Hematopoietic and lymphoreticular system Flashcards
DiGeorge syndrome (AKA: 22q11.2 microdeletion syndrome, also velocraniofacial syndrome)
- microdeletion on the long arm of chromosome 22, locus 11.2
- 3rd and 4th pharyngeal pouches, leading to thymus and parathyroid gland involvement respectively.
- sporadic mostly, but can be familial (AD)
- cardiac malformations, immunodeficiency, hypocalcemia, cleft palate
- associated cardiac anomalies include: Tetrology of Fallot, truncus arteriousus, and interrupted aortic arch, VSD is the commonest.
- cognitive deficits, schizophrenia
- milder phenotypes might go undiagnosed until later in childhood, presenting with recurrent infections, or go undetected
- molecular tests (such as FISH) on amniotic fluid prenatally, and blood, postnatally
- Echo. for the cardiac anomalies, and X-rays show absent thymic shadows
- low CD3+ T cell count
- Low Ca, PTH
- hypoxemia and cyanosis
- depletion of T cell zones on histologic exams
- DiGeorge-like phenotypes include: retinoids and ethanol exposure prenatally, without the chromosomal deletion, and HIV-induced immunosuppression
- Tr. includes: stem cell transplant, reconstructive surgery, calcium and vit.D supplements
- prognosis depends on the severity of immunosuppression and cardiac anomalies
Thymoma
*benign epithelial neoplasm
*it represents half of the anterior mediastinal tumors
*it is associated with autoimmune disorders, a third of thymoma patients also have mysthenia gravis
*typically presents in the 4th or 5th decades of life
*clinically, patients may exhibit signs and symptoms of superior vena cava syndrome, chest pain, dyspnea, manifestations of MG
*thymic abnormalities are seen in 75% of patients with AchR antibody-positive MG patients
*tumor may manifest incidentally
*imaging, electrodiagnostic and AchR antibody screening tests
*AchR antibodies are positive in most patients with thymoma and MG
*pathological picture:
Gross examination: firm gray-white mass ranging in size up to 20 cm.
Cytologically benign thymomas may be noninvasive or invasive.
Microscopic: The tumors are morphologically heterogeneous and consist
of a mixture of thymic epithelial cells without atypia and lymphocytes.
*Tr: surgery, chemoradiation if mass is unresectable, good prognosis if surgically removed, recurrence is rare
G6PD deficiency
*XR
*NADPH is deficient. It is required to reduce glutathione
*RBCs are susceptible to oxidative stress
*common in males of African or Mediterranean descent
*normochromic, normocytic anemia, indirect hyperbilirubinemia, hemoglobinuria, methemoglobinemia (Severe hemolysis due to G6PD deficiency may manifest as methemoglobinemia,4 in which the heme iron is in the oxidized ferric state rather than the ferrous state.5 This resultant hemoglobin, known as methemoglobin (met-Hb), cannot carry oxygen and the remaining oxyhemoglobin develops increased oxygen affinity resulting in impaired oxygen delivery. This results in a left shifted oxygen–hemoglobin dissociation curve and secondary tissue hypoxia. Normal people generate met-Hb but in very low levels in the range of 0.5% to 3%.), Heinz bodies (oxidized Hb), negative fluorescent spot test ( the qualititative fluorescent spot test, also known as Beutler test, is used to screen for enzyme defects such as G6PD def., and galactossemia), quantitative biochemical G6PD assay after the acute hemolytic episode wanes
*Triggers include: fava beans, exposure to oxidizing agents, infections
*there is no chronic, baseline hemolysis
*Tr. includes:
Treatment of underlying infection if applicable
Avoidance of medications that trigger hemolysis
Discontinuation of inciting medications
Hydration of patient during hemolytic episode
Normal life expectancy
*physiological correlate: G6PD synthesizes NADPH and reduced glutathione
(GSH) in the hexose monophosphate shunt; they provide protection against
antioxidants. In the absence of G6PD, RBCs are sensitive to oxidative stress.
As hemoglobin oxidizes, it precipitates into Heinz bodies that are cleared by
the spleen, leaving ‘bite’ cells.
*examples of drugs to be avoided: primaquine, sulfa drugs, nitrofurantoin, methylene blue
*
Cutaneous mastocytosis
- increased number of cutaneous mast cells due to mutated KIT gene
- it is the commonest form of urticaria pigmentosa
- clinically, urticaria, pruritus, bullae or pigmented macules or patches develop at skin sites exposed to local heat or irritation
- Darier’s sign: erythema, urticaria, and pruritus develop at skin sites upon stroking within minutes
- Ix: elevated tryptase level (Tryptase is an enzyme that is released, along with histamine and other chemicals, from mast cells when they are activated as part of a normal immune response as well as in allergic (hypersensitivity) responses.), normal CBC, mutation in KIT gene upon molecular testing
- Microscopic: numerous mast cells (mononuclear cells with heavy basophilic granulation) in the epidermis which stain positive for tryptase
Lymphoma-T cell lymphoma
*gain of function mutation in the NOTCH gene, leading to upregulation of transcription factors such as c-myc
*epi. common in young male adults and adolescents
*clinically: fever, night sweats, weight loss, 50% present with a mediastinal mass
*imaging studies, CT/MRI, biopsy, LP to exclude CNS
involvement
*<25% blasts that are positive for
-TdT, CD7, CD2, CD3
and negative for
-MPO
*Tr: chemo/radiotherapy, stem cell transplant
*5 year survival rate is 85%, prognosis is worse with advancing age
*cyclophosphamaide is commonly used to treat lymphoma, here is a couple of things you should know:
- it is an alkylating agent that binds guanine and hinders DNA replication
- along to bone marrow suppression, it causes hemorrhagic cystitis, that is dose-dependent, and for which Mesna is given as prophylaxis
Acute myeloid leukemia
*middle-aged adults
*CF: fatugue, fever, weight loss, elevated white blood cell count, anemia, thrombocytopenia, DIC
*leukocytosis with elevated blast count
Cytogenetics can identify translocations in certain subtypes:
t(15:17) PML-RARA in acute premyelocytic leukemia
*Auer rods in blasts on histopathology
*BM shows >20% blasts that stain positive for MPO, CD34
blasts that are positive for CD13, CD33
DDx: On peripheral blood smear, it is impossible to
distinguish myeloblasts from lymphoblasts unless Auer rods are seen (they are never seen in lymphoblasts). Acute lymphoblastic leukemia (ALL) more commonly affects children but can rarely affect adults. Determining the immunophenotype of the blasts, either by flow cytometry or staining of the bone marrow biopsy, clarifies the lineage of the blasts.
*the 5-year survival for adults is about 25%
*t(15:17) PML-RARA has better prognosis, treated aith all-trans retinoic acid
*FLT3 mutation has a worse prognosis
*all-trans retinoic acid (ATRA) is used to treat APL, it targets the fusion protein product which involves the retinoic acid receptor alpha RARA, binding to this receptor induces the differentiation of promyelocytes into myelocytes, side effects occur in the so-called “differentiation syndrome)
*Differentiation syndrome (DS), formerly known as retinoic acid syndrome, is the main life-threatening complication of therapy with differentiating agents (all-trans retinoic acid [ATRA] or arsenic trioxide [ATO]) in patients with acute promyelocytic leukemia (APL).
*
Myelodysplastic syndrome
*clonal stem cell disorder
*primary MDS, mean age>50
*secondary MDS, mean age is young adulthood in patients postchemotherapy/radiation,
Or in individuals with heritable disorder of DNA repair (ex: Fanconi anemia)
*epidemiology: it is a disease of older adults with male predominance.
Clinical features:
Epidemiology: it is a disease of older adults with a slight male predominance
*patients are asymptomatic and diagnosed when routine labs reveal cytopenias, symptoms of chest pain, fatigue, SOB, dizziness may be present
Dx: CBC cytopenia, mostly anemia
BM biopsy is confirmatory
*pathology:
Morphology: nucleated red blood cells with basophilic stippling (ribosomal inclusions) or Howell-Jolly bodies (DNA inclusions)
Microscopy: bone marrow is hypercellular with <20% blasts, fibrosis, with dysplasia in at least one cell line: Pelger-Huet cells (WBCs with
bilobed nuclei shaped like aviator sunglasses), ringed sideroblasts
(RBC precursors with iron granules), and “pawn ball” megakaryocytes (trilobed nuclei).
DDx: myeloproliferative neoplasms are clonal disorders of the bone marrow cell line
-essential thrombocytosis
-polycythemia vera (JAK2)
-chronic myeloid leukemia t(9;22)
Tr: treatment lines depend on the sverity, they could be merely conservative (blood transfusions for the cytopenias), or might include chemotherapeutic agents, or even stem cell transplantation in those with high risk of progression
*risk of progression increases as blast count approaches 20%, progression to AML is a poor prognostic sign
*risk of death is higher in patients with blast count>10%, severe cytopenia(s), complex karyotype, and older age.
ITP
*type two hypersensitivity reaction in which antibodies form against platelet surface antigens
*can be acute or chronic
-acute cases are seen in children following a viral infection
-chronic cases occur in women of child-bearing age, and they should be of a duration of at least 3 months to be considered chronic
-pt. tend to have a platelet count of less than 20,000
Dx:
- low pt. count on CBC
- the rest of the blood workup is normal
- increased megakaryocytes on bone marrow exam.
DDX:
- TTP (hemolytic anemia, neurological symptoms, fever, acute kidney injury + low pt.)
- Aplastic anemia (due to drugs or an infection), usually combined with a reduced WBC and/or RBC count
Tr:
Acute ITP is usually self-limited and unlikely to recur.
Corticosteroids and intravenous immunoglobulin (IVIG) are mainstays of therapy for chronic ITP; splenectomy is second-line.
Platelet transfusion is reserved for patients with ITP who are actively bleeding.
*ITP is class II hypersensitivity reaction
