Case presentation:
A 55-year-old Tunisian female presented to the hospital with confusion, aphasia, and a Glasgow Coma Scale (GCS) of 12/15. A Computed Tomography (CT) scan head revealed two well-defined adjacent lobulated intra-axial lesions in the left occipital lobe. MRI head detected multiple left cerebral lesions in the temporo-occipital area. A stereotactic biopsy of one of the lesions was performed, and histopathology revealed Anaplastic Astrocytoma World Health Organization (WHO) grade 3. The tumor cells were strongly positive with Glial Fibrillary Acidic Protein (GFAP), Oligodendroglial Lineage Marker (OLIG-2), while negative with CD20 and CD30. Few scattered lymphocytes were seen within the tumor cells staining with CD3, CD8, CD45, and CD4. Ki-67 index was high, reaching 50% in some areas. Isocitrate Dehydrogenase (IDH) 1 and 2, P53, and BRAF mutations were negative, whereas the ATRX nuclear staining was retained. The patient underwent excision of the tumor after two weeks. Histopathology results of excision biopsy revealed Glioblastoma, WHO grade 4, with wild type IDH – 1, P – 52, and ATRX and a 50 % proliferative index of Ki – 67. Post-operation, she had two episodes of generalized tonic-clonic seizures and was started on levetiracetam 500 mg twice daily. She also developed pulmonary embolism, for which she was started on enoxaparin twice daily.
One–month post-surgery, she was started on partial brain radiotherapy and concurrent chemotherapy with Temozolomide at a dose of 144mg for six weeks with the plan to maintain on Temozolomide alone afterward.
During concurrent -chemo-radiotherapy; after 19 sessions patient presented with bleeding from injection sites on her thigh and bruises on her upper and lower limbs for one day. She did not complain of headache, fever, or bleeding from any other site. The patient was on enoxaparin and levetiracetam at the time of admission with bleeding and bruises from injection sites. Enoxaparin was withheld due to the bleeding. On examination, she was vitally stable, and apart from limb bruises and oozing blood from the injection site, her physical examination was unremarkable. Blood profile revealed pancytopenia with a white blood cell (WBC) count of 0.2 x10^3/uL (normal range: 4 – 10 x10^3/uL), hemoglobin of 8.5 gm/dL (normal range: 12 – 15 gm/dL ), platelet count of 7 x10^3/uL (normal range: 150 – 400 x10^3/uL) and absolute neutrophil count of 0.0 x10^3/uL (normal range: 2 – 7 x10^3/uL).
Temozolomide was discontinued as it was suspected to be the underlying cause of her pancytopenia. Her absolute reticulocyte count was 0.2 (normal level: > 2), indicating a hypo proliferative marrow. Peripheral smear showed marked pancytopenia, but no abnormal cells were visualized. She was initiated on Filgrastim 300 mcg subcutaneous daily and received multiple platelet infusions without any ANC or platelet count improvement. The patient developed febrile neutropenia three days after admission, secondary to the right axillary cellulitis. Swab culture grew Pseudomonas Aeruginosa for which intravenous cefepime was given for ten days. The patient became afebrile after completion of cefepime but remained pan cytopenic despite platelet and Filgrastim transfusions. Radiotherapy sessions were also held since this admission due to critically low platelet and WBC counts.
Given the non resolving pancytopenia without an apparent cause, a bone marrow biopsy was performed. Bone marrow aspirate showed few tiny particles with hypocellular smear and markedly decreased trilineage hematopoiesis, many scattered lymphocytes and relatively increased plasma cells (28%) with no increase in blasts. Bone marrow biopsy showed pronounced hypocellularity (5%-15%) with a remarkably decreased trilineage hematopoiesis and a relative increase in plasma cells . [Figure 2].Flow cytometry on bone marrow aspirate showed approximately 50% T-cells, 3% B-cells, and increased plasma cells (15%) with no immunophenotypic evidence of monotypic B-cell or plasma cell populations. The bone marrow did not show any evidence of paroxysmal nocturnal hemoglobinuria in flow cytometry analysis.. As the patient took Temozolomide, which was recently started, she was diagnosed with aplastic anemia secondary to it.
Two days after the bone marrow biopsy, the patient developed left facial swelling with fever. A CT scan of the face revealed a subtotal opacification of the anterior left nasal cavity with low soft tissue density, extending to the left cheek medially. There was also a partial opacification of both maxillary sinuses, noted more on the left side, with hyperdense foci. The collective picture was suggestive of suspected fungal infection. She was started on IV Meropenem 1 gm 8 hourly and Amphotericin – B 435 mg daily, empirically, and cultures were sent to the lab. However, the patient remained febrile and pan cytopenic.[Figure.1].Treatment options for AA were discussed with the hematology team; however, she was not a candidate for Anti thymocyte globulin (ATG) or cyclosporin or eltrombopag because of underlying malignancy and pulmonary embolism. A trial of IV Immunoglobulin was given with no improvement in counts. The cheek swelling worsened involving the left eye, and an urgent debridement was performed. The infected area’s biopsy revealed necrotic tissue, heavily infiltrated by fungal organisms, compatible with aspergillosis. Although the necrotic tissue was debrided, and she was on appropriate antifungal medication, the facial cellulitis did not respond to the treatment, and she deteriorated with desaturation, hypotension, and confusion. On the 38th-day post-admission, the patient was transferred to the Medical Intensive Care Unit (MICU) and was intubated to protect the airways and started on vasopressors for her septic shock. The patient remained transfusion-dependent and was sedated and intubated for a total of 10 days. Eventually, the patient developed a cardiac arrest with asystole and succumbed to the sepsis and pancytopenia with a complicated and prolonged hospital stay of 47 days. Over the course of her hospital stay, the patient had bacteremia with Multi-Drug Resistant Organisms (MDRO) including Stenotrophomonas, Enterococcus casseliflavus and Achromobacter xylosoxidans, and fungemia with Aspergillus flavus.