A 24-year-old woman with no remarkable previous medical history had a 7-month history of coughing and blood-stained sputum. She also presented with a visual disturbance in the right eye occurring over 1-month. She visited a local ophthalmologist and was referred to an ophthalmologist at our hospital. Detailed examinations revealed no ophthalmological abnormality. Brain MRI showed multiple intracranial lesions and she was referred to us. On examination, she was awake and alert with no disorientation except for visual deficits rated as counting fingers in the right eye, whereas the left visual acuity was 30/50. There were no other focal neurological deficits. A brain CT scan revealed multiple 5-15 mm high-density nodules with perifocal edema in the bilateral cerebrum and cerebellum [Figure 1a]. The sulci appeared obscured, indicating the increased intracranial pressure. Emergency cerebral angiography ruled out vascular diseases such as sinus thrombosis. However, on angiography, the intracranial perfusion time of the contrast medium was prolonged, suggesting mild intracranial hypertension. MRI demonstrated that the signal of nodules was hypointense to isointense on T1-weighted images [Figure 1b] and hypointense on T2-weighted [Figure 1c]. Susceptibility-weighted images [Figure 1d] showed numerous low-intensity spots, indicating old hemorrhages. These lesions were accompanied by significant peritumoral edema. Postcontrast studies revealed little enhancement in most lesions, but a weak enhancement in some nodules [Figure 1e]. Under the suspicion of multiple brain metastasis from malignancies in other organs, chest CT scan was performed, which revealed multiple small nodules with bleeding in the lung [Figure 2a]. An abdominal CT scan showed a similar-sized mass without intralesional hemorrhage in the liver [Figure 2b]. The hepatic lesions were enhanced homogeneously [Figure 2c]. These findings were not typical of primary lung and hepatic cancers. Serum tumor markers including carbohydrate antigen 19-9, squamous cell carcinoma, and Sialyl LewisX were also negative. Sputum and bronchial lavage fluid cytology were class 1. Based on the MRIs and CT scans indicative of multiple hemorrhagic brain tumors, intracranial metastasis of melanoma, or choriocarcinoma were also included in the differential diagnoses. However, detailed dermatological inspection denied the presence of abnormal skin lesions. In addition, 5-S-cysteinyldopa, a serum tumor marker for melanoma, was negative. Gynecological examinations also excluded the possibility of any pelvic tumors. In addition, thallium scintigraphy indicated no abnormal uptake in any part of the body. The systemic and multiorgan nature of the disease led us to suspect other conditions such as metabolic, hematological, and infectious diseases. However, laboratory tests showed only mild anemia. The possibility of systemic amyloidosis was ruled out from the results of serum protein fractions and urinalysis. To eliminate the possibility of tuberculous lesions, bacterial cultures from the sputum and bronchial lavage fluid, acid-fast bacteria staining, Mycobacterium tuberculosis polymerase chain reaction, and interferon-gamma release assay were conducted; however, these examinations did not indicate tuberculosis.
During the course of these examinations, the patient's condition significantly progressed. Her bilateral visual acuity rapidly declined for 3 days after admission. She also had frequent general clonic seizures. The steroid, osmotic diuretics, carbamazepine, and levetiracetam were administered to control her seizures. Although her seizures were controlled over the following 3 days, her bilateral visual acuity had further declined to light perception. Because of the necessity of determining pathological diagnosis, a biopsy of the right frontal brain lesion was performed 14 days after admission. Increased intracranial pressure was observed intraoperatively. The lesion with slight enhancement on MRIs in the right frontal lobe was removed using a navigation guide. The tumor was moderately hemorrhagic, presenting a reddish-brown color [Figure 3]. The consistency of the tumor was elastic and hard.
Histopathological examination showed a diffuse cellular proliferation upon hematoxylin and eosin stain. Fine vascular channels, hemorrhage, and hemosiderosis were observed in the tissue [Figure 4a]. Cells contained a round and slightly coarse nucleus and a large volume of clear cytoplasm including large and small balloon-like lesions and erythrocytes [Figure 4b]. Immunohistochemical staining showed positivity for vimentin and CD31 of the cell membrane and cytoplasms [Figure 4c] and mild positivity for CD34 of the cytoplasm. Tumor cells were all negative for S-100, neurofilament, glial fibrillary acidic protein, IbaI, CD1a, CK AE1/3, epithelial membrane antigen, leukocyte common antigen, CD68, and alpha-smooth muscle actin. Mitotic nuclei were rare, and the MIB-1 labeling index was <3% in the tumor cells [Figure 4d]. Based on these histopathological findings and the multiplicity of lesions in the brain, lung, and liver, we finally determined the diagnosis as EHE.
The patient's conditions were stable for 3 months after biopsy. After a discussion about the treatment strategy with the patient and her family, we opted for conservative therapy comprising only rehabilitation on the basis of the low proliferation rate indicated by the histopathological findings. However, after 3 months, the patient gradually developed moderate disturbance of consciousness, headache, and vomiting. MRIs demonstrated aggravation of peritumoral edema without apparent enlargement of each nodule [Figure 5a]. The bilateral ambient cisterns had narrowed, suggesting increased intracranial pressure [Figure 5b]. Steroid pulse therapy with osmotic diuretics improved her consciousness for 2 weeks, and she became able to eat. Palliative whole-brain radiation was initiated, but she did not respond to the treatment and developed diabetes insipidus requiring administration of desmopressin. Her consciousness continued to deteriorate. When she became comatose, her family hoped the termination of radiation and the provision of the best supportive care. She died after 4 months of hospitalization.
The autopsy revealed the cause of death as brainstem necrosis, possibly induced by brain herniation. In addition to the multiple intracranial, pulmonary, and hepatic lesions confirmed on diagnostic imaging, multiple white nodules were observed, including two in the spleen, two in the left kidney, one in the right kidney, and one in the third lumbar vertebra. All were confirmed as EHE.
(a) Chest computed tomography scan showed multiple nodules with hemorrhage in the lung.