David Fajgenbaum, MD, MBA, MSc: Relevant Pathology Findings

What are the relevant findings from his pathology report?

This patient had regressed or atrophic germinal centers, hypervascularization between follicles, plasmacytosis—plasma cells throughout but not sheet-like plasma cells, and finally hyperplastic germinal centers. These features are often found in a disease called idiopathic Multicentric Castleman Disease. They are not specific or pathognomonic for MCD but they are certainly consistent. Based on the really dramatic vascularization and really dramatic atrophic germinal centers, you would call this case a mixed case. So it wouldn’t be plasmacytic or hyaline-vascular, we would call it mixed pathology.

The setting of this patient’s fluid overload—he’s got 50 plus pounds of anasarca throughout his body, fluid overload, thrombocytopenia, really low platelets, reticulin fibrosis on bone marrow, renal dysfunction, and his hepatosplenomegaly, plus these lymph node findings of what we call mixed or really exaggerated atrophic germinal centers.

We need to be thinking about a syndrome within Multicentric Castleman Disease called TAFRO syndrome. TAFRO stands for Thrombocytopenia, Anasarca, Fibrosis of the bone marrow, Renal dysfunction, and Organomegaly. These patients really have been reported for decades, but they’ve only recently been described in the literature, initially in Japan and now around the world, as a subtype of Multicentric Castleman Disease. Based on the really dramatic anasarca and the low platelets, that gets you thinking that this could be TAFRO syndrome. The reason that’s important is that Multicentric Castleman Disease is such a heterogeneous disorder that you want to be able to start to lump patients together. What we started to find is that patients with TAFRO syndrome respond one way to therapies, and patients that are non-TAFRO Multicentric Castleman Disease patients respond in other ways. In this patient, based on the constellation of symptoms and features, we are thinking that this is idiopathic Multicentric Castleman Disease with mixed cellularity with TAFRO syndrome.

Multicentric Castleman Disease: Case 2

Garrett is a 47-year old male carpenter who was formerly a Marine, with a 4-week history of fatigue, night sweats, and weight loss. He reported difficulty breathing for 2 weeks, and 1 week of fevers. He also reported that he’s noted fluid in his legs. He presented to the emergency department for a work-up. His past medical history was only notable for Raynaud’s phenomenon. His family history included a mother that died from a myocardial infarction at 71 and a father who died from lung cancer at 61. His physical exam was notable for bilateral cervical and inguinal lymphadenopathy (1-2 cm), moderate edema (10 lb weight gain in past 7 days), and pleural effusions.

Laboratory findings showed anemia (Hgb: 11 gm/dl), low platelets (109k), and elevated alkaline phosphatase levels. The patient was admitted with a presumed viral illness and then moved to MICU when the patient began experiencing severe difficulty breathing, transaminitis, and increased fluid gain (30 lbs). Further testing showed his CRP >300 mg/L, albumin 1.2 g/dL, renal dysfunction, and Hgb trending downward (now 9 gm/dl), and PLTs trending downward (now 35k). His infectious workup was pan-negative, except for possible EBV infection (8/29/10: EBV PCR positive). He was diagnosed with acute EBV mononucleosis early in admission, but the diagnosis was rescinded when he was found to be EBV IgG+. A rheumatology workup was negative except for a positive ANA (1:120).

The patient was started on 125mg BID of solumedrol without improvement. His hematology/oncology workup was notable for: .

• Elevated B-2-microglobulin
• CT scan: diffuse LAD, splenomegaly
• PET: patchy FDG uptake in SI only (while on high dose steroids)
• Normal Igs (IgG: 930, range: 650-2000; IgM 63, range: 40-270; IgA: 202, range: 50-500)
• Normal/moderately elevated IL-6 (6, nml <5)
• No light chain restriction
• Negative SPEP and UPEP

A bone marrow biopsy reported:

• Hypercellular marrow (90%) with myeloid and megakaryocytic hyperplasia, and emperipoesis.
• Small perivascular lymphohistiocytic aggregate
• Reticulin fibrosis was also noted with &ldquo;cytological atypia of the megakaryocyte lineage (FVIII+, CD61+)&hellip;&rdquo;
• &ldquo;increased CD68+ macrophages (10%)&hellip;&rdquo;
• &ldquo;myeloid: erythroid ratio of 6:1&rdquo;
• &ldquo;Large CD34- cKit+ blasts.&rdquo;
• &ldquo;Rare macrophages and megakaryocytes that contain red and white blood cells.&rdquo;

A lymph node biopsy was scheduled to be performed.