reactive cytopenia - esp-congress.org · o usually incomplete anamnesis suspect of malignancy o...
TRANSCRIPT
Outline
• Background
indications and expectations towards bone marrow biopsies in cytopenia
• Practical approach to bone marrow biopsies in cytopenia
• Take homes
• Please notice the e-handout; PDF of the presentation freely available
Outline
• Background
indications and expectations towards bone marrow biopsies in cytopenia
• Practical approach to bone marrow biopsies in cytopenia
• Take homes
Bone marrow biopsies (BMB) in cytopenia:indications and expectations
• Common indication for trephine bone marrow biopsy
• Part of a multimodal approach for as specific as possible diagnosis
Bone marrow biopsies in cytopenia:expectations of pathologists to clinicians
• Anamnestic hints any suspicion of congenital / inherited / constitutional / genetic disease
any acute toxic or drug exposure, any previous chemo- or/and radiotherapy
any underlying systemic disease (e.g. collagenoses, systemic infections etc.)
duration
• Basic laboratory parameters and hints from the clinical examination blood cell counts and differential hemogram
iron / folic acid / vitamin B12 / copper status
findings suggesting autoimmune hemolysis or hemophagocytic lymphohistiocytosis
fever, splenomegaly, hepatomegaly, lymphadenopathy, relevant skin findings
any hints suggesting infection / nephropathy / hepatopathy / pneumopathy
Bone marrow biopsies in cytopenia:expectations of clinicians to pathologists
• Irreplaceability of the histopathological work-up
focal processes
o focal blast (islets)
fibrosing processes
o dry tap
o occasionally, the only specimen available for molecular work-up
disorders extrinsic to the bone marrow
o infections
o metastases
o granulomatous myelitis
o thrombotic microangiopathy
o etc.
Outline
• Background
indications and expectations towards bone marrow biopsies in cytopenia
• Practical approach to bone marrow biopsies in cytopenia
• Take homes
• Histopathological pattern-based and blood count-based approach
• Constitutional bone marrow failures will not be specifically addressed in this lecture but can be found in the PDF of the presentation
My approach to reactive cytopenia
Pancytopenia – general considerations
• Clear indication for biopsy part of the disease definition
often dry taps (no other diagnostic specimen except for the BMB)o cutting-edge molecular diagnostic methods available and applicable
plethora of significant (focal) and to a part treatable underlying disorderso significant expectations of clinicians to pathologists
particular inflammatory patterns (e.g. granulomas)
specific infections (e.g. virocytopathic changes)
(autoimmune) myelofibrosis
microangiopathic changes
underlying malignancies
metabolic diseases
o unawareness of clinicians that most diagnoses can be established only in an integrative way underestimation of the effects of drugs/toxic exposures (e.g. idiopathic vs. secondary AA)
Pancytopenia with bone marrow hypo-/aplasia
• Aplastic anemia (AA) definition
Fanconi-, SDS- and DC-patients at risk
• Pitfalls subcortical pseudohypolasia
hypoplastic MDS/AML/ALL/lymphoma
Am J Clin Pathol. 2013;139:9-29.
E-ca
dh
erin
• Proliferation and/or survival pressure on hematopoietic stem cells 50% of AA patients have
clonal hematopoiesis• commonly affected: PIGA or
BCOR/BCORL1, and DNMT3Aor ASXL1
• rare mutations in TET2, TP53, RUNX1 and splicing factor genes
• +6 or +15, and +8, -7 and del(5q)
AA – from pathogenesis to molecular testing
Blood. 2016;128:337-47.
Pancytopenia with increase of histiocytes (± hemophagocytosis)
• Hemophagocytic lymphohistiocytosis
Am J Clin Pathol. 2013;139:713-27.
Pitfalls
• post-transfusion changes
• post-myeloablative changes
• storage disorders
•metabolic disorders
• infections
• histiocytic neoplasms
Bicytopenia with bone marrow necrosis or microangiopathic changes
• Endothelial damage
carcinoma dissemination
hemolytic-uremic syndrome
transplant-associated microangiopathy
thrombotic-thrombocytopenic purpura
Anemia – general considerations
• Subject of laboratory medicine definitions normo-/hyper-/hypochromic, normo-/macro-/microcytic
± reticulocyte count changes
etc. …
• Generally not an indication for biopsy
• Unless long-lasting and/or severe
suspect of malignancy
treatment-resistant
unexplained
Anemia with erythroblastopenia
• Pure red cell aplasia alloimmune in HCT over the ABO-barrier
drug-induced (e.g. phenytoin)
idiopathic (autoimmune)
paraneoplastic o thymoma
o T-LGL LPD
• Parvovirus B19 infection
• Transient erythroblastopenia
of childhood (2-y-aged)Gly-A
Anemia with increased erythroid precursors
• Intrinsic or acquired erythroid survival and maturation defects
vitamin and/or other substrates deficiency
hemoglobinopathies, thalassemias & CDA
(autoimmune) hemolytic anemias
membrane defects incl. PNH
enzyme defects
…
medications antagonizing folate-, purine-and pyrimidine metabolism (allopurinol!)
Anemia of aging / of chronic disease
Blo
od
. 20
08
;12
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9-3
0.
• Integrative diagnosis
• Multifactorial disease(s)
• Non-specific findings
often hypercellularity & dysplasia
increased (stainable) iron
polytypic plasmacytosis
• Key features of significant underlying diseases?
occult neoplasm
chronic/specific infection
(autoimmune) myelofibrosis
renal/parathyroid osteopathy
Neutropenia – general considerations
• Neutrophils <500/μl
• Often in acute viral infections
• Generally not an indication for biopsy
• Unless long-lasting
unexplainedo usually incomplete anamnesis
suspect of malignancyo T-LGL LPD
o others
Neutropenia with myeloid hypoplasia or maturation disturbance
• Drug toxicities (arylamine-containing drugs)
• Infections or autoimmunity
Neutropenia with granulocytic hyperplasia
• Increased consumption of mature granulocytes in the periphery autoimmune neutropenia (of childhood)
septic conditions
• Pitfalls steroids
growth factors
MPO
Pitfall: neutropenia with myeloid hyperplasia• APML
CD117+
CD2+
FISH+
Leukemia. 1994;8:1108-12.Am J Clin Pathol. 2002;118:31-7.
Thrombopenia – general considerations
• <150.000/µl
• Generally not an indication for biopsy
• Unless unexplained
treatment-resistant
long-lasting and/or severe
suspect of malignancyo B-cell lymphomas
o MDS
o others
Thrombopenia with decreased megakaryocytes
• AA
• Toxic myelopathy (chemotherapy, mycophenolate, mTOR-inhibitors …)
• Virus infection (HIV, CMV)
• Autoimmunity with anti-C-MPL abs.
• Pitfall MDS
Thrombopenia with increased megakaryocytes
• “Megakaryocytic thrombopenia”
• Increased peripheral platelet consumption infections/septic conditions
mechanic destruction
ITP
HIT
TTP
DIC
PAS
Outline
• Background
indications and expectations towards bone marrow biopsies in cytopenia
• Practical approach to bone marrow biopsies in cytopenia
• Take homes
Summary: BMB in cytopenia
• Part of multimodal diagnostic process in cytopenia
obligatory diagnostic procedure in pancytopenia
important diagnostic procedure in (unexplained) cytopenia
• Irreplaceable in focal, fibrosing and non-hematopoietic diseases
• Useful guidance for our clinical colleagues and patients, particularly if
known caveats considered
ancillary techniques purposefully deployed
morphologic patterns and phenotypic findings properly interpreted
• Li KD, Salama ME. Therapy effect: Impact on bone marrow morphology. Surg Pathol Clin. 2016;9:177-87.
• Tzankov A, Dirnhofer S, Beham-Schmid C. Normal bone marrow and common reactive alterations. Pathologe. 2012;33:496-507.
• Ogawa S. Clonal hematopoiesis in acquired aplastic anemia. Blood. 2016;128:337-47.
• Tzankov A, Medinger M. Aplastic anemia: possible associations with lymphoproliferative neoplasms. Int J Lab Hematol. 2014;36:382-7.
• Rosado FG, Kim AS. Hemophagocytic lymphohistiocytosis: an update on diagnosis and pathogenesis. Am J Clin Pathol. 2013;139:713-27.
• Weinzierl EP, Arber DA. The differential diagnosis and bone marrow evaluation of new-onset pancytopenia. Am J Clin Pathol. 2013;139:9-29.
• Leguit RJ, van den Tweel JG. The pathology of bone marrow failure. Histopathology. 2010;57:655-70.
• Foucar K, Reichard K, Czuchlewski D. Bone marrow pathology. 3rd ed. Chicago, ASCP Press; 2010.
• Chang KL, Gaal KK, Huang Q, Weiss LM. Histiocytic lesions involving the bone marrow. Semin Diagn Pathol. 2003;20:226-236.
• Diebold J, Molina T, Camilleri-Broët S, Le Tourneau A, Audouin J. Bone marrow manifestations of infections and systemic diseases observed in bone marrow trephine biopsy review. Histopathology. 2000;37:199-211.
Helpful references
This is a rough practical sketch without any claim of being complete.
For comprehensive information I kindly refer to:• Foucar K, Reichard K, Czuchlewski D. Bone marrow pathology. 3rd ed. Chicago, ASCP Press; 2010.
• Iwafuchi H. The histopathology of bone marrow failure in children. J Clin Exp Hematop. 2018;58:68-86.
• Adam S, Melguizo Sanchis D, El-Kamah G, Samarasinghe S, Alharthi S, Armstrong L, Lako M. Concise Review: Getting to the core of inherited bone marrow failures. Stem Cells. 2017;35:284-98.
• Khincha PP, Savage SA. Genomic characterization of the inherited bone marrow failure syndromes. Semin Hematol. 2013;50:333-47.
• Leguit RJ, van den Tweel JG. The pathology of bone marrow failure. Histopathology. 2010;57:655-70.
Addendum: practical approach to congenital cytopenias
Congenital anemias
• Low reticulocytes, normal erythrocyte morphology, erythroid hypo-/aplasia = proliferation defects– Constitutional
• Fanconi anemia (+systemic/anatomic abnormalities)– chromosomal breakage (13 different genes)
• Diamond-Blackfan anemia (+systemic/skeletal abnormalities)– ribosomal biogenesis failure (9 different genes)
• Shwachman-Diamond syndrome (+neutropenia/pancreatic insufficiency)
• Dyskeratosis congenita (+cutaneous/nail/pulmonary abnormalities)– telomere maintenance failure (6 different genes)
– Acquired• Transient erythroblastopenia of childhood (+neutropenia)
– older than 1Y, HHV6, Parvo B19
Congenital anemias
• Low reticulocytes, macrocytosis, dysmorphy, erythroid hyperplasia = maturation defects
– Constitutional• Congenital dyserythropoietic anemias
– mitotic defects due to mutations of genes responsible for the nuclear integrity nuclear budding, bi-/mutinucleated forms, karyorrhexis
• Congenital megaloblastic anemia
– Gastric Intrinsic Factor mutation
– Transcobalamin II mutation
Congenital anemias
• High reticulocytes, dysmorphy, erythroid hyperplasia = hemoglobinization-, membrane- or enzyme defects (decreased life-span)– Constitutional
• Thalassemias and sickle cell disease
• Congenital sideroblastic anemias– heme synthesis genes (erythropoietic protoporphyria) or mitochondrial
DNA defects (Pearson syndrome) ring sideroblasts
• Sphero-/elliptocytosis
• G6PDH deficiency
– Acquired• TTP
Congenital neutropenias
• Low granulocytes, hyperplastic and left-shifted myelopoiesis = decreased life-span
– Acquired• Alloimmune, perinatal (anti-CD16b)
• Maternal drug exposure
• Autoimmune (anti-CD16b) (+emperipolesis of granulocytes in BM)
– 5-15 months of age
– Constitutional• Accompanying immunoglobulin deficiency syndromes
Congenital neutropenias
• Low granulocytes, hyperplastic and right-shifted myelopoiesis = decreased release
– W(arts)H(ypogamma)I(nfections)M(yelokathexis) syndrome• CXCR4 mutation (retention in BM
hypersegmentation/filamentous nuclear strands
– Chediak-Higashi (+large inclusions even in Ly, albinism)
Congenital neutropenias
• Low granulocytes, hypo-/aplastic (and left-shifted) myelopoiesis = decreased production– Acquired
• Viruses (CMV trough CD13, HIV, EBV, Parvo B19)
• Drugs (genetic metabolization defects)
– Constitutional• Shwachman-Diamond syndrome (+anemia, pancreatic insufficiency,
chondrodysplasia)– SBDS mutation (nucleolus & mitotic dysfunctions)
• Severe or cyclic congenital neutropenia– ELANE or HAX1 mutations (elastase misfolding, anti-apoptotic failure increased intramedullary neutrophilic apoptosis); GCSF sensitive
– CSF3R mutations – GCSF-resistant
• Fanconi & Dyskeratosis congenita
Congenital thrombopenias
• Low platelets, hypo-/amegakaryopoiesis = proliferation defects/amegakaryocytic thrombopenia
– Acquired (viruses)
– Constitutional• Fanconi, Dyskeratosis congenita, Shwachmann-Diamond syndrome
• Thrombocytopenia with absent radii syndrome
• Congenital amegakaryocytic thrombopenia
– MPL mutation (THPO high, no response to THPO)
Congenital thrombopenias
• Low platelets, increased megakaryopoiesis = increased consumption/megakaryocytic thrombopenia
– Acquired• Alloimmune
• Parainfectious
– Constitutional• With large platelets
– Grey platelet syndrome and other (GATA1, MYH9 … mutations) platelet defects (+myelofibrosis, ± hypo-/alobated megas)
• With small platelets
– Wiskott-Aldrich syndrome (+eczema & infections, hypolobated megas)