Leukemic Synovitis - Los Angeles Society of Pathologists

Leukemic Synovitis - Los Angeles Society of Pathologists

Sara C. Acree, M.D.
LA County + USC Medical Center
Los Angeles, CA 90033
[email protected]
Case Presentation
• PE: Left knee effusion and joint tenderness
• PMH: Stage IVB diffuse large B-cell
lymphoma (DLBCL), status post 5 cycles of
R-CHOP (last regimen: 28 months ago)
• CC: Fatigue, weakness, dizziness, and left
knee pain.
• Pt: 53 year-old Asian female
History
L
Chondrocalcinosis with patellofemoral compartment narrowing,
osteophytes and effusion (? r/o malignant effusion).
L
L
Tricompartment osteoarthritis, with osteophytes. Loss of
patellofemoral cartilage and loose bodies.
L
Synovial fluid
SS
CD45
CD71
Flow Cytometry - Synovial Fluid
CD33
CD15
CD11b
CD13
Flow Cytometry - Synovial Fluid
CD14
Synovial Fluid
• Granulocytic markers:
– CD13 dim
– CD15 subpopulation
– CD33 moderate/dim
• Monocytic Markers:
– CD11b moderate
– CD14 bright/moderate
Flow Cytometry - Results
Synovial fluid
MPO
NSE
CBC
• Hb
• Hct
• WBC
• Plts
7.0 g/dL
21%
5.4 x103 μL
107 x103 μL
Labs
Peripheral blood
BM Aspirate
BM Aspirate
MPO
NSE
SS
CD45
CD11b
Flow Cytometry - Marrow
CD15
CD14
CD13
CD3
Flow Cytometry - Marrow
CD4
Bone Marrow
• CD15 subpop
• CD33
• CD4 dim
• CD11b dim
• CD14 subpop
• CD34 subpop
• CD117 subpop
• HLA-DR
INTERPRETATION: Myelomonocytic phenotype
Synovial Fluid
• CD15 subpop
• CD33 mod/dim
• CD13 dim
• CD11b moderate
• CD14 bright/mod
Flow Cytometry - Results
– Additional abnormalities suggest evolution
of disease.
• Observed in MDS
• Intermediate prognostic marker
– Deletion 12p:
• 46,XX, del(1)(p13q22),t(8;11)(p11.2;p15),
del(12)(p11.2)
Cytogenetics
• Leukemic Synovitis
– Associated with doxorubicin therapy
(aka, Hydroxydaunorubicin = R-CHOP)
• Acute Myelomonocytic Leukemia,
Therapy Related
Diagnosis
• The average rheumatic prodrome is 3 months
• Can be the initial manifestation of leukemia or
of relapse (even if not present initially).
• Acute & chronic lymphocytic & myeloid leukemia
– 4% of adult leukemias
• Acute lymphoblastic leukemia
– 14% of pediatric leukemias
• Well-recognized but rare complication of acute
and chronic leukemias
Leukemic Synovitis (LS)
• Clinical Presentation:
– Joints warm, swollen, tender
– Distal and symmetric, or asymmetric,
involving large joints
– Effusions usually small
– Severe pain is common
– Osteopenia, lytic lesions on X-rays
– Seronegative reactive arthritis-like
Leukemic Synovitis (LS)
– Note: may fail to sample neoplastic infiltrate
– Immunohistochemistry
• Synovial biopsy (? “Gold Standard”)
– Enzyme cytochemistry
– Flow cytometry
• Synovial fluid exam with cytospin morphology
• Imaging studies often non-specific
Leukemic Synovitis - Diagnosis
• Decreasing joint pain often is the first sign
of a clinical response to chemotherapy.
• Therapy for the underlying leukemia is the
treatment of choice.
• Leukemic synovitis is a sign of systemic
involvement and should prompt immediate
and aggressive therapy even in the absence
of signs of bone marrow involvement.
Treatment of Leukemic Synovitis
Case 3
Early
AMML
Early
AMML
Diagnosis
CMML
(relapse)
Late
63yo Asian
Male
L knee
effusion
DLBCL
Osteoarthritis
CMML
Osteoarthritis
? OA vs RA
Synovial Fluid Synovial Biopsy Synovial Fluid
53yo Hispanic
53yo Asian
Female
Female
L knee effusion R knee effusion
Case 2
Time course
of LS
Exam
PMH
Si/Sx
Age/Gender
Case 1
Summary of Leukemic Synovitis
Cases at LAC+USC
5 Cases:
58 yo M:
24 yo F:
60 yo M:
68 yo M:
75 yo F:
76 yo M:
27 yo F:
Arthrit Rheum. 1994;24(1):48
Med 2003:34;717
6Rheumatol 2006:45;1143
8Saudi Med J. 2001;22(9):808-11.
4Lab
2Sem
All FAB types of AML (i.e. AMML, AMoL)1
AMML2
Acute biphenotypic leukemia3
AMML4
CMML5
MDS → AMML6
AMoL7
CML → AMML blast phase8
Haematol 1999:101;1
3Clin Rheumatol 2006:25;380
5J Rheumatol 2006:33;1709
7Br J Haematol 2004:124;258
1Acta
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Types of Myeloid Leukemia in
Adult Leukemic Synovitis
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5 Cases:
58 yo M:
24 yo F:
60 yo M:
68 yo M:
75 yo F:
76 yo M:
27 yo F:
53 yo F:
53 yo F:
63 yo M:
All FAB types of AML (i.e. AMML, AMoL)
AMML
Acute biphenotypic leukemia
AMML
CMML
MDS → AMML
AMoL
CML → AMML blast phase
MDS → AMML
AMML
CMML
Types of Myeloid Leukemia in
Adult Leukemic Synovitis
• What role does osteoarthritis play?
• What is the association with monocytes?
UNANSWERED QUESTIONS
Leukemic Synovitis:
Etiology in Myeloid Leukemia
– Monocyte chemoattractant protein-1 (MCP-1)
– IL-8 (CXCL8)
– Hepatocyte Growth Factor (HGF)
• TNFα increases synovial fibroblast production of:
• TNFα is increased by fibroblasts, synoviocytes
and damaged chondrocytes
OSTEOARTHRITIS
Leukemic Synovitis:
Etiology in Myeloid Leukemia
• Effect is potentiated by other
cytokines (ie, HGF)
• Recruits monocytes to sites
of injury, infection
• Expressed by osteoclasts
and osteoblasts
• Found at the site of bone
degradation
• Part of CC chemokine family
• Also known as CCL2
MCP-1 (CCL2)
MONOCYTE CHEMOTACTIC PROTEIN-1
• Target cells: neutrophils,
macrophages, mast cells,
keratinocytes, and
endothelial cells
• Chemoattractant and potent
angiogenic factor
• A member of the CXC
chemokine family
• Also known as Granulocyte
Chemotactic Factor
IL-8 (CXCL8)
INTERLEUKIN-8 (CXCL8)
• Induces secretion of MCP-1 by
fibroblast-like synovial cells
(FLS) and chondrocytes
• Recently shown to facilitate
osteophyte development
• Traditionally thought to play a
role in cartilage repair in OA
• Acts on epithelial, endothelial,
and hematopoietic cells
• Paracrine cytokine secreted by
mesenchymal cells
J of Ortho Res 2007;25:569-577
Hepatocyte Growth Factor
HEPATOCYTE GROWTH FACTOR (HGF)
↑MCP-1/CCL2
↑IL-8/CXCL8
↑HGF
+
Positive
Feedback
Cause monocyte and granulocyte
migration to the affected joint
TNFα
Fibroblasts
Synoviocytes
Chondrocytes
– Other adhesion proteins
– Mutated receptors on leukemic cells
• Why is leukemic synovitis rare when
osteoarthritis is common?
UNANSWERED QUESTIONS
Leukemic Synovitis:
Etiology in Myeloid Leukemia
• May be associated with osteoarthritis
– Chemokine-induced adhesion and
migration
• In adults, it is associated with myeloid
leukemia exhibiting a monocytic component
• Leukemic synovitis is a rare complication of
leukemia, presenting early or late.
Summary
Gura H, Korena V, Ehrenfelda M, Ben-Bassatc I, Sidia Y. Rheumatic manifestations preceding
adult acute leukemia: characteristics and implication in course and prognosis. Acta
Haematologica 1999;101:1-6.
Evans TI, Nercessian BM, Sanders KM. Leukemic Arthritis. Seminars in arthritis and
rheumatism. 1994;24(1):48-56.
Kim HR, Hong JH, Yoon CH, Lee SH, Park SH, Kim HY. Arthritis preceding acute biphenotypic
leukemia. Clinical Rheumatology. 2006;25:380-381.
Solanki SK, Latif S, Veillon DM, Nordberg ML, Saccaro SJ, Cotelingam JD, Berney SM. A
swollen painful knee in an elderly man with recently diagnosed acute myelogenous leukemia.
Laboratory Medicine. 2003;10(34):717-723.
Cros CA, Gutierrez I, Gómez JP. Leukemic infiltration of the knee. Journal of Rheumatol.
2006;33(8):1709.
Ziakas PD, Giannouli S, Tzioufas AG, Voulgarelis M. Leukemic synovitis. Rheumatology
(Oxford). 2006 Sep;45(9):1143.
Ramadan K, Cahill M. Successful intra-articular chemotherapy for relapsed acute myeloid
leukaemia infiltrating the knee joint. British Journal of Haematology. 2004;124(3):258.
Al-Rayes HM, Al-Shaikh AA, Halim MA, Al-Qurashi FS, Al-Jurf MM. Leukemic synovitis as a
presentation of myelomonocytic blast crisis of chronic myeloid leukemia. Saudi Med .
2001;22(9):808-811.
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References
Tak PT. Chemokine inhibition in inflammatory arthritis. Best Practice & Research Clinical
Rheumatology. 2006;20(5):929-939
Buckley CD. Why do leucocytes accumulate within chronically inflamed joints?.
Rheumatology. 2003;42:1433-1444.
Fernandes JC, Martel-Pelletier J, Pelletier JP. The role of cytokines in osteoarthritis
pathophysiology. Biorheology. 2002;39(1-2):237-246.
Ogura N, Tobe M, Sakamaki H, Nagura H, Abiko Y, Kondoh T. Tumor necrosis factor-alpha
increases chemokine gene expression and production in synovial fibroblasts from human
temporomandibular joint. Journal of Oral Pathology & Medicine. 2005;34:357-363.
Gregory JL, Morand EF, McKeown SJ, Ralph JA, Hall P, Yang YH, McColl SR, Hickey MJ.
Macrophage migration inhibitory factor induces macrophage recruitment via CC chemokine
ligand 2. The Journal of Immunology. 2006;177:8072-8079.
Benito MJ, Veale DJ, Fitzgerald O, van den Berg WB, Bresnihan B. Synovial tissue
inflammation in early and late osteoarthritis. Annals of the Rheumatic Disease. 2005;64:12631267.
Dankbar B, Neugebauer K, Wunrau C, Tibesku CO, Skwara A, Pap T, Fuchs-Winkelmann S.
Hepatocyte growth factor induction of macrophage chemoattractant protein-1 and osteophyteinducing factors in osteoarthritis. Journal of Orthopaedic Research. 2007;25:569-577.
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References
LAC+USC Hematopathology Fellow
George Yang, MD
LAC+USC Staff Pathologist, Anatomic Pathology
Surgical Pathology, Cytopathology, Hematopathology
Raul G. Simental-Pizzaro, MD
Director, LAC+USC Hematopathology Fellowship Program
Co-director, LAC+USC Medical Center Core Laboratory
Russell K. Brynes, MD
Acknowledgements
Thank You