Blood and BM Path Chapter 5 - Pathology of the Marrow Flashcards
(39 cards)
Cells that are not captured well by bone marrow aspirate
Megakaryocytes and macrophages
Hypo- and Hyper-cellularity cutoffs
Hypo: <25% cells
Hyper: >75% cells
Typical M:E ratio
BM Smear: 2.0-8.3
Histologic section: 1.5-3.0
Kala azar
Visceral leishmaniasis
Pearson syndrome
Mitochondrial cytopathy with recognizable features on BM biopsy.
Most cases are sporadic, but can be maternally (mitochondrially) or autosomally inherited.
Characterized by sideroblastic anemia with pancytopenia, exocrine pancreatic dysfunction, and hepatic dysfunction.
Histologically, BM reveals a hypoplastic anemia with ringed sideroblasts and vacuoles in many cell lineages.
Reactive plasmacytosis vs multiple myeloma
What is the normal kappa / lambda ratio?
About 2:1
Langerhans cell histiocytosis
Clonal proliferation of Langerhans cells
Characteristic LCH features: Cells are CD1a and S100 positive, have Birbeck granules on EM.
Has a peak incidence in childhood (~5-10 years of age).
Often causes osseous swelling and pathologic fractures. Appears as an osteolytic lesion on X-ray. The skull is the most common site.
May be accompanied by a brown-to-purple papular or eczematous rash. Hepatosplenomegaly and lymphadenopathy are often present. Hypopitutarism is an important assocation, and may manifest as central diabetes insipidus.
Juvenile xanthogranuloma
Benign proliferative histiocytic proliferation. Most commonly seen in kids (hence juvenile).
Clinical: Solitary red-brown, yellowish papule or nodule.
Histological: Presence of histiocytes, foam cells, and Touton giant cells (the fat-filled type).
Generally spontaneously resolve after a few years.
Erdheimer-Chester disease
Clonal proliferation of histiocytes
Almost always involves bone, especially bones of the lower extremities. ~50% of cases also have extraosseous manifestations (retroperitoneal, cardiovascular, lungs, kidneys). Caused by an activating mutation in the MAPK pathway.
Clinical: Bone pain in the distral extremities. Other symptoms depend on site involved. May be totally asymptomatic or lethal (wide range).
Serology: Unique cytokine profile of high IFN-a, IL-12, MCP-1, and low IL-4 and IL-7.
Histology: Infiltrate of bland-apperaing foamy histiocytes with surrounding fibrosis. Touton giant cells are often present.
Hemophagocytic lymphohistiocytosis
May be familial or sporadic
Familial form is an autosomal recessive progressive disease starting from a young age. There is decreased NK cell function. Mutations are often in perforin. Acquired form is often associated with some immunodeficiency and may be triggered by infection, malignancy, GVHD, or HELLP.
Generally caused by a failure of NK cells to elimiate targets of anitenicity and ensuing immune frustration.
Clinical: Sudden onset SIRS with accompanying cytopenias, hepatosplenomegaly, and lymphadenopathy. Jaundice and rash may be present.
Histologic: Hemophagocytosis of all blood lineages.
Features that distinguish reactive from malignant marrow histiocytosis
- Pleomorphism of macrophages
- Features of atypia and immaturity
- Prominent nucleolus
- Dinstict, thick membrane
- Irregular nuclear chromatin
- Multinuclearity
- Presence of monoblasts and promonocytes among clusters of macrophages (shown)
Immunohistochemical / flow cytometry features of M0/MΦ
- CD68 positivity (macrosialin, not totally specific)
- CD163 positivity (quite specific for M0/MΦ)
Genetic etiologies of familial HLH
- Perforin loss-of-function or deletion (PRF1)
- SH2D1A (SAP) mutation, aka SLAM-associated protein. Acts as an adaptor for Fyn and thus promotes tyrosine kinase activity.
- UNC13D mutation (encodes MUNC13-4, which is vital for cytolytic granule fusion)
- STX11 mutation (member of the t-SNARE family, also associated with vesicle fusion).
Chediak-Higashi syndrome
Autosomal recessive disorder
Homozygous LoF in the Lyosomal trafficking regulator (LYST) gene.
Defect in microtubule polymerization and chemotaxis of neutrophils, ultimately resulting in defective phagosome-lysosome fusion.
Clinically characterized by recurrent pyogenic infections, partial albinism, peripheral neuropathy, and HLH.
Histologically associated with giant cytoplasmic granules in granulocytes and platelets, often with pancytopenia.
Treatment is HSC transplant.
Griscelli syndrome
Autosomal recessive
Three “types” with different genetic origins and clinical manifestations:
- Type 1: Myosin Va mutation (Ch 15q21). Silver-gray hair and neurologic abnormalities. Developmental delay, hypotonia, seizures. Supportive care.
- Type 2: Rab27a mutation (Ch15q21). Silver-gray hair and immunodeficiency. Predisposed to HLH and hypogammaglobulinemia. Treat with HSC transplant.
- Type 3: MLPH mutation (2q37.3), F exon of Myosin Va. No neurologic or immunologic abnormalities. Cosmetic issue only, no treatment necessary.
Microscopically, all types demonstrate large clumps of pigment distributed irregularly along the hair shaft on hair microscopy. Biologically, the problem is that the pigment cannot be distributed due to the defective actin-myosin-Rab system.
X-linked lymphoproliferative syndrome
Divided into XLP1 (or classic XLP) and XLP2
- Both:
- Exaggerated response to EBV infection.
- Without treatment, most survive only into childhood. HLH is the most common cause of death.
XLP1: Mutation in SH2D1A, aka SLAM-associated protein. An adaptor for Fyn tyrosine kinase. 33% will develop a lymphoma of some sort. 33% have dsygammaglobulinemia.
XLP2: Mutation in XIAP, aka X-linked inhibitor of apoptosis. It works with TRAF-1 and TRAF-2 and serves to inhibit caspase activity. More likely to have HLH outside the context of EBV infection. May have splenomegaly and VEO-IBD.
Wiskott-Aldrich syndrome
- X-linked recessive inheritance
- Mutation in WAS, gene product is WASp
- WASp functions to activate actin polymerization and serve as a nucleation-promoting factor for Arf2/3. In T cells, WASp controls the cytoskeletal rearrangement enabling formation of the immunological synapse.
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Wiskott-Aldrich triad:
- Thrombocytopenia
- Atopy/Eczema
- Immunodeficiency
- Microscopically characterized by eosinophilia and microplatelets.
- Leukocytes in WAS patients also have defective CD43 expression (normally on most lymphocytes, monocytes, granulocytes).
Lysinuric protein intolerance
Metabolic disorder resulting in inability to metabolize lysine, arginine, and ornithine.
Caused by an autosomal recessively inherited mutation in SLC7A7, a basolaterally expressed cationic amino acid transporter. Classically thought of as a urea cycle disorder. However, arginine becomes trapped inside of cells due to loss of this transporter, resulting in excessive arginase activity and NO2 production. This can result in pulmonary alveolar proteinosis, renal disease, and HLH. Erythropoiesis is also defective in these patients, as HSCs lack arginine to reproduce due to serum hypoargininemia.
Clinically manifests as postprandial nausea and vomiting which develop after infants are weaned from milk onto solids along with immunodeficiency and predispositon to HLH and PAP. Other signs and symptoms are related to failure to thrive.
Treated with special diet.
Hermansky-Pudlak syndrome
Caused by mutations in several genes (HPS proteins, AP3B1, and dysbindin), all of which show autosomal recessive inheritance.
Disorder characterized by “occulocutaneous albinism.”
Clinically manifests as fair skin and white or light-colored hair, reduced retinal pigment with visual impairment, nystagmus, and photophobia. Virtually 100% of these patients have some degree of pulmonary fibrosis. These patients also have increased risk of skin cancers. Other assocations include platelet dysfunction, granulomatous colitis, and immunodeficiency with increased risk of HLH.
On TEM, platelets lack dense bodies.
Most cases of acquired HLH have. . .
. . . a predisposing acquired immunodeficiency or fulminant bloodborne infection
For example, HIV infection, post-transplant immunosuppression, malignancy, or autoimmunity.
Isolated granulocyte phagocytosis
May be seen in drug-induced agranulocytosis
Isolated erythrocytic phagocytosis
May be observed in antibody-mediated hemolytic diseases:
Autoimmune hemolytic anemia, paroxysmal cold hemoglobinuria, malaria, transfusion reaction (acquired alloantibody)
Tons of these cells are seen in the blood and marrow of a kid with failure to thrive. What is the diagnosis?
Some form of lysosomal or mucopolysaccharide storage disease.
This particular image is from a child with Niemann Pick.
