Last Resort

The most likely diagnosis at this point is lymphoma. Bone marrow biopsy is indicated to further assess his thrombocytopenia and hypoproliferative anemia and may be diagnostic for malignancy. Pathologic examination of a lymph node should be performed. Due to concern for lymphoproliferative disease, excisional biopsy is preferred to preserve tissue architecture.

Hematology was consulted for evaluation of the lymphadenopathy, anemia, and thrombocytopenia and recommended bone marrow and excisional lymph node biopsies. Bone marrow biopsy showed trilineage hypercellularity (Figure 3A) with reduced erythropoiesis and reticulin fibrosis (Figure 3B). An axillary lymph node biopsy with flow cytometry was nondiagnostic for a lymphoproliferative disorder or malignancy.

Both biopsies fail to provide a definitive diagnosis. Hypercellularity in the marrow (>70% cellularity) and reticulin fibrosis are nonspecific and could be from a malignant or reactive disease process. Lymphoma remains the most likely diagnosis. Peripheral blood for flow cytometry, lactate dehydrogenase (LDH), and uric acid should be sent. A repeat excisional biopsy of another lymph node should be performed.

Gastroenterology was consulted to evaluate the loose stools, anasarca, and hepatomegaly, and esophagogastroduodenoscopy, enteroscopy, and colonoscopy with biopsies were performed. Gastric biopsy revealed mild gastropathy. Duodenal, jejunal, and right and left colon biopsies were all normal. A liver biopsy was performed and revealed periportal inflammation. Rheumatology and infectious disease consultations did not suspect that the patient had a rheumatologic or infectious disease.

After appropriate workup and no definitive diagnosis, it is important to reassess the patient for overall stability and the presence of any new or changing symptoms (worsening symptoms, persistent fevers) that could direct further evaluation. Lymphoma remains on the differential despite multiple negative biopsies, but other less common diseases that mimic lymphoma and cause multisystem disease should be investigated. Review of the previous lymph node and tissue biopsies with the pathologist and hematologist should focus on features of adult Still’s disease (paracortical immunoblastic hyperplasia), MCD (histopathology of angiofollicular lymph node hyperplasia and presence of human herpes virus-8 (HHV-8), and HLH (hemophagocytosis). A positron emission tomography scan may not distinguish between malignancy and other fluorodeoxyglucose avid inflammatory processes but is recommended to determine the site of a future excisional lymph node biopsy.

A 10-day trial of prednisone 50 mg daily was initiated for presumed lymphoma. He experienced symptomatic improvement with decreased peripheral edema and ascites and resolution of his fevers. He was discharged home seven days after completing steroids with follow-up.

Five days after discharge, he was readmitted with worsening anasarca, massive ascites, and acute kidney injury. Admission laboratory studies revealed creatinine 1.66 mg/dL, hemoglobin 11.5 g/dL, and platelets 94 k/mm³. In addition, his ferritin level was 1,907 ng/L (reference range, 20-400 ng/L), erythrocyte sedimentation rate (ESR) was 50 mm/h (reference range, 0-20 mm/h), and C-reactive protein concentration (CRP) was 12.1 mg/dL (reference range, 0-0.5 mg/dL).

Steroids are used to treat a wide variety of illnesses, some of which are still under consideration in this patient including lymphoma, MCD, adult Still’s disease, and HLH. His symptoms recurred quickly after discontinuation of steroids in the setting of elevated ferritin, ESR, and CRP levels reflecting marked ongoing inflammation. Serologic testing for soluble IL-2 receptor, often elevated in MCD and HLH, should be performed. Excisional biopsy of an accessible node should be performed urgently.

His acute kidney injury resolved; however, he continued to have intermittent fevers, anemia, thromobocytopenia, lymphadenopathy, and hepatosplenomegaly. A hematology case-conference recommended testing for HLH, including soluble IL-2 receptor (CD25), soluble CD163, and natural killer cell degranulation assay, all of which were negative. A right inguinal lymph node biopsy revealed reactive lymphoid tissue and stained negative for HHV-8. Based on the lack of an alternative diagnosis (particularly lymphoma), the presence of multiple areas of lymphadenopathy, anemia, fevers, organomegaly, weight loss, reactive lymphoid tissue on lymph node biopsy, and elevated CRP and ESR, a working diagnosis of MCD was made. The negative HHV-8 testing was consistent with idiopathic MCD (iMCD); however, features inconsistent with iMCD included lack of polyclonal hypergammaglobulinemia and the presence of significant anasarca and thrombocytopenia. Therefore, an internet search was performed using the patient’s salient symptoms and findings. The search revealed a few recently published case reports of a rare variant of iMCD, TAFRO syndrome. TAFRO syndrome, characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis and/or renal insufficiency, and organomegaly, fully explained the patient’s presentation. He was started on prednisone, rituximab (anti-CD20 antibody), and furosemide. After one month of treatment, he showed complete resolution of cytopenias, lymphadenopathy, organomegaly, anasarca, and ascites. Therapy continued for approximately three months, and he has remained symptom-free.