A 69 year old Hispanic female with a past medical history significant for hypertension, diabetes mellitus, coronary artery disease status post revascularization, ischemic cardiomyopathy and chronic kidney disease had presented to our hospital for further evaluation and care. For the past few months the patient had suffered weight loss (approximately 30–35 lb), generalized malaise, low grade fevers (99.9 F), non-productive cough, myalgias and arthralgias. She did not endorse any night sweats or recent travel history, and there were no sick contacts at home. Prior to admission to our institution the patient was at an outside hospital and was being treated for sepsis with combinations of antibiotics including intravenous vancomycin, meropenem, echinocandin, metronidazole, and piperacillin tazobactam for 2 to 3 weeks duration as she was developing fevers and productive cough.
The physical exam yielded a thin and chronically ill appearing female patient.
Vital signs at the time of admission were notable for hypertension (186/79 mmHg). Her eyes did not show any conjunctival hemorrhaging or icterus, however there was conjunctival pallor. Oropharynx did not show any active exudates or ulcerative lesions. Her cardiac exam did not reveal any murmurs and her airways were clear to auscultation. Abdominal exam revealed palpable splenomegaly. Examination of the extremities did not show nail deformities including splinter hemorrhages or nail pitting. Her skin had no evidence of skin nodularities or other lesions. There was a 1 cm non tender, movable left axillary lymph node. The rest of the physical examination was unremarkable.
Initial laboratory work revealed that the patient had pancytopenia. White blood cell count (WBC) was stated at 2.4 K/uL, absolute neutrophil count (ANC) 1.92 K/uL, hemoglobin (Hgb) of 11.6, and platelet count of 39,000/uL. B2-microglobulin was seen elevated at 9.2 mg/L. Basic metabolic panel obtained showed sodium 134 mEq/L, Potassium 3.5 mEq/L, Chloride 103 mEq/L, Bicarbonate 26 mEq/L, Blood urea nitrogen 30 mg/dl, Creatinine 0.90 mg/dl, glucose 220 mg/dl. Liver function panel showed Albumin 2.2 g/dl, normal transaminases, total bilirubin 0.8 mg/dl, direct bilirubin 0.4 mg/dl. Urine analysis showed 200 mg/dl of protein and occasional amorphous crystals.
Initial computed tomography (CT) scan of the abdomen and pelvis during hospital admission showed a 15 cm spleen which was heterogenous and micronodular, as well as scattered abdominal and pelvic lymphadenopathy (Fig. 1a). No imaging signs of portal hypertension were noted.
During the hospitalization our patient was noted to become more confused and agitated, and there was concern that the patient was having seizures as she was seen numerous times to lose consciousness and awaken, with occasional loss of bladder function. A brain magnetic resonance imaging (MRI) showed subcortical non enhancing FLAIR hyper intense foci in the bilateral posterior occipital lobes.
Lumbar puncture and cerebral spinal fluid (CSF) studies were further performed for further analysis, and showed: WBC 1; no red blood cells; protein 62 mg/dL; glucose 35 mg/dL; and, lactate dehydrogenase 234 mIU/mL. Most notable negative findings in the CSF included no detectable viral cultures for cytomegalovirus, adenovirus, herpes virus, and varicella zoster virus, negative cryptococcal antigen serology and negative bacterial and fungal cultures.
Electroencephalogram studies showed triphasic morphology waves with and without sharp negative component at 2–3 hertz. These were seen in continuum mostly with subtle waxing and waning features. To 0.5 mg intravenous alprazolam, above discharges had slowly resolved, replaced by organized background that consists of 6 hertz rhythms. Importantly, there was a clinical improvement after alprazolam; suggesting a nonconvulsive seizures responding to benzodiazepine.
Two weeks later after the initial CT imaging and after the patient was more stable from the neurological perspective in order to attempt a lymph node excisional biopsy, a PET-CT imaging was performed and showed complete resolution of the previously detected lymphadenopathy and splenomegaly. (Fig. 1b).
Additional serologies for viral hepatitis and autoimmune etiology work up were performed. A bone marrow biopsy was performed and additional serum erythropoietin level, iron profile; cobalamin and folate level were determined.
The patient returned to the benign hematology clinic after discharged from the hospital. During her follow up appointment she appeared in better spirits and recovering well. Physical examination was notable for an absence of lymphadenopathy particularly in the cervical and axillary region, as well as no palpable organomegaly in the abdomen. It was further revealed that her antinuclear antibody (ANA) titer was highly positive (1:640), ESR 108 mm/hr with a CRP 6.74 mg/L. Negative viral hepatitis B, C and Human Immunodeficiency virus serologies.
Serum quantitative immunoglobulin showed a mildly elevated Ig A and Ig G level, without other abnormalities. Serum and urine protein electrophoresis did not reveal a monoclonal gammopathy. Serum free light chain levels showed kappa 96.3 mg/L and lambda 60.06 mg/dL with a normal ratio 1.6 in a patient with chronic kidney disease.
Complement C3 level was normal with a slightly elevated C4 at 46 mg/dL.
Bone marrow aspirate yielded a predominance of CD3 positive polytypical small T cells and a population of polyclonal B-cells by flow cytometry and negative for lymphoma or other malignant process. A focal lymphohistiocytic aggregate with granuloma formation was noted; occasional larger cells with prominent nucleolus identified; eosinophils were increased mildly in the vicinity of this aggregate. Acid fast bacilli and fungal stains were attempted; however the focal granuloma could not be appreciated at subsequent sections.
The patient’s pancytopenia was thought to be likely secondary to systemic lupus erythematosus and she was thus referred to rheumatology for further work up, and further testing included anti-double-stranded DNA, anti-RNP, anti-CCP antibody, ANCA vasculitis panel, direct antiglobulin test, lupus anticoagulant, anticardiolipin antibody, anti-double-stranded DNA antibody, and anti-SSA and anti-SSB. All these tests were negative, thus ruling out systemic erythematous lupus, rheumatoid arthritis, and other connective tissue disorders.
The interval improvement and self-limited clinical course in our case led us to believe that her elevated ANA titers, her bone marrow granuloma were secondary to an EBV infection-related syndrome. Monospot test was not performed and at that point we evaluated for EBV PCR and EBER staining in the bone marrow. Initial EBV PCR results were positive (960 copies/mL), while Epstein–Barr virus-encoded small RNAs staining in the bone marrow was negative. Our in situ hybridization stain is validated to work on decalcified bone marrow trephine biopsies and all stains include an on-slide positive control. As such, the likelihood of a false negative result is low. A possible explanation includes a sampling factor with lack of infected B-cells in the bone marrow despite the presence of viremia.
Her follow up labs during subsequent clinic visits showed WBC 5.3 K/uL, ANC 3.15 K/uL, Hgb 7.4 g/dL, calculated reticulocyte index of 1.1 and platelets 172 K/uL. Iron was 68 ug/dL, transferrin 124.1 mg/dL, ferritin 2952 ng/mL and serum erythropoietin levels were 31.7 mIU/mL. Serum cobalamin was 394 pg/mL and serum folate 12.3 ng/mL. Since there was spontaneous interval resolution of her neutropenia and her thrombocytopenia our diagnosis at that point was cytopenias secondary to infectious mononucleosis and anemia of chronic kidney disease related to diabetes.
Our patient presented 7 weeks later at the emergency room with a recurrent febrile syndrome with diffuse cervical and axillary lymphadenopathy and splenomegaly (Fig. 1c-d) and worsening cytopenias: WBC 1800/uL, ANC 1480/uL, Hgb 8.3 gr/dL, platelet count 20,000/uL; a repeat EBV titer revealed 6580 copies/mL. CT imaging with contrast found bilateral axillary, mediastinal and hilar lymphadenopathy. Low volume retroperitoneal and pelvic lymphadenopathy, hepatosplenomegaly with numerous small ill-defined hypodense lesions was in the spleen and probably also within the liver (Fig. 1d). At this time a repeat bone marrow biopsy and an excisional lymph node biopsy were performed and reviewed. The bone marrow specimen showed a solitary large cell positive for CD30 identified in the clot. No atypical cells are identified in core biopsy as assessed by IHC for CD30 and Pax-5. EBER was positive in few and scattered cells. The lymph node sections demonstrated near-total effacement of the lymph node architecture by a neoplasm comprised of neoplastic cells with Hodgkin-Reed-Sternberg morphology. The neoplastic cells were positive for CD15, CD30, PAX5 (weak), and MUM1. They were negative for CD3, CD20, CD45, ALK, and EMA. The findings were diagnostic of classical Hodgkin lymphoma, best subtyped as lymphocyte-depleted. (Fig. 2a-c). The expression of PAX5 with weak intensity coupled with MUM1 expression by the neoplastic cells is diagnostic of classical Hodgkin lymphoma. The expression of PAX5, a gene encoding a B-cell-specific transcription factor, excluded T-cell lymphoma as a diagnostic consideration. It is worth noting also that flow cytometry done on a bone marrow sample with involvement by lymphoma showed no evidence of T-cell or B-cell immunophenotypic aberrancies.
The patient was started on ABVD chemotherapy regime, bleomycin was held secondary to patient’s history of cardiomyopathy. She received three cycles of chemotherapy with complete clinical remission. Additional cycles of chemotherapy were not completed given prolonged and severe chemotherapy-induced cytopenias that eventually recovered over the following months. A bone marrow biopsy at completion of treatment revealed no morphologic evidence of residual Hodgkin lymphoma. Her most recent surveillance PET-CT imaging, nine months from completion of treatment, showed no hypermetabolic lymphoma and continuing complete metabolic response to therapy.
