46 terms

Myeloproliferative Disorders, Myelodysplastic Syndrome Leukemias, Lymphomas, and Plasma Cell Dyscrasias

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Myeloproliferative Disorders
-Definition
-Notable disorders in this category
Definition:
-A group of four disorders featuring abnormal proliferation of one or more BM hematopoietic cell lines.

Includes:
1. Polycythemia vera (PV)
2. Myelofibrosis
3. Essential (1o) Thrombocythemia
4. Chronic Myelogenous Leukemia (CML)
Myeloproliferative Disorders:
- Unifying Concepts
-Each disorder is caused by clonal expansion that arises from a pluripotent stem cell.

Result:
-Abnormal production of erythroid, myeloid, and megakaryocytic precursors in BM
* (reflected in PB smear & CBC results).

-Multiple BM cell lines are usually affected, although one cell line may dominate.
Myeloproliferative Disorders:
-Polycythemia Vera (PV)
Definition:
-A chronic myeloproliferative disorder of unknown cause characterized by ^'d Hgb concentration & ^ RBC mass

-Incidence: ~ 5/1,000,000 persons

-Slightly more common in MALES 1.4:1

-Mean age at diagnosis is 60 years old

-See PANMYELOSIS: ^ RBCs, WBCs, &Plts
Polycythemia Vera:
- Three classes of polycythemia
Relative:
-Due to low plasma volume:
* dehydration, burns, diuretics.

Secondary ="Reactive Polycythemia":
-Hypoxia, seen with smoking, high altitude, lung disease.

Primary = Polycythemia Vera:
-"Malignant" hematologic disorder, not self-limiting.
-Treated with phlebotomy, anti-neoplastic drugs.
Myeloproliferative Disorders:
-Polycythemia Vera (PV)
* Signs/Sxs:
-Expanded blood volume & hyperviscosity
* lead to:
+ weakness
+ headache
+ light-headedness
+ visual disturbances
+ fatigue
+ dyspnea

-Bleeding diathesis (tendency) is common (epistaxis)

-Pruritus is frequent

-Face may be red, retinal veins engorged

-Hepatomegaly frequent

-Splenomegaly in > 75% of patients
* is due to extramedullary hematopoiesis (takes place in liver as well)
* may be massive extending to the pelvic brim
* splenic infarcts common with massive swelling
Myeloproliferative Disorders:
-Polycythemia Vera (PV)
* Blood O2 & Viscosity
-Oxygen content of blood increased, but oxygen saturation of tissues is decreased

-Tissue hypoxia due to increased blood viscosity, causing problems with tissue perfusion & vessel thrombosis

-Raynaud's phenomenon is common

-Chronic cases result in increased cardiac output & increased capillary beds in an effort to decrease tissue hypoxia
Myeloproliferative Disorders:
-Polycythemia Vera (PV)
* Diagnosis
So, when should you consider PV in your differential diagnosis?
-When Hct is > 52% in white males
-When Hct is > 47% in blacks & females
-When Hgb is > 18 g/dL in white males
-When Hgb is > 16 g/dL in blacks & females

-Also, consider when elevations of all three blood cell lines (RBC, WBC & Platelets) occur, especially in conjunction with splenomegaly.
Myeloproliferative Disorders:
-Polycythemia Vera (PV)
* Highly suspect
Also likely to see:
- ^'d Uric acid levels due to ^'d nucleic acid (purine) turnover in > 30%


-Erythropoietin: low or undetectable

-RBC count > 6,000,000 /mm3

-BM is usually hypercellular (all cell lines)

-RBC survival time decreases in 25%
* resulting in anemia and myelofibrosis may develop during this phase.

Image shows: PV bone marrow (hypercellular)
Picture of normal bone marrow for comparison
Myeloproliferative Disorders:
-Polycythemia Vera (PV)
* Peripheral blood findings
-Immature WBCs

-Immature RBCs

-marked anisocytosis

-marked poikilocytosis:
* microcytes, elliptocytes, and DACROCYTES may be seen

-Neutrophilia with abnormal morphology

-Thrombocytosis with abnormal morphology & if function also abnormal: ^'d bleeding

Image shows: peripheral blood of PV. Little image shows a dacrocyte.
Myeloproliferative Disorders:
-Myelofibrosis
* Definition
* Major characteristics
Definition:
-Idiopathic condition in which BM becomes fibrotic

Characterized by:
-BM fibrosis
-Splenomegaly
-NORMOCYTIC/NORMOCHROMIC anemia
-with DACROCYTES
-MYELOID METAPLASIA:
* Extramedullary hematopoiesis, cells formed in liver & spleen
Myeloproliferative Disorders:
-Myelofibrosis
* Pathophysiology
-The hallmark of myelofibrosis is increased reticulin staining.

-However, increased reticulin can also be seen in patients with acute leukemias, especially acute myeloid leukemia (AML).

-Bone marrow fibrosis in childhood acute lymphoblastic leukemia correlates to biological factors, treatment response and outcome.
Myeloproliferative Disorders:
-Myelofibrosis
* Age
* Prognosis
* Dx
-Peak incidence 50-70 years

-Median survival 10 years from onset

-Dx by BM biopsy showing fibrosis, marrow aspiration commonly dry

-WBC & platelet counts frequently high initially, become low as disease progresses

Image shows: myelofibrosis bone marrow
Myeloproliferative Disorders:
-Myelofibrosis
* CBC & Peripheral Blood Smear
LEUKOERYTHROBLASTIC

Peripheral blood shows: immature WBCs and RBCs.

RBCs:
-Normocytic normochromic anemia
-mild poikilocytosis
-polychromatophilia & NRBCs
-DACROCYTES

WBCs:
-Initial leukocytosis with immature neutrophils (BANDS)

Platelets:
-Initially H/L/N
-Later thrombocytopenia
Myeloproliferative Disorders:
-Myelofibrosis
* Other conditions that manifest secondary myelofibrosis
Other conditions that manifest a "secondary myelofibrosis" as part of their respective disease courses:
-PV: 15-30% of cases
-Leukemias, lymphomas, multiple myeloma
-TB and osteomyelitis
-Myelodysplastic Syndrome MDS
-Exposure to benzene, X-Rays, Gamma Rays
Myeloproliferative:
-Essential (1o) Thrombocythemia
Definition:
-Idiopathic platelet count
-increase above 500,000/microL, in the absence of the features of the other myeloproliferative disorders.
-Seen in 50-70 yo

Characterized by:
-Markedly ^'d platelet count
-BM megakaryocyte hyperplasia
-Either a hemorrhagic or thrombotic tendency.
Myeloproliferative
-Essential 1o Thrombocythemia
* Diagnosis
-PLT 500,000 to 1,000,000

-Normal RBC mass

-LACK OF BM fibrosis

-ABSENCE of dacrocytes

-ABSENCE of "Philadelphia Chromosome" (CML)

PICTURE: Peripheral blood:
-Platelet aggregates, Giant Platelets, and Megakaryocyte fragments may be seen.
Myeloproliferative
-Essential 1o Thrombocythemia
* Ddx
Differentiate from causes of 2o Thrombocythemia:
-Acute infection
-Chronic inflammatory dz (RA, TB)
-Iron deficiency anemia
-Hemolysis
-Cancer
-Lymphoma
-Splenectomy

How?:
-Plt Count usu. < 1,000,000;
-Hx; PE
-normal platelet aggregation test in secondary thrombocythemia
Myelodysplasia Disorders (MDS)
-Definition
Myelodysplasia:
-A heterogenous group of disorders that result in ineffective hematopoiesis.

Definition:
1. Proliferation of ABN CLONES OF HEMATOPOIETIC CELLS IN BM, but with ineffective & ABN blood cell production >
> cytopenias >
> extramedullary hematapoiesis >
> Spleenomegaly, hepatomegaly

2. BM may be N or hypercellular & contains
< 30% blasts.

3. MDS disorders considered "pre-leukemic" condition > predilection to evolve into acute nonlymphocytic leukemias (ANLL/Acute Myelogenous Leukemia)

-Clonal stem cell disorders characterized by progressive cytopenia(s),
-usually in the presence of a hypercellular bone marrow although BM may be NORMAL.
-Usually, all 3 cell lines (myeloid/monocyte, erythroid, megakaryocyte) are involved.
Myelodysplasia Disorders (MDS):
-Sxs & CBC Picture
Patient sxs = Nonspecific:
-Fatigue
-weakness
-anorexia
-weight loss
-abdominal fullness.
-May have ^'d bleeding & infections.

CBC:
1. MACROCYTIC anemia with anisocytosis
2. THROMBOCYTOPENIA with variations in PLT size.
3. WBCs may be N/H/L
4. May see monocytosis and UP TO 5% BLASTs in PB (Merck p. 954).

[Consider this in any patient with refractory anemia, especially if it is macrocytic.]
Leukemias
Definition:
-Malignant neoplasms of the blood-forming tissues.
-A neoplasm is an uncontrolled proliferation of a malignant clone of a single cell line, with eventual marrow replacement by that cell line.

-Leukemic cells increase due to decreased rate of apoptosis
Leukemias
- 4 General Classifications
Acute: Immature cells (usually blasts) predominate.
1. ALL: acute lymphocytic leukemia
2. AML: acute myelogenous leukemia

Chronic: More mature cells are present.
3. CLL: chronic lymphocytic leukemia
4. CML: chronic myelogenous (thought to have slower onset)
Leukemias
-Etiologies
-Philadelphia chromosome in CML

-The human (HTLV) T-cell lymphotropic virus link to both leukemias & lymphomas

-Oncogenes possibly activated by chromosome abnormalities

-Environmental factors, EMF near schools

-Ionizing radiation and some chemicals (benzene & antineoplastics) associated with increased risk of leukemia, e.g.
Leukemias
1. Acute Lymphocytic Leukemia (ALL)
-Incidence
1. ALL - Acute Lymphocytic Leukemia:
-Most common malignancy in children
-Peak incidence 3-5 yrs.
-80% of cases in children.

-Second, lower peak in adults.

-Prognosis depends on factors present at dx:
* 3-7 years, total WBC < 25,000, no CNS dz (50/50), all fare the best.

(ALL CNS involvement = Meningeal infiltration leads to increased intracranial pressure leads to papilledema and cranial nerve palsies.)
Leukemias
2. Acute Myelogenous Leukemia (AML)
-Incidence
2. AML - Acute Myelogenous Leukemia:
-85-90% in adults.

-Also includes acute myelomonocytic leukemia (AMML) in adults

-Poor prognosis, especially patients > 50 years
Leukemias
3. Chronic Myelocytic Leukemia
-Incidence
3. CML - Chronic Myleocytic Leukemia:
-20% of all leukemias, both sexes affected

-Common btw. ages of 20-50, rare in childhood

-Poor prognosis

-Thrombocytosis connection:
* Malignant disorders, esp CML (malignancy is found in 50% of those with unexpected increased platelet counts)
Leukemias
4. Chronic Lymphocytic Leukemia
-Incidence
4. CLL - Chronic Lymphocytic Leukemia:
-30% of all leukemias

-Usually middle age to elderly

-Twice as common in men than women

-Average survival of 3-7 years after dx
Leukemias
1. Acute Lymphocytic Leukemia (ALL)
-Diagnosis
-Anemia in 90%

-Thrombocytopenia in 80% of cases

-WBC is variable: N/L/H

-LYMPHOBLASTS common in peripheral smear

-Always do BM exam as it is replaced by blast cells:
* MORE THAN 30% BLASTS IN MARROW usually means LEUKEMIA!
Leukemias
2. Acute Myelogenous Leukemia (AML)
-Diagnosis
-90% Anemia & thrombocytopenia

-WBC variable: N/L/H

-MYELOBLASTS common in peripheral blood

-As before, always do bone marrow exam.
* MORE THAN 30% BLASTS IN BM usually means LEUKEMIA!

-AUER RODS:
* Found in Blasts.
* Small, rod-shaped
* cytoplasmic elements.
* Thought to be abnormal lysosomes.

-In the Peripheral Blood:
* Increased segmented neutrophils
* Increased myelocytes
* Increased metamyelocytes

Picture shows: Myeloblast with Auer rods.
Leukemias
3. Chronic Myelocytic Leukemia
-Diagnosis
-CML in young adults > Philadelphia chromo in 95%

-Asymptomatic if WBC < 50,000

-Symptomatic if WBC 200,000-1,000,000

-Platelets high in 60%; low in 10%

-Some Blast forms in PB

-Absolute eosinophil & basophil counts increased

-Absolute lymphocytes & monocytes may be normal.
Leukemias
3. Chronic Myelocytic Leukemia
-Philadelphia Chromosome
-Reciprocal translocation between a portion of chromosome #9 and Chromosome #22

-Test is called "karyotyping"
Leukemias
-Chronic Lymphocytic Leukemia
-Middle & older ages

-PLT Low in 20-30%

-WBC 20-150,000/ml
* mature lymphocytes

-Dx is made from a sustained
* ABS lymphocytosis of > 5000/ml

-Generalized lymphadenopathy & hepatospleenomegaly

-Uncommon in Asians

-Dx is made from a sustained ABS lymphocytosis of > 5000/ml (N up to 4,000)
* Note: There is an expansion of mature appearing lymphocytes involving the lymph nodes and other lymphoid tissues with progressive infiltration of the bone marrow and circulating blood.

-Suspect CLL in any adult with an absolute lymphocytosis not explained by other causes, e.g. viral infection
Leukomias
-Chronic Leukemia
* Harry Cell Leukemia
-Neoplasm of B-lymphocytes

-Men 40-60 years

-Chronic course if untreated, mean 4 years

-Death is usually from infection

-Most common blood picture: NORMOCYTIC NORMOCHROMIC ANEMIA WITH PANCYTOPENIA in 60%

-Hairy cells are present in PB of 90% of patients

-Note:
* Hairy cells are similar in appearance to lymphocytes but the cytoplasm appears to have hairlike projections, or can be frayed.
* Bone marrow infiltration by hairy cells begins in small patches becoming more generalized over time.
Lymphomas
-Definition
-Types
Lymphomas are a heterogeneous group of neoplasms that arise in the lymphatic and reticuloendothelial (RE) systems.

Two major types:
1. Hodgkin's disease
2. Non-Hodgkin's lymphoma (NHL)

One other rare type:
3. Burkitt's Lymphoma
Lymphomas
1. Hodgkin's Lymphoma
-REED-STERNBERG CELLS:
* Dx is by lymph node biopsy showing them

-There can be a slight-to-moderate neutrophilia

-Lymphocytopenia can occur early & become pronounced with advanced disease

-EOSINOPHILIA is present in 20% of patients

-Thrombocytosis can be present

-Increased ESR & LAP reflect active disease

-Microcytic hypochromic anemia in advanced dz
* Note: With advanced disease a hypochromic microcytic anemia can develop.

Picture shows: Biopsy of a lymph node w/ Reed-Sternberg Cells
Lymphomas
1. Hodgkin's Lymphoma
-Age
-Etiology/Risk Factors
-Sx
-Bimodal age distribution,
* peaks age 15-34 & after age 60

-Spreads to CONTIGUOUS LYMPH NODES

-Etiology unknown, but twin studies have shown genetic component.

-Pt mb Hx of EBV, HIV, occupations (woodworkers)

-PAIN IN AFFECTED AREAS AFTER CONSUMING ALCOHOL

-FEVER, NIGHT SWEATs

-INTENSE PRURITIS is an early sign
Lymphomas
2. Non-Hodgkin's Lymphoma (NHL)
-Clonal proliferation of lymphoid cells in lymph nodes, bone marrow, tonsils, spleen, liver, or GI

-Etiology unknown.
* Mb dt HTLV-1, Human T-cell Lymphoma Virus 1

-ANEMIA PRESENT in 33% INITIALLY
* most develop it as disease progresses with NON-CONTIGUOUS SPREAD

-LEUKEMIC PHASE develops in 20-40% of lymphocytic lymphomas

Diagnosis:
-can only be made via LYMPH NODE BIOPSY
The histologic presence of characteristic neoplastic cells & destruction of N lymph node architecture
-Small-, intermediate-, and large-cell variations
Lymphomas
-Burkitt's Lymphoma
-Highly undifferentiated B cell lymphoma

-Can involve sites other than the lymph nodes & reticuloendothelial system

-Most common in Central Africa

-EBV: Associated with history of infection
Plasma Cell Dyscrasias (PCDs)
-Definition
-Types
-The PCDs are a group of clinically and biochemically diverse diseases characterized by the PROLIFERATION OF ONE CLONE OF PLASMA CELLS normally engaged in immunoglobulin (Ig) production.

-They are typified by the presence of a monoclonal Ig or polypeptide subunit in serum or urine.

Two Main forms discussed:
1. Multiple Myeloma
2. Waldenstrom's Macroglobulinemia
Plasma Cell Dyscrasias (PCDs)
-Multiple Myeloma
* Symptoms
-Unexplained:
* bone pain (back, thorax)
* renal failure
* recurrent bacterial infections most common (b/c the ABN plasma cells are using all of the resources to make useless antibodies, so the ones we need can't be made)

-May see pathological fractures in vertebrae & anemia.
Plasma Cell Dyscrasias (PCDs)
-Waldenstrom's Macroglobulinemia
* Symptoms
-MOST are ASYMPTOMATIC (until BM can no longer compensate).

-May have indications of:
* "HYPERVISCOSITY SYNDROME"
* fatigue
* bleeding from skin and mucous membranes
* weakness
* visual disturbances
* headaches.

-Also RAYNAUD's phenomenon from polycythemia vera
Plasma Cell Dyscrasias (PCDs)
-Multiple Myeloma (MxMy)
* Pathophysiology
-Progressive neoplastic dz

-Plasma cell tumors in BM

-Increased production of specific monoclonal Ig:G,A,D,E
OR
-Urinary BENCE JONES protein
* Free monoclonal kappa or lamda light chains
+ Light chain = higher bone lytic
+ lesions and associated:
>hypercalcemia
>renal failure
>anemia
>increased susceptibility to infection
>diffuse osteoporosis (esp. pelvis, spine, ribs, skull)
Plasma Cell Dyscrasias (PCDs)
-Multiple Myeloma (MxMy)
* Labs
-Anemia: normocytic, normochromic

-RBCs form rouleaux due to ^'d viscosity from abnormal proteins

-WBC & platelets counts usually normal

-ESR??
* often markedly elevated, > 100 mm/hr

Note: What other diseases have a markedly high ESR?
-Polymyalgia rheumatica, Temporal Arteritis, other cancers with hyperfibrinogenemia.

-55% produce IgG
-20% produce IgA.

-Total protein, BUN, creatinine, uric acid elevated

-Hypercalcemia in 1/3 of patients

-40% Bence Jones proteinuria
* need sulfosalicylic acid urine test to detect.

-Serum protein electrophoresis SPELP:
* increased monoclonal Ig protein, or "M protein" in 80%
Plasma Cell Dyscrasias (PCDs)
-Waldenstrom's Macroglobulinemia
* Definition
* Signs/Sxs
-CLONAL EXPANSION OF PLASMA CELLS that normally synthesize & SECRETE IgM

-Macroglobulinemia resembles lymphomas

-many of its clinical manifestations are due to large amounts of circulating macroglobulin

-Many patients have a hx of RAYNAUD's phenomenon

-RECURRENT BACTERIAL INFECTIONs are a major problem.
Plasma Cell Dyscrasias (PCDs)
-Waldenstrom's Macroglobulinemia
* labs
-Moderate anemia

-Marked rouleaux formation

-VERY HIGH ESR

-Occasionally occur:
* Leukopenia
* relative lymphocytosis
* thrombocytopenia

-May be present:
* Cryoglobulins
* rheumatoid factor
* cold agglutinins may be present.

-Relative SERUM VISCOSITY is usually > 4.0
* (normal=1.4-1.8)

-Note: Rouleaux formation is determined largely by increased levels of plasma fibrinogen and globulins, and so the ESR reflects mainly changes in the plasma proteins that accompany acute and chronic infections, some tumors and degenerative diseases.