and systematic work-up, and management is critical to avoid further complication and mortality.

| CASE PRESENTATION
In November 2021, a 68-year-old man with a past history of hypertension presented to the emergency department of our center affiliated with Tehran University of Medical Sciences with a gradual deterioration of consciousness, shortness of breath, and also symptoms of volume overload, which included edema in lower limbs, especially in the right lower limb, as size difference was clearly observed.
He had also experienced dizziness and fall incidents during the last few months, but reported no head injury. He denied having a history of abdominal pain, fever, nausea, vomiting, urinary symptoms, or significant weight loss. He denied the use of any medications except for hypertension. His habitual history was negative, and he did not report a family history of cancer or hematologic disorders. The vital signs showed tachycardia (105 bpm), tachypnea (23 rpm), and fever (38.1 C); his blood oxygen saturation was also low (77%). His physical examination showed severe edema (level 3) on lower limbs, genitalia, and also upper limbs. His abdomen was soft, without tenderness or hepatosplenomegaly; however, moderate ascites were notable. Several bruising and ecchymosis were noted on the back and lower limbs.
Upon auscultation, no abnormal cardiac sounds were heard, but pulmonary sounds, particularly on the right side, were diminished. The cranial nerve examination and cerebellar tests, including Romberg's test, were normal. No lymphadenopathy was discovered in physical examination.
The laboratory data of the patient showed hemoglobin of 8.6 g/ dL [normal range: 14-17 g/dL], white blood cell count of 7.7 Â 10 3 / mm 3 [4.5-11. Table 1). The DIC score was 7 based on the International Society of Thrombosis and Hemostasis diagnosis criteria. 6 The patient was diagnosed as having overt DIC and treatment with cryoprecipitate and fresh frozen plasma was initiated immediately. Cranial and thoracic computed tomography (CT) scans, and also abdominal sonography were requested. The cranial CT scan revealed mild SDH (<1 mm) in the left cerebral hemisphere, while the consultation with the neurosurgical department indicated the patient did not require surgical intervention ( Figure 1A). Meanwhile, a chest CT scan revealed bilateral severe pleural effusion (more severe on the right) and collapsed consolidation on both sides, which was suggestive of bacterial pneumonia ( Figure 2). The sonographic evaluation showed free fluid in the abdomen, and although no pathology within the parenchyma of the liver or spleen was recorded, the inferior vena cava and hepatic veins were markedly dilated. A color doppler sonography of the lower limb vessel was also performed, which was negative for deep vein thrombosis. According to the findings, along with an echocardiographic assessment, we ruled out pulmonary thromboembolism with a ventilation-perfusion scan. The evaluation was furthered after the correction of coagulopathy, using pleural fluid tapping, which showed that the pleural effusion was exudative, and subsequently, antibiotic therapy with levofloxacin was initiated ( Table 2). Echocardiography revealed increased pulmonary artery pressure (LVEF: 55%-60%, PAP: 44 mm Hg), which confirmed the suspected preserved ejection fraction heart failure.
A search to determine the underlying etiology was continued and a comprehensive malignancy work-up was performed. Serum prostate-specific antigen (PSA) was 12 ng/mL (normal: <4 ng/mL).
Prostatic induration was identified through the digital rectal exam.
Abdominal ultrasound investigation reported enlarged prostate with a volume of about 70 cc with a mass effect on the bladder. Increased distended bladder wall thickness was also noted. The patients underwent an abdominopelvic CT scan without contrast, which revealed a prostate enlargement (57 Â 57 Â 44 mm) with two hypo-signal nodules in the right middle and left inferior portions of the inner gland, along with multiple left para-aortic, left external and internal iliac, and left peri-rectal lymphadenopathies ( Figure 3). Further investigations also revealed bone metastases, specifically in the pelvic bone, however, no liver metastasis was observed. As the patient's condition became stable, a prostate biopsy was also performed, which reported prostate adenocarcinoma with a Gleason score of 8 and grade group of 4 with perineural invasion. Based on the above findings, a diagnosis of metastatic prostate cancer was confirmed in the patient. Urology and oncology consultation was requested accordingly, and medical androgen deprivation therapy (ADT) including triptorelin and bicalutamide was recommended for the patient. Four days after the diagnosis confirmation, the patient lost consciousness, and another brain CT scan showed that SDH had exacerbated ( Figure 1B). As there was a clear midline shift, immediate acute care with surgical intervention and craniotomy along with mannitol fluid therapy was performed, and the patient was transferred to the intensive care unit (ICU). Unfortunately, the symptoms exacerbated, resuscitation and cardiopulmonary resuscitation (CPR) were unsuccessful, and the patient expired.

| DISCUSSION
This study reports a case presented to the emergency department with dyspnea and signs of volume overload. His evaluations revealed mild SDH and pleural effusion, which turned out to be exudative.  Lower fibrinogen levels usually indicate a more severe DIC, but, as fibrinogen is an acute-phase reactant, serial measurements can be a more reliable indicator. 7 International Society of Thrombosis and Hemostasis has set the criteria by which DIC could be identified. 6 According to this criteria, a score greater than or equal to five is indicative of DIC (Table 3).
DIC occurs due to widespread activation of coagulation pathways, characterized by thrombotic occlusion of blood vessels, which can compromise organ blood supply, and at the same time, increased the probability of bleeding secondary to consumption of coagulation factors and platelets. DIC usually occurs secondary to an underlying cause, including severe trauma, severe infectious disease, obstetric disorders, immunological disorders, reactions to toxins, and hematological and solid malignancies. 8 Therefore, it is important to search for underlying conditions in cases with no apparent cause. 7 In the current report, there were a number of differential diagnoses including thrombotic The association between DIC and malignancies has been well documented by potential mechanisms such as procoagulants secreted by malignant cells. 9,10 Acute or chronic DIC are coagulation-related complications of prostate cancer, and the incidence of subclinical DIC might range between 24% and 40% in metastatic prostate cancer patients. 11 Nevertheless, the pathophysiology linking prostate cancer and DIC is not fully understood. 12 According to previous studies, the expression of procoagulant molecules from tumor cells, notably tissue factor, activates the host's hemostatic system, resulting in thrombosis and the consumption of coagulation factors, which ultimately leads to DIC. 13 Besides, previous studies showed that patients

F I G U R E 3 (A) Pelvic computed tomography scan showing prostate (arrow), (B) para-aortic lymphadenopathies (arrows), and (C) metastatic pelvic bone lesions (arrows).
T A B L E 3 International society of thrombosis and hemostasis scoring system for disseminated intravascular coagulation. Writingoriginal draft (equal); writingreview and editing (equal).