David Fajgenbaum, MD, MBA, MSc: Patient's Diagnosis

What is the most likely diagnosis for this patient?

Dr. David Fajgenbaum, Perelman School of Medicine, University of Pennsylvania, says the lymph node biopsy, the absence of other disorders that can lead to similar pathology, and the negative viral studies in the setting of generalized lymphadenopathy suggest that the correct diagnosis is HHV-8 negative (iMCD). iMCD can cause some immune dysregulation, and low positive ANA has been reported in approximately 30% of patients. This can delay diagnosis or even lead to inappropriate therapy. More specific testing for SLE should always be performed to confirm or exclude the diagnosis when a positive ANA is discovered. This patient was found to have a mildly elevated IL-6 level (6 pg/mL, normal range: <5 pg/mL), which may play a role with other cytokines in driving the inflammatory response. Elevated IL-6 can also reduce the production of albumin-causing hypoalbuminemia. Hypoalbuminemia together with high VEGF levels can cause leaky capillaries, which produce marked third spacing, explaining the pleural effusions, ascites, and peripheral edema in this patient. Third spacing can also contribute to circulatory collapse and organ failure. The cause of renal failure in iMCD is not well understood and in cases where kidney biopsy was performed, a variety of pathologies has been reported. IL-6 increases hepcidin production by the liver, which reduces iron absorption, iron release from macrophage, and iron exit from the liver, all contributing to the development of anemia. IL-6 promotes thrombopoiesis, and often increases in platelet counts are seen. Interestingly, most patients with iMCD have low platelet counts.

The etiology of thrombocytopenia in iMCD has not been fully elucidated, but it is especially seen in patients who are severely ill. iMCD can be accompanied by autoimmune phenomena such as autoimmune hemolytic anemia. Disseminated intravascular coagulation (DIC) was ruled out in this patient. It has been proposed, but not validated, that the presence of thrombocytopenia, normal gamma globulin levels, and the presence of bone marrow fibrosis in a patient with iMCD may represent a subentity in the clinical spectrum of iMCD.







Guess the Diagnosis: Case 2

Mark F. is a 25-year-old law school student from Florida with a 3-week history of severe fatigue, night sweats, and weight loss; he has also reported high fevers for the past week. He did not complain of joint pain.

• He presents to the emergency department complaining of abdominal pain. His past medical history is notable for enlarged thyroid incidentally found 5 years before; family history relevant for an aunt with rheumatoid arthritis
• Physical exam was notable for generalized lymphadenopathy (1-2 cm), hepatosplenomegaly, bilateral pleural effusions, ascites, and 4+ peripheral edema. Laboratory findings show anemia (7 gm/dL), elevated CRP (150 mg/L), ESR (120mm/hr), creatinine (3.0 mmol/L), Albumin of 2.1 g/dL and normal immunoglobulin levels (IgG: 1100 mg/dL, IgA: 300 mg/dL, IgM 200 mg/dL), low platelets (50,000/mL), positive ANA 1:160 with a speckled pattern. RhF was negative. Coagulation screen was not suggestive of DIC. LDH was normal

The patient was admitted for further assessment.

• Regressed germinal centers, scattered hyperplastic follicles, preserved architecture with patent peripheral sinuses and florid interfollicular plasmacytosis with no light chain restriction
• Rheumatologist diagnosed the patient with SLE and treated with high-dose steroids; this did not result in a major improvement in symptoms, laboratory parameters or lymphadenopathy

Mark&rsquo;s SLE diagnosis was reviewed and further testing was performed:

• The patient was believed to be too sick to be taken to the OR to undergo a lymph node biopsy, so a bone marrow biopsy was performed. Bone marrow showed a hypercellular marrow with mild increase in polyclonal plasma cells and moderate reticulin fibrosis
• Laboratory work: Negative dsDNA, anti-Smith and anti-phopsholipid antibodies with normal complement levels; ANCA and anti-streptolysis O titer are negative. No M protein on protein electrophoresis. 24-hour urine showed mild proteinuria. Monospot negative. TSH, T4, and T3 normal. Normal thyroglobulin and thryoid peroxidase antibodies. Urinary sediment is negative as are urine and blood cultures. IL-6 is 6 pg/mL
• CT-PET: generalized lymphadenopathy with low-positive FDG uptake
• Without a clear diagnosis, a lymph node biopsy was performed of the cervical chain: Regressed germinal centers, scattered hyperplastic follicles, preserved architecture with patent peripheral sinuses; florid interfollicular plasmacytosis, prominent vascularization with absence of light chain restriction. Negative LANA-1, IgG4, and EBER stains. Negative PCR for B-cell clonality