Genetic / Multi system Flashcards
(133 cards)
1
Q
Cystic fibrosis is an inherited disorder of x that affects fluid secretion in x glands and in the epithelial lining of the x,x and x
Clinical presentation
A
abnormal transport of chloride and bicarbonate ions mediated by an anion channel encoded by the cystic fibrosis transmembrane conductance regulator (CFTR)
that affects fluid secretion in exocrine glands and in the epithelial lining of the respiratory, gastrointestinal, and reproductive tracts.
In many individuals this disorder leads to abnormally viscous secretions that obstruct organ passages, resulting in most of the clinical features of this disorder, such as chronic lung disease secondary to recurrent infections, pancreatic insufficiency, steatorrhea, malnutrition, hepatic cirrhosis, intestinal obstruction, and male infertility. These manifestations may appear at any point in life from before birth to much later in childhood or even in adolescence.
Although cystic fibrosis follows an autosomal recessive transmission pattern, recent data suggest that even heterozygote carriers have a higher incidence of respiratory and pancreatic disease compared with the general population.
2
Q
The primary defect in cystic fibrosis is abnormal transport of …
A
chloride and bicarbonate ions mediated by an anion channel encoded by the cystic fibrosis transmembrane conductance regulator (CFTR) gene on chromosome 7q31.2
3
Q
The many clinical manifestations of mutations in the cystic fibrosis gene, from most severe to asymptomatic.
A
4
Q
Pancreatic abnormalities are present in approximately x% of patients with cystic fibrosis.
A
85% to 90%
Exocrine pancreatic insufficiency occurs in the majority (85% to 90%) of patients with cystic fibrosis and is associated with “severe” CFTR mutations on both alleles (e.g., ΔF508/ΔF508), whereas 10% to 15% of patients with one “severe” and one “mild” CFTR mutation (e.g., ΔF508/R117H)
In milder cases, there may be only accumulation of mucus in the small ducts with some dilation of the exocrine glands. In more severe cases, usually seen in older children or adolescents, the ducts are completely plugged, causing atrophy of the exocrine glands and progressive fibrosis
5
Q
CF. Over time, focal biliary cirrhosis develops in approximately x
Endocrine pancreatic insufficiency (i.e., diabetes mellitus) occurs in up to x% of adults with cystic fibrosis and is thought to be caused by severe destruction of pancreatic parenchyma including the islets.
A
one-third of patients
50%
6
Q
Azoospermia and infertility are found in x% of males who survive to adulthood; congenital bilateral absence of the vas deferens is a frequent finding in these patients.
In some males, bilateral absence of the vas deferens may be the only feature suggesting an underlying CFTR mutation.
A
95%
7
Q
Most common cause of death (~80%) in cystic fibrosis?
A
Cardiorespiratory complications, such as persistent lung infections, obstructive pulmonary disease, and cor pulmonale, are the
8
Q
Clinical Features and Diagnostic Criteria for Cystic Fibrosis
A
9
Q
A
10
Q
Melanoma is the most deadly of all skin cancers and is strongly linked to acquired mutations caused by x (exposure to ?)
A
exposure to UV radiation in sunlight.
11
Q
The great preponderance of melanoma arises in the skin; other sites of origin include the x
A
oral and anogenital mucosal surfaces (i.e., oropharynx, gastrointestinal and genitourinary tracts), the esophagus, the meninges, and the uvea of the eye
12
Q
In about x% of affected patients, the risk of melanoma is inherited as an autosomal dominant trait with variable penetrance.
A
10% to 15%
13
Q
Once a melanoma is excised, a number of pathologic features are used to gauge the probability of metastatic spread and prognosis. One model used to predict outcome is based in part on the following pathologic variables:
A
(1) tumor depth of invasion(Breslow thickness), (2) number of mitoses, (3) evidence of tumor regression (presumably due to the host immune response), (4) ulceration of overlying skin, (5) presence and number of tumor-infiltrating lymphocytes, and (6) location (central body or extremity).
14
Q
The most important cause of cutaneous squamous cell carcinoma is DNA damage induced by exposure to UV light. Tumor incidence is proportional to the degree of lifetime sun exposure. A second common association is with x
A
immunosuppression
15
Q
The term neuroblastic tumor includes tumors of the sympathetic ganglia and adrenal medulla that are derived from primordial neural crest cells populating these sites.
Neuroblastoma is the most important member of this family. It is the (how common) extracranial solid tumor of childhood, and the x diagnosed infant malignancy.
The median age at diagnosis is x months; approximately 40% of cases are diagnosed in infancy.
A
most common
most frequently
18
16
Q
In childhood, about x% of neuroblastomas arise in the adrenal medulla.
A
40%
The remainder occur anywhere along the sympathetic chain, with the most common locations being the paravertebral region of the abdomen (25%) and posterior mediastinum (15%). Tumors may arise in numerous other sites, including the pelvis, the neck, and within the brain (cerebral neuroblastomas).
17
Q
Neuroblastomas
Metastases, when they develop, appear x
In addition to local infiltration and lymph node spread, there is a pronounced tendency to spread through the bloodstream to the …
A
early and widely.
In addition to local infiltration and lymph node spread, there is a pronounced tendency to spread through the bloodstream to the liver, lungs, bone marrow, and bones
18
Q
Prognostic Factors in Neuroblastomas
A
19
Q
International Neuroblastoma Staging System
A
20
Q
MEN-1, or Wermer syndrome, is a rare heritable disorder with a prevalence of about 2 per 100,000.
MEN-1 is characterized by abnormalities involving the
A
Parathyroid: Primary hyperparathyroidism is the most common manifestation of MEN-1 (80% to 95% of patients) and is the initial manifestation of the disorder in most patients, appearing in almost all patients by 40 to 50 years of age. Parathyroid abnormalities include both hyperplasia and adenomas.
Pancreas: Endocrine tumors of the pancreas are a leading cause of morbidity and mortality in persons with MEN-1. These tumors are usually aggressive and often present with metastatic disease. It is not uncommon to find multiple “microadenomas” scattered throughout the pancreas in conjunction with one or two dominant lesions. **gastrinomas and insulinomas most common
Pituitary: The most frequent anterior pituitary tumor encountered in MEN-1 is a prolactinoma; some patients develop acromegaly from somatotropin-secreting tumors.
In addition, carcinoid tumors, thyroid and adrenocortical adenomas, and lipomas are more frequent than in the general population.
21
Q
MEN-1 syndrome is caused by germline mutations in the MEN1 tumor suppressor gene, which encodes a protein called x.
A
menin
22
Q
MEN-2 is subclassified into three distinct syndromes:
A
MEN-2A, MEN-2B, and MEN-4.
23
Q
MEN-2A, or Sipple syndrome, is characterized by:
A
phaeochromocytoma, medullary carcinoma of the thyroid, and parathyroid hyperplasia
24
Q
MEN-2A is clinically and genetically distinct from MEN-1 and is caused by germline gain-of-function mutations in the x
A
RET protooncogene.
25
MEN-2B
Patients develop medullary thyroid carcinomas, which are usually multifocal and more aggressive than in MEN-2A, and pheochromocytomas.
Neuromas or ganglioneuromas involving the skin, oral mucosa, eyes, respiratory tract, and gastrointestinal tract, and a marfanoid habitus, with long axial skeletal features and hyperextensible joints
26
x is mutated in the germline of individuals with Li-Fraumeni syndrome, who have a greatly increased incidence of osteosarcoma.
TP53
27
BRCA1 and 2 associated cancers
and others
28
NF1
This is a common autosomal dominant disorder with a frequency of 1 in x.
It is a systemic disease associated with nonneoplastic manifestations and with a variety of tumors, including x.
3000
neurofibromas of all types, MPNSTs, gliomas of the optic nerve, other glial tumors and hamartomatous lesions, and pheochromocytomas
Other features include intellectual disability or seizures, skeletal defects, pigmented nodules of the iris (Lisch nodules), and cutaneous hyperpigmented macules (café au lait spots)
29
This is an autosomal dominant disorder resulting in a range of tumors, most commonly x
This disorder is much less common than NF1, having a frequency of 1 in x
This is an autosomal dominant disorder resulting in a range of tumors, most commonly bilateral eighth nerve schwannomas, multiple meningiomas, and ependymomas of the spinal cord. Many individuals with NF2 also have nonneoplastic lesions, which include nodular ingrowth of Schwann cells into the spinal cord (schwannosis), meningioangiomatosis (a proliferation of meningeal cells and blood vessels that grows into the brain), and glial hamartia (microscopic nodular collections of glial cells at abnormal locations, often in the superficial and deep layers of cerebral cortex).
This disorder is much less common than NF1, having a frequency of 1 in 40,000 to 50,000.
40,000 to 50,000.
30
Port wine stain in the distribution of the trigeminal nerve can be associated with x syndrome
Sturge-Weber syndrome
31
Marfan Approximately x% of cases are familial and transmitted by autosomal dominant inheritance. The remainder are sporadic and arise from new mutations.
70% to 85
32
Marfan phenotype
Skeletal abnormalities are the most striking feature of Marfan syndrome. Typically the patient is unusually tall with exceptionally long extremities and long, tapering fingers and toes. The joint ligaments in the hands and feet are lax, suggesting that the patient is double-jointed; typically the thumb can be hyperextended back to the wrist.The head is commonly dolichocephalic (long-headed) with bossing of the frontal eminences and prominent supraorbital ridges. A variety of spinal deformities may appear, including kyphosis, scoliosis, or rotation or slipping of the dorsal or lumbar vertebrae. The chest is classically deformed, presenting either pectus excavatum (deeply depressed sternum) or a pigeon-breast deformity.
Ocular changes take many forms. Most characteristic is bilateral subluxation or dislocation (usually outward and upward) of the lens, referred to as ectopia lentis. This abnormality, resulting from weakening of ciliary zonules, is so uncommon in persons who do not have this disease that the finding of bilateral ectopia lentis should raise the suspicion of Marfan syndrome.
Cardiovascular lesions are the most life-threatening features of this disorder. The two most common lesions are mitral valve prolapse, which occurs in 40% to 50% of cases and, of greater importance, dilation of the ascending aorta due to cystic medionecrosis. Histologically the changes in the media are virtually identical to those found in cystic medionecrosis not related to Marfan syndrome. Loss of medial support results in progressive dilation of the aortic valve ring and the root of the aorta, giving rise to severe aortic incompetence. Weakening of the media predisposes to an intimal tear, which may initiate an intramural hematoma that cleaves the layers of the media to produce aortic dissection. After cleaving the aortic layers for considerable distances, sometimes back to the root of the aorta or down to the iliac arteries, the hemorrhage often ruptures through the aortic wall.
33
Connective tissue disorder
As might be expected, tissues rich in collagen, such as skin, ligaments, and joints, are frequently involved in most variants of x
Ehlers-Danlos Syndromes (EDSs)
34
Rheumatoid arthritis (RA) is a x
Chronic autoimmune disorder that principally attacks the joints, producing a nonsuppurative proliferative and inflammatory synovitis
The autoimmune response in RA is initiated by CD4+ helper T cells.
35
Anti-citrullinated peptide antibodies (ACPAs) are diagnostic markers that can be detected in serum of up to x% of RA patients
70
It is estimated that 50% of the risk of developing RA is related to inherited genetic susceptibility.
36
RA typically affects small joints of the hands and feet. The characteristic histologic features include:
(1) synovial cell hyperplasia and proliferation;
(2) dense inflammatory infiltrates (frequently forming lymphoid follicles) of CD4+ helper T cells, B cells, plasma cells, dendritic cells, and macrophages
(3) increased vascularity due to angiogenesis
(4) fibrinopurulent exudate on the synovial and joint surfaces; and
(5) osteoclastic activity in subchondral bone, allowing the inflamed synovium to penetrate the bone and cause periarticular erosions and subchondral cysts.
Together, these changes produce the pannus, a mass of edematous synovium, inflammatory cells, granulation tissue, and fibroblasts that grows over and causes erosion of articular cartilage. In time, after the cartilage has been destroyed, the pannus bridges the apposing bones to form a fibrous ankylosis, which eventually ossifies and results in bone fusion, or bony ankylosis.
37
SLE is ...
an autoimmune disease involving multiple organs, characterized by a vast array of autoantibodies, particularly antinuclear antibodies (ANAs), in which injury is caused mainly by deposition of immune complexes and binding of antibodies to various cells and tissues.
38
The hallmark of SLE is the production of autoantibodies, several of which (x) are virtually diagnostic.
antibodies to double-stranded DNA and the so-called Smith [Sm] antigen
39
SLE demographics
SLE predominantly affects women, with a frequency of 1 in 700 among women of childbearing age and a female-to-male ratio of 9 : 1 in the reproductive age group of 17 to 55 years.
40
Criteria for Classification of Systemic Lupus Erythematosus
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Autoantibodies in Systemic Autoimmune Diseases
42
About 5% of Sjögren patients develop x, an incidence that is 40-fold greater than normal.
lymphoma
Certain other autoimmune disorders (e.g., Hashimoto thyroiditis) are also associated with a high risk of marginal zone lymphoma
43
x is characterized by: (1) chronic inflammation thought to be the result of autoimmunity, (2) widespread damage to small blood vessels, and (3) progressive interstitial and perivascular fibrosis in the skin and multiple organs.
Systemic sclerosis
44
Five groups of adults at high risk for developing AIDS
Men who have sex with men account for more than 50% of the reported cases
Heterosexual transmission, chiefly due to contact with members of other high-risk groups (e.g., intravenous drug users)
Intravenous drug users with no previous history of h sexuality are the next largest group, representing about 20% of infected individuals.
HIV infection of the newborn. Children of HIV-positive women are at risk for infection in utero, at birth, or through breast milk
Patients with hemophilia, especially those who received large amounts of factor VIII or factor IX concentrates before 1985, make up about 0.5% of all cases.
Recipients of blood and blood components who are not hemophiliacs but who received transfusions of HIV-infected whole blood or components (e.g., platelets, plasma) account for about 1% of patients. (Organs obtained from HIV-infected donors can also transmit the virus.)
45
AIDS-Defining Opportunistic Infections and Neoplasms Found in Patients With HIV Infection
46
The anatomic changes in the tissues are neither specific nor diagnostic. Common pathologic features of AIDS include ...
opportunistic infections, KS, and B-cell lymphomas
47
Amyloidosis is a disorder characterized by...
the extracellular deposits of misfolded proteins that aggregate to form insoluble fibrils.
48
Hemophilia A is inherited as x trait
an X-linked recessive and thus affects mainly males and homozygous females
About 30% of patients have no family history; their disease is caused by new mutations.
49
Comparative Features of Type 1 and Type 2 Diabetes
49
Comparative Features of Type 1 and Type 2 Diabetes
50
Glucose homeostasis is tightly regulated by three interrelated processes:
glucose production in the liver; glucose uptake and utilization by peripheral tissues, chiefly skeletal muscle; and actions of insulin and counter-regulatory hormones, including glucagon, on glucose uptake and metabolism.
51
The most important class of hormones responsible for promoting insulin secretion from pancreatic β cells following feeding is the
incretins
The two most important incretins are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), both secreted by cells in the intestines following oral food intake.
52
The most important locus is the x, which according to some estimates contributes as much as 50% of the genetic susceptibility for T1D.
HLA gene cluster
90-95% of caucasions have this compared to normal
53
The fundamental immune abnormality in x is a failure of self-tolerance in T cells specific for islet antigen
T1D
54
Pathogenesis of T2D
The development of T2D involves two key abnormalities:
* Insulin resistance: Decreased response of peripheral tissues, especially skeletal muscle, adipose tissue, and liver, to insulin
* β-cell dysfunction: Inadequate insulin secretion in the face of insulin resistance and hyperglycemia
Genetic susceptibility contributes to the pathogenesis, as evidenced by the disease concordance rate of greater than 90% in monozygotic twins, a rate higher than in T1D. Furthermore, first-degree relatives have 5- to 10-fold higher risk of developing T2D than those without a family history, when matched for age and weight.
The most important environmental risk factor for T2D is obesity, particularly central or visceral obesity. >80% of individuals with T2D are obese
Sleep disorders (such as obstructive sleep apnea) and circadian disruption are additional environmental risk factors for T2D.
55
Long-term complications of diabetes
56
T2D and diabetic nephropathy
Three lesions are encountered:
(1) g merular lesions; (2) renal vascular lesions, principally arteriolosclerosis; and (3) pyelonephritis, including necrotizing papillitis.
The most important glomerular lesions are capillary basement membrane thickening, diffuse mesangial sclerosis, and nodular glomerulosclerosis.
57
Nodular Glomerulosclerosis. This is also known as intercapillary glomerulosclerosis or x
Kimmelstiel-Wilson disease.
58
Macrovascular complications such as x,x and x are the most common causes of mortality in long-standing diabetes.
myocardial i tion, renal vascular insufficiency, and cerebrovascular accidents
59
x is a leading cause of end-stage renal disease in the United States.
Diabetic nephropathy
60
T1D is an autoimmune disease characterized by progressive x, leading to absolute insulin deficiency
destruction of islet β cells
61
Long-term complications of diabetes include both large-vessel disease (macroangiopathy), such as x as well as small vessel disease (microangiopathy), the latter manifesting mainly as x
atherosclerosis, ischemic heart disease, and lower extremity ischemia
retinopathy, nephropathy, and neuropathy.
62
Deposition of x is a characteristic feature of many insulinomas
amyloid
63
Sickle cell disease is a common hereditary hemoglobinopathy caused by a point mutation in x that promotes the polymerization of deoxygenated hemoglobin, leading to red cell distortion, hemolytic anemia, microvascular obstruction, and ischemic tissue damage.
β-globin
64
Hb types
Normal adult red cells contain mainly x, along with small amounts of x and x
HbA (α2 β2 )
HbA 2 (α2 δ2 )
fetal hemoglobin (HbF; α2γ2).
65
About x% of African Americans in the United States are heterozygous for HbS, a largely asymptomatic condition known as sickle cell trait.
The high prevalence of sickle cell trait in certain African populations stems from its protective effects against x
8% to 10%
falciparum malaria.
66
HbF inhibits the polymerization of HbS even more than HbA; hence, infants with sickle cell disease do not become symptomatic until they reach x of age, when the level of HbF normally falls.
5 or 6 months
67
In sickle cell anemia, the peripheral blood demonstrates variable numbers of x, reticulocytosis, and target cells, which result from red cell dehydration.
Howell-Jolly bodies (small nuclear remnants) also are present in red cells due to x.
The bone marrow is hyperplastic as a result of a compensatory erythroid hyperplasia. Marked expansion of the marrow leads to bone resorption and secondary new bone formation, producing prominent x.
Extramedullary hematopoiesis may also appear.The increased breakdown of hemoglobin may cause hyperbilirubinemia and formation of pigment gallstones.
irreversibly sickled cells
asplenia
cheekbones and changes in the skull that resemble a “crewcut” on radiographic studies
68
Changes in spleen in sickle cell anaemia
In early childhood, the spleen is enlarged (up to 500 g) by red pulp congestion caused by the trapping of sickled red cells in the cords and sinuses.
With time, however, chronic erythrostasis leads to splenic infarction, fibrosis, and progressive shrinkage, so that by adolescence or early adulthood only a small nubbin of fibrous splenic tissue is left, a process called autosplenectomy
69
Sickle cell disease
Vaso-occlusive crises, also called pain crises, are episodes of hypoxic injury and infarction that cause severe pain in the affected region. Although x,x and x (all of which favor sickling) may act as triggers, in most instances no predisposing cause is identified. The most commonly involved sites are the bones, lungs, liver, brain, spleen, and penis.
infection, dehydration, and acidosis
70
Sickle cell
Aplastic crises stem from the infection of red cell progenitors by x, which causes a transient cessation of erythropoiesis and a sudden worsening of the anemia.
parvovirus B19
71
Thalassemia is a genetically heterogeneous disorder caused by germline mutations that x of either α-globin or β-globin, leading to anemia, tissue hypoxia, and red cell hemolysis related to the imbalance in globin chain synthesis.
decrease the synthesis
72
Sickle cell disease. β?
(1) x mutations, associated with absent β-globin synthesis, and
(2) x mutations, characterized by reduced (but detectable) β-globin synthesis.
β0
β +
Impaired β-globin synthesis results in anemia by two mechanisms. The deficit in HbA synthesis produces “underhemoglobinized” hypochromic, microcytic red cells with subnormal oxygen transport capacity. Even more important is the diminished survival of red cells and their precursors, which results from the imbalance in α- and β-globin synthesis.
73
Consequences of severe β-thalassemia:
ineffective erythropoiesis in the setting of severe uncompensated anemia leads to massive erythroid hyperplasia in the marrow and extensive extramedullary hematopoiesis. The expanding mass of red cell precursors erodes the bony cortex, impairs bone growth, and produces skeletal abnormalities . Extramedullary hematopoiesis involves the liver, spleen, and lymph nodes, and in extreme cases produces extraosseous masses in the thorax, abdomen, and pelvis.
Another serious complication of ineffective erythropoiesis is excessive absorption of dietary iron. Erythroid precursors secrete a hormone called erythroferrone that inhibits production of hepcidin, a key negative regulator of iron uptake in the gut (described later in this chapter). In thalessemia, the marked expansion of erythroid precursors leads to increased absorption of iron from the gut, and this together with repeated blood transfusions inevitably lead to severe iron accumulation (secondary hemochromatosis) unless preventive steps are taken. Injury to parenchymal organs, particularly the heart and liver, often follows
74
Clinical and Genetic Classification of Thalassemia
75
Context of leukaemia/lymphoma
When present, proliferation centers are pathognomonic for x
CLL/SLL - chronic/small
76
CLL/SLL has a distinctive i phenotype. The tumor cells express the pan B-cell markers x and x, as well as x and x
CD19 and CD20
CD23 and CD5
Low-level expression of surface Ig (usually IgM or IgM and IgD) is also typical, as is high-level expression of BCL2.
77
Favorable prognostic markers for ALL include
(1) age between 2 and 10 years; (2) a low white cell count; (3) hyperdiploidy; (4) trisomy of chromosomes 4, 7, and 10; and (5) the presence of a t(12;21).
78
Another factor that impacts patient survival is the tendency of CLL/SLL to transform to a more aggressive tumor. Most commonly this takes the form of a transformation to x
diffuse large B-cell lymphoma (DLBCL), so-called Richter syndrome
79
x is the most common form of indolent NHL in the United States, trailing only x in frequency among lymphomas.
Follicular lymphoma
diffuse large B-cell lymphoma
80
Follicular lymphoma is strongly associated with chromosomal translocations involving x
BCL2
Its hallmark is a (14;18) translocation that juxtaposes the IGH locus on chromosome 14 and the BCL2 locus on chromosome 18.
Although incurable, it usually follows an indolent waxing and waning course
81
x is the most common form of NHL
Diffuse large B-cell lymphoma (DLBCL)
82
Within the category of Burkitt lymphoma fall three classes:
(1) African (endemic) Burkitt lymphoma
(2) sporadic (nonendemic) Burkitt lymphoma
(3) a subset of aggressive lymphomas occurring in individuals infected with HIV
83
All forms of Burkitt lymphoma are associated with translocations of the x gene on chromosome 8 that lead to x
MYC
increased MYC protein levels
Burkitt lymphoma is among the fastest-growing human tumors
The MYC translocation partner is usually the IGH locus [t(8;14)]
84
x% endemic Burkitt lymphomas are latently infected with EBV, which also is present in about x of HIV-associated tumors and x of sporadic cases.
all ~100%
25%
15% to 20%
85
Both endemic and sporadic Burkitt lymphomas are found mainly in x(age group)
children or young adults
Burkitt lymphoma is very aggressive but responds well to intensive chemotherapy. Most children and young adults can be cured. The outcome is more guarded in older adults.
86
Marginal lymphoma
They often arise within tissues involved by chronic inflammatory disorders of autoimmune or infectious etiology; x
examples include the salivary gland in Sjögren disease, the thyroid gland in Hashimoto thyroiditis, and the stomach in Helicobacter gastritis.
* They remain localized for prolonged periods, spreading systemically only late in their course.
* They may regress if the inciting agent (e.g., H. pylori) is eradicated.
87
Mantle Cell Lymphoma
Highly associated with translocations involving the x
Hairy Cell Leukemia
Highly associated with mutations in the x
cyclin D1 gene
BRAF serine/threonine kinase.
88
all peripheral T-cell lymphomas are derived from mature T cells. They usually express CD...
CD2, CD3, CD5, and either αβ or γδ T-cell receptors. Some also express CD4 or CD8
Although cures of peripheral T-cell l phoma have been reported, these tumors have a significantly worse prognosis than comparably aggressive mature B-cell neoplasms (e.g., DLBCL).
89
Extranodal NK/T-cell lymphoma is highly associated with x (i.e virus/bacteria/fungus)
Epstein-Barr virus (EBV).
90
Multiple myeloma is a plasma cell neoplasm commonly associated with x(clinical)
lytic bone lesions, hypercalcemia, renal failure, and acquired immune abnormalities.
91
Multiple myeloma usually presents as destructive plasma cell tumors (plasmacytomas) involving the axial skeleton.
The bones most commonly affected (in descending order of frequency) are the x
vertebral column, ribs, skull, pelvis, femur, clavicle, and scapula.
92
Clinical features of MM
CRAB criteria
The clinical features of multiple myeloma stem from (1) the effects of plasma cell growth in tissues, particularly the bones; (2) the production of excessive Igs, which often have abnormal physicochemical properties; and (3) the suppression of normal humoral immunity.
Bone resorption often leads to pathologic fractures and chronic pain. The attendant hypercalcemia can give rise to neurologic manifestations, such as confusion, weakness, lethargy, constipation, and polyuria, and contributes to renal dysfunction. Decreased production of normal Igs sets the stage for recurrent bacterial infections. Cellular immunity is relatively unaffected. Of great significance is renal insufficiency, which trails only infections as a cause of death. The pathogenesis of renal failure (Chapter 20), which occurs in up to 50% of patients, is multifactorial. However, the single most important factor seems to be Bence Jones proteinuria
CRAB criteria (hypercalcemia, renal dysfunction, anemia, and bone lesions).
93
Monoclonal Gammopathy of Undetermined Significance
By definition, patients are asymptomatic and the serum M protein level is less than 3 g/dL. <10% plasma cells marrow cellularity
Approximately 1% of patients with MGUS develop a symptomatic plasma cell neoplasm, usually multiple myeloma, per year.
Smoldering Myeloma
This entity defines a middle ground between multiple myeloma and MGUS. Plasma cells make up 10% to 30% of the marrow cellularity, and the serum M protein level is greater than 3 g/dL, but patients are asymptomatic. About 75% of patients progress to multiple myeloma over a 15-year period.
94
Lymphoplasmacytic lymphoma is a B-cell neoplasm of older adults that usually presents in the sixth or seventh decade of life. Although superficially resembling CLL/SLL, it differs in that a substantial fraction of the tumor cells undergo terminal differentiation to plasma cells. Most commonly, the plasma cell component secretes monoclonal IgM, often in amounts sufficient to cause a hyperviscosity syndrome known as x
Waldenström macroglobulinemia.
95
Solitary osseous plasmacytoma: solitary bone lesion identical to disseminated myeloma; ?(time frame) progresion to MM
most progress to myeloma within 7 to 10 years.
96
Differences Between Hodgkin and Non-Hodgkin Lymphomas
97
Hodgkin lymphoma arises in a single node or chain of nodes and spreads first to x lymphoid tissues.
Morphologically, the distinctive feature of Hodgkin lymphoma is the presence of neoplastic giant cells called x
anatomically contiguous
Reed-Sternberg cells
It was the first human cancer to be successfully treated with radiation therapy and chemotherapy and is curable in most cases
98
The WHO classification recognizes five subtypes of Hodgkin lymphoma:
1. Nodular sclerosis
Most common
2. Mixed cellularity
Diagnostic Reed-Sternberg cells and mononuclear variants are usually plentiful.The Reed-Sternberg cells are infected with EBV in about 70% of cases.
3. Lymphocyte-rich
4. Lymphocyte depletion
5. Nodular lymphocyte predominance
99
Activation of the transcription factor x is a common event in classic Hodgkin lymphoma and turns on genes that are believed to promote the growth and survival of Reed-Sternberg cells.
NF-κB
100
Hodgkin lymphoma must be distinguished from other conditions in which cells resembling Reed-Sternberg cells may be seen, x.
such as infectious mononucleosis, solid tissue cancers, and large-cell NHLs
The diagnosis of Hodgkin lymphoma depends on the identification of Reed-Sternberg cells in a background of nonneoplastic inflammatory cells. Reed-Sternberg cells also have a characteristic immunohistochemical profile, a feature that is used to confirm the morphologic impression. ?CD15+, CD30+
101
The spread of Hodgkin lymphoma is remarkably stereotypic:
nodal disease first, then splenic disease, hepatic disease, and finally involvement of the marrow and other tissues.
102
The diagnosis of AML is based on the presence of at least x% myeloid blasts in the bone marrow.
20%
The cytoplasm often contains fine, peroxidase-positive azurophilic granules. Auer rods, distinctive needle-like azurophilic granules, are present in many cases; they are particularly numerous in AML
103
The term “myelodysplastic syndrome” refers to a group of clonal stem cell disorders characterized by maturation defects that are associated with ineffective hematopoiesis and a high risk of transformation to x
Primary MDS is predominantly a disease of older adults; the mean age of onset is x years
AML
70
104
The common pathogenic feature of myeloproliferative neoplasms is the presence of mutated, constitutively activated x that lead to growth factor independence.
tyrosine kinases or other acquired aberrations in signaling pathways
105
CML is distinguished from other myeloproliferative neoplasms by the presence of a x gene
chimeric BCR-ABL derived from portions of the BCR gene on chromosome 22 and the ABL gene on chromosome 9
In more than 90% of cases, BCR-ABL is created by a reciprocal (9;22)(q34;q11) translocation (the so-called Philadelphia chromosome [Ph])
106
Polycythemia vera (PCV) is characterized by x
increased marrow production of red cells, granulocytes, and platelets (panmyelosis), but it is the increase in red cells (polycythemia) that is responsible for most of the clinical symptoms. PCV must be differentiated from relative polycythemia resulting from hemoconcentration and other causes of absolute polycythemia
107
In PCV, the transformed progenitor cells have markedly decreased requirements for erythropoietin and other hematopoietic growth factors due to activating mutations in the x
tyrosine kinase JAK2
More than 97% of cases are associated with a mutation in JAK2
108
Late in the course, PCV often progresses to a x characterized by extensive marrow fibrosis that displaces hematopoietic cells.
spent phase
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The abnormal blood flow and platelet function that accompany PCV lead to an increased risk of ...
major bleeding and thrombotic episodes
110
Essential thrombocytosis (ET) is associated with diverse mutations that increase x signaling and mimic constitutive growth factor receptor signaling.
JAK-STAT
Over 90% of cases have either activating mutations in JAK2 (approximately 50% to 60% of cases); MPL (5% to 10% of cases),
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Essential thrombocytosis (ET) clinical features
Platelets are not only increased in number but also frequently demonstrate qualitative abnormalities in functional tests. The types of thrombotic events resemble those observed in PCV; they include deep venous thrombosis, portal and hepatic vein thrombosis, and myocardial infarction. One characteristic symptom is erythromelalgia, a throbbing and burning of hands and feet caused by occlusion of small arterioles by platelet aggregates, which also may be seen in PCV.
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The genetics of primary myelofibrosis, approximately x% cases have activating mutations of JAK2, CALR, or MPL.
90%
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Langerhans Cell Histiocytosis
The term histiocytosis is an “umbrella” designation for a variety of proliferative disorders of x
dendritic cells or macrophages.
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The presence of x in the cytoplasm is characteristic of LCH
Birbeck granules
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Multifocal multisystem Langerhans cell histiocytosis (LettererSiwe disease)
Occurs most frequently before 2 years of age
A dominant clinical feature is the development of cutaneous lesions resembling a seborrheic eruption, which is caused by infiltrates of Langerhans cells over the front and back of the trunk and on the scalp
Most of those affected have concurrent hepatosplenomegaly, lymphadenopathy, pulmonary lesions, and (eventually) destructive osteolytic bone lesions. Extensive infiltration of the marrow often leads to anemia, thrombocytopenia, and a predisposition to recurrent infections, such as otitis media and mastoiditis.
The course of untreated disease is rapidly fatal. With intensive chemotherapy, 50% of patients survive 5 years.
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The combination of calvarial bone defects, diabetes insipidus, and exophthalmos is referred to as the x
Hand-Schüller-Christian triad
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The combination of x is referred to as the Hand-Schüller-Christian triad
Calvarial bone defects, diabetes insipidus, and exophthalmos
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Pulmonary Langerhans cell histiocytosis represents a special category of disease, most often seen in adult smokers, which may regress spontaneously upon cessation of smoking. These lesions have been described as reactive proliferations of Langerhans cells, but fully 40% are associated with x mutations, suggesting that in many instances they too are neoplastic in origin
BRAF
Young smokers
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Chronic immune thrombocytopenic purpura (ITP) is caused by autoantibody-mediated destruction of platelets.
It can occur in the setting of a variety of predisposing conditions and exposures (secondary) or in the absence of any known risk factors (primary or idiopathic).
The contexts in which chronic ITP occurs secondarily are numerous and include individuals with x
systemic lupus erythematosus, HIV infection, and B-cell neoplasms such as chronic lymphocytic leukemia
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The principal changes of thrombocytopenic purpura are found in the spleen, bone marrow, and blood, but they are not specific.
Secondary changes related to the bleeding diathesis may be found anywhere in the body.
The spleen is x. Typically, there is congestion of the sinusoids and enlargement of the splenic follicles, often associated with prominent reactive germinal centers. In many instances scattered megakaryocytes are found within the sinuses, possibly representing a mild form of extramedullary hematopoiesis driven by elevated levels of thrombopoietin.
The marrow reveals a modestly increased number of megakaryocytes. Some are apparently immature, with large, nonlobulated, single nuclei. These findings are not specific but merely reflect accelerated thrombopoiesis, being found in most forms of thrombocytopenia resulting from increased platelet destruction. The importance of bone marrow examination is to rule out thrombocytopenias resulting from marrow failure or other primary marrow disorders.
The secondary changes relate to hemorrhage, often in the form of petechial bleeds into the skin and mucous membranes. The peripheral blood often reveals abnormally large platelets (megathrombocytes), which are a sign of accelerated thrombopoiesis.
of normal size
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Like chronic ITP, acute ITP condition is caused by autoantibodies to platelets, but its clinical features and course are distinct.
Acute ITP is mainly a disease (age group) occurring with equal frequency in both sexes. Symptoms appear abruptly, often 1 to 2 weeks after a self-limited viral illness, which appears to trigger the development of autoantibodies through uncertain mechanisms. Unlike chronic ITP, acute ITP is self-limited, usually resolving spontaneously within 6 months.
of childhood
Glucocorticoids are given only if the thrombocytopenia is severe. In about 20% of children, usually those without a viral prodrome, thrombocytopenia persists; these children have a childhood form of chronic ITP that follows a course similar to the adult disease.
122
Takayasu arteritis classically involves the x
aortic arch
<50 years old
>50 years old aortitis is GCA
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PAN is a systemic vasculitis of small- or medium-sized muscular arteries that typically affects renal and visceral vessels but spares the x.
pulmonary circulation
124
There is no association with ANCAs, but x% patients with PAN have chronic hepatitis B
PAN is primarily a disease of (age group) but can occur in all age groups.
third
young adults
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Kawasaki disease is an acute, febrile, usually self-limited illness of infancy and childhood associated with x-sized vessel arteritis; x% of the patients are younger than 4 years of age.
large- to medium
80%
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x is a necrotizing vasculitis that generally affects capillaries as well as small arterioles and venules. Unlike PAN, all the lesions tend to be of the same age in any given patient, suggesting a single episode of antibody or immune complex deposition.
Microscopic polyangiitis
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GPA: Classic features include ...
bilateral pneumonitis with nodules and cavitary lesions (95%), chronic sinusitis (90%), mucosal ulcerations of the nasopharynx (75%), and renal disease (80%)
Renal lesions range from mild, focal glomerular necrosis with isolated capillary loop thrombosis (focal and segmental necrotizing glomerulonephritis) to more advanced glomerular lesions with diffuse necrosis with parietal cell proliferation resulting in crescent formation (crescentic glomerulonephritis).
128
Churg-Strauss syndrome (also called allergic granulomatosis and angiitis) is a small-vessel necrotizing vasculitis classically associated with x
Cutaneous involvement (with palpable purpura), gastrointestinal bleeding, and renal disease (primarily as focal and segmental glomerulosclerosis) are the major associations.
asthma, allergic rhinitis, lung infiltrates, peripheral eosinophilia, extravascular necrotizing granulomas, and a striking eosinophilic infiltration of vessels and tissues.
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Churg-Strauss vasculitis
x (ANCA) are present in a minority of cases, suggesting that the disorder is pathogenically heterogeneous.
The vascular lesions differ from those of PAN or microscopic polyangiitis by virtue of the presence of x
MPO-ANCAs
both granulomas and eosinophils.
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Fibromuscular dysplasia is a focal irregular thickening in medium and large muscular arteries including x
The cause is unknown. Segments of the vessel wall are focally thickened by a combination of medial and intimal hyperplasia and fibrosis, resulting in luminal stenosis. In the renal arteries, it can be a cause of renovascular hypertension. Immediately adjacent vessel segments can have markedly attenuated media (on angiography the vessels are said to have a “string of beads” appearance) leading to vascular outpouchings (aneurysms) that can rupture.
renal, carotid, splanchnic, and vertebral vessels.
131
PAN organs involved:
Kidney, heart, liver, and gastrointestinal tract vessels are involved in descending order of frequency.
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LCH pathology
Langerhans cell histiocytosis (LCG)
o Monoclonal neoplastic proliferation of an immature, dendritic cell population,
o BRAF mutation.
o Distinctive morphology: Folded or grooved nuclei; Bierbak granules tennis rackets
