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Myelopoiesis and White Blood Cells

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					                                     Myelopoiesis and White Blood Cells 2009
                                                   May 5, 2009
- Circulating Blood
             o The earliest recognizable myeloid cell is the myeloblast (10-20m diameter) with a large round to
                  oval nucleus. There is fine diffuse immature chromatin (without clumping), and a prominent
                  nucleolus. The cytoplasm is basophilic without or few granules. Although one may see a small
                  golgi area adjacent to the nucleus, granules are not usually visible or barely visible by light
                  microscopy. One should not see blast cells in the peripheral blood.
             o The promyelocyte (10-20m) is slightly larger than a blast. Its nucleus, although similar to a
                  myeloblast shows slight chromatin condensation and less prominent nucleoli. The cytoplasm
                  contains striking azurophilic granules or primary granules. These granules contain
                  myeloperoxidase, acid phophatase, and esterase enzymes. Normally no promyelocyte are seen in
                  the peripheral blood. At the point in development when secondary granules can be recognized,
                  the cell becomes a myelocyte.
             o At the point in development when secondary granules can be recognized, the cell becomes a
                  myelocyte. Myelocytes (10-18m) are slightly smaller than promyelocytes and have eccentric
                  round-oval nuclei, often flattened along one side. The chromatin is fine, but shows evidence of
                  condensation. Nucleoli may be seen in early stages but not in the late myelocyte. Primary
                  azurophilic granules are still present, but secondary granules predominate. Secondary granules
                  (neut, eos, baso) first appear adjacent to the nucleus. In neutrophils this is the “dawn” of
                  neutrophila. Myelocytes are not normally found in the peripheral blood.
             o The neutrophilic myelocyte has a broad range of appearances when viewed by light microscopy
                  on a Wright-Giemsa stain. The earliest stage is characterized by the appearance of fine, pink
                  (neutrophilic) granules (secondary granules) in the Golgi area, and as a result this area appears
                  brighter. This stage has been referred to as the "dawn of neutrophilia".
             o Myelocyte: At this early stage, most of the granules are still primary granules, most of the
                  cytoplasm is still blue, and nucleoli are still visible, but the nuclear chromatin is more coarse and
                  is starting to clump. From this stage the maturation progresses to a mature neutrophilic
                  myelocyte with the cytoplasm being all pink in appearance, and the primary granules having
                  been completely replaced with neutrophilic or secondary granules.
             o Metamyelocytes (10-18m) are slightly smaller than myelocytes. They have kidney shaped
                  indented nuclei and relatively dense chromatin, especially along the nuclear membrane. The
                  cytoplasm is faintly pink with almost no blue background. Numerous secondary granules
                  (neutrophils, eosinophils or basophils) clearly outnumber primary granules. Zero to one percent
                  of the peripheral blood white cells may be metamyelocytes (juveniles)
             o Bands, slightly smaller than juveniles, are marked by a U-shaped or deeply indented nucleus.
                  Opposite sides or lobes are of roughly equal size or diameter. There is no nuclear constriction >
                  than 1/2 the lobe diameter. The chromatin is heavily clumped and secondary or specific granules
                  either neutrophilic or basophilic predominate. Normal band counts vary but are usually in the
                  range of 0-6%.
             o Segmented (segs) or polymorphonuclear (PMN) leukocytes (average 14 m dia) are distinguished
                  by definite lobation with thin thread-like filaments of chromatin joining the 2-5 lobes. The
                  chromatin of the segmented neutrophil is coarsely clumped and the cytoplasm is pink due to
                  large numbers of secondary granules. In practice when examining peripheral blood, neutrophils
                  are the only leukocytes to be divided into myelocyte, juvenile, band, and PMN stages. Eosinophils
                  and basophils of all stages are lumped together in most instances.
                  Normally approximately 45-75% of the peripheral blood white cells are segmented neutrophils.
                  Life span of 6-7 hours or up to 4 days in the connective tissue
- Blood cell count and blood smear
             o Careful examination of the formed elements in the blood
                         Quantification of leukocytes
                         Quantification of the relative and absolute concentration of each type
                         Meticulous microscopic examination of morphology


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- WBC count and differential
              o Total WBC count is measured; reference range varies
              o Diff count is the relative concentration of the various leukocytes
              o One of the most useful tests in the laboratory
                       Confirms a suspected hematological disorder (leukemia)
                       Demonstrates response to infection a/o inflammation
                       Monitors treatment
              o Total and absolute numbers of each leukocyte
                       Alterations in the total numbers of leukocytes and in the relative proportions are
                           clinically significant
                       Left shifted maturation is clinically significant (more immature leukocytes)
              o The most important information from the differential count is not the relative count (% of cells)
                 but the absolute count
              o The absolute count for a specific leukocyte is the total WBC count multiplied by the % of that
                 leukocyte in the diff count
- Left shifted maturation
              o Left shift
                       An increase proportion of immature cells
                       Band forms or younger are increased
                       Note: immature forms include: bands, metamyelocytes, melocytes
                       Early release from the bone marrow
                       Stress, acute infections, inflammation
              o Bandemia
                       Increase in the fraction of band neutrophils
                       Bone marrow is responding to stress
                       Neutrophils are shifting from marginated pool to circulating pool
              o Examples of immature cells
                       Blasts – lymphoblasts and myeloblasts, NOS
              o Promeylocytes, myelocytes, and metamyelocytes
              o Nucleated RBCs
              o Band neutrophils > reference range
              o The most significant left shift has the more immature cells.

Quantitative Abnormalites of leukocytes
- Cytopenia
             o Leucopenia: decreased WBC count
             o Neutropenia: reduced granulocytes
             o Lymphocytopenia: decreased lymphocytes
                     Marked reduction in the peripheral blood lymphocytes
                                <1500 cells/mm
                                                  3
                                                              <700 (severe)
             o Aplastic anemia: pancytopenia of the RBC, granulocytes and platelets
             o Agranulocutopenia: marked reduction in the granulocytes in the blood
                                          3
                     < 1000 cells/mm
                                        3
                     <500 cells/mm (risk of infections)
- Cytosis
             o Leukocytosis: increased WBC count above reference range
                     Reactive: infections, inflammation, necrosis
                     Malignant: leukemia (uncontrolled proliferation of leukocytes, causing an accumulation
                         of leukemia cells in bone marrow and blood)
             o Specific types – neutrophilic, eosinophilic, lymphocytosis, monocytosis
             o Most commonly results from an increase in neutrophils
             o Mechanisms of neutrophilic leukocytosis
                     Neutrophils and their precursors are distributed in five pools:


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                                  A bone marrow precursor (mitotic) pool (myeloblasts, promyelocytes,
                                   myelocytes)
                                  A bone marrow non-mitotic pool (metamyelocytes, band and segments
                                   neutrophil)
                                  A peripheral blood marginating pool
                                  A peripheral blood circulating pool
                                  And an extrvascular tissue pool
- Case – examples
            o 67 year old Caucasian male presented to the emergency department with complaints of high
                grade fever, cough with yellowish phlegm for the past three days. He also had exertional
                dyspnea, which was attributed to his heart failure from under lying ischemic heart disease. The
                dyspnea had worsened from Grade 2 to Grade 3 over the past 5–6 months. There was no chest
                pain. He had a history of atherosclerotic heart disease status post coronary artery bypass graft
                done three years ago and CHF. He smoked a pack of cigarettes every day for 30 years. On
                examination, the patient was in no apparent distress. He was icteric, not cyanosed, no clubbing,
                no palpable lymph nodes, poor peripheral pulses and bilateral pedal edema. Jugular venous
                distension of 3–4 cm was noted. Auscultation of the lungs revealed decreased air entry in right
                lower zone and bibasilar rales. A systolic ejection murmur grade 2/6 was heard in the aortic area.
                Abdomen was soft with a 2 finger breadth enlargement of the liver. Rest of the examination was
                normal. Complete blood count showed leukocytosis with predominant neutrophils and a left
                shift. Hemoglobin-hematocrit and platelet count was normal. The patient had slight
                hyponatremia (132 meq), hypercalcemia 13.5 mg/dl, while other serum electrolytes were within
                normal range. He had a raised total bilirubin (5.3 mg/dl) while other liver function tests were
                normal. Chest X-ray showed bilateral pleural effusion, right lower lung field infiltrate,
                cardiomegaly and chronic interstitial lung changes. The impression was right lower lobe
                pneumonia. A presumptive diagnosis of pneumonia was made and he was started on intravenous
                antibiotics. The increase in bilirubin was speculated to be secondary to congestion of the liver.
                Chest CT without contrast showed a mixed density pleural based lesion in the right lower lobe
                measuring 7 cm × 5.4 cm) × 7.9 cm for which a diagnostic consideration of cavitating neoplasm,
                infectious lesion and sequestration was entertained. There was no evidence of mediastinal,
                axillary or hilar adenopathy. The purulent material obtained on CT guided biopsy of the lung
                revealed squamous cell carcinoma with extensive coagulation necrosis. There was no evidence of
                infection. Hence, all antibiotics were discontinued and oncology consult was obtained. CT guided
                needle core biopsy of the liver was negative for malignancy and showed mild inflammatory
                changes. Lung cancer is the leading cause of death among the cancers seen in the United States.
                Hypercalcemia and leukocytosis are two common paraneoplastic syndromes associated with lung
                cancer.
- Leukocytosis
            o Reactive (not malignant)
            o Neutrophilc, lekocytosis, reactive
                      Expect left shift
                      Bacterial infection is the most common cause
            o Leukemoid reaction (suggestive of a leukemia, but it is leukemia) – marked neutrophilia
                      Marked reactive neutrophilia with immature neutrophil (is not leukemia)
- Case
            o The patient is a 55-year-old white male who presents to the emergency room complaining of
                chest pain and labored breathing. His temperature is 98.6° F. He is overweight and smokes two
                packs of cigarettes a day. His EKG and cardiac enzyme profile reveal changes compatible with an
                acute myocardial infarction. The complete blood count (CBC) shows:
            o Hg 13 (12-15.2) and total WBC 15,500 (5000-10000)
            o A differential white cell count was included in the CBC report, showing 75% segmented
                neutrophils (polymorphonuclear neutrophils), 15% "band" (expect band count less than 10%);



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                  neutrophils, 7% lymphocytes, and 3% atypical lymphocytes. Based on the reported neutrophilic
                  leukocytosis and "bandemia," an extensive infectious disease work-up was initiated
- Neutrophilic leukocytosis
              o Increase in the number of neutrophils in the peripheral blood. This may be caused by pyogenic
                  infections or by non-microbial stimuli, such as tissue destruction. The neutrophil increase results
                  primarily from release of mostly mature neutrophils from the marrow storage pool, and hence
                  neutrophil precursors are rare in the peripheral blood.
              o Leukemoid reaction refers to an extreme form of reactive neutrophilic leukocytosis in which the
                  peripheral blood contains not only mature neutrophils but also immature leukocytes, resembling
                  leukemia. However, in leukemoid reactions, there are fewer immature myeloid cells (myeloblasts
                  are rare)
              o Acute and chronic myelogenous leukemias are clonal neoplastic disorders that are discussed
                  later.
              o Leukemoid (leukemia-like) reaction
                        Marked leukocytosis, often with immature leukocytes
                        Marked acceleration of leukocyte production and release
                        Bacterial infection, stress, etc.
                        WBC count
                                  Above reference range of 12,000
                                  15,000 – 25,000; as high as 40,000
                                  Occurs most often with neutrophils (neutrophilia) , but also lymphocytes
                                  Considerable left shift
                        As in a “leukemia,” but a reactive, self limiting rather than leukemic
                        Differential is chronic myelogenous leukemia (CML) or acute myelogenous leukemia
                            (AML) if numerous myeloblasts and promyelocytes
- Clinical features, causes, prognostic significance of extreme leukocytosis in adults
              o Extreme leukocytosis was attributed to
                        infection in 48 cases (48%)
                        advanced malignancy in 13 cases (13%)
                        hemorrhage in 9 cases
                        glucocorticoids in 8 cases
                        other causes in 22 cases.
              o Four patients had previously diagnosed conditions resulting in chronic leukocytosis.
              o Higher leukocyte counts were associated with malignancy
              o Fever was more common in patients with infection
              o Mortality was high overall (31%), and was greater in patients with non-infectious diagnoses
                  compared with infected patients
              o CONCLUSION: Clinicians should be aware that extreme leukocytosis with a predominance of
                  granulocytes is associated with infection in only 48% of cases.
              o The presence of fever increases the likelihood that infection is the cause. Mortality is high,
                  particularly in patients without infection.
- Case
              o After a several day prodrome of fever, chills, cough, and shortness of breath, an elderly patient
                  presented to the emergency department (ED). In the ED, the subject was febrile, hypotensive
                  and hypoxemic. The white count was elevated.
              o CBC: Leukocytosis, marked left shift with increased percentage of neutrophils, bands and
                  occasional myeloid precursors (from marrow). Thrombocytosis (platelets are an acute phase
                  reactant
              o DX: Sepsis; defined as the presence or presumed presence of an infection accompanied by
                  evidence of a systemic response referred to as the "systemic inflammatory response syndrome"
              o Differential Diagnosis: When marked leukocytosis (leukemoid reaction), must differentiate from
                  myeloid neoplasms like chronic myelogenous leukemia (CML)



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            o    Pathogenesis: The changes in the blood smear indicate that the bone marrow is responding to a
                 strong inflammatory stimulus (mediated by relevant cytokines and growth factors)
- Monocytosis
          o Monocytosis often occurs during chronic inflammation. Diseases that produce this state:
                Infections: tuberculosis, brucellosis, subacute bacterial endocarditis, syphilis, infectious
                   mononucleosis and and many protozoal and rickettsial infections (Rocky Mountain
                   spotted fever).
                Autoimmune diseases and vasculitis: systemic lupus erythematosus, rheumatoid
                   arthritis and inflammatory bowel disease.
                Malignancies: Hodgkin's disease and monocytic leukemia.
                Recovery phase of neutropenia or an acute infection.
                Miscellaneous causes: sarcoidosis




           o
- Lymphocytes
           o Normal lymphocytes vary in size and shape
                 Arbitrarily divided into large and small lymphocytes
                 Immunological subsets are recognized
                 Functional subsets are recognized
           o Morphology
                 Small lymphocytes
                           Mature small agranular lymphocyte
                           Plasmocytoid lymphocute
                           Granular lymphocytes
                 Large lymphocytes
                           Downey cells (large reactive lymphocytes)
                 Atypical lymphocytes
                           Best example in infectious mononucleosis
                                   o Large mononuclear cell with variable appearance
                                   o Reniform or lobated nucleus
                                   o Abundant foamy cytoplasm, often blue
                 §Atypical, or reactive, lymphocytes are lymphocytes that, as a result of antigen
                     stimulation, have become quite large. §The cells vary greatly in size and shape. The
                     nucleus is less clumped than that of the normal lymphocyte. §The shape of the nucleus
                     ranges from elliptic to cleft to folded. The chromatin patterns appear similar to those of
                     a blast and faintly stained multiple nucleoli are visible. §The cytoplasm may range from
                     large, deeply basophilic, and abundant to unevenly stained and granular. Causes of


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                      reactive lymphocytosis may be: cytomegalovirus, drugs, Epstein-Barr virus (infectious
                      mononucleosis), syphilis, toxoplasmosis, vaccination, and viral hepatitis.
                     The WBCs seen here are "atypical" lymphocytes. They are atypical because they are
                      larger (more cytoplasm) and have nucleoli in their nuclei. The cytoplasm tends to be
                      indented by surrounding RBCs. Such atypical lymphocytes are often associated with
                      infectious mononucleosis.
                     The cytologic differences between atypical lymphocytes (a & c) and monocytes (b). The
                      cytoplasm of monocytes usually is gray and frequently contains vacuoles while the
                      cytoplasm of atypical lymphocytes reveals a bluish tinge.
- Case
         o   A previously fit 20 year old man was admitted with a three day history of fever, sore throat,
             dyspnea, and malaise. Ten days before admission he had fallen on to his left side with pain over
             the left chest wall. A chest radiograph did not show a fracture, but the pain had been sufficiently
             severe to warrant overnight observation.
         o   On admission he was feverish, with a temperature of 39.7°C, and had generalized
             lymphadenopathy, non-exudative pharyngitis, mild hepatomegaly, and splenomegaly of 2 cm
             below the costal margin.
         o   He looked pale but well, and his blood pressure was 115/95 mm Hg, with a pulse rate of 96
             beats/min. He had mild left and right abdominal tenderness without guarding.
         o   CBC: Initial investigations showed a normal CBC except for an elevated percentage of
             lymphocytes An increased percentage of large, atypical lymphocytes with abundant, bluish
             cytoplasm and enlarged, irregular nuclei generally without nucleoli. Cell membrane frequently
             indented by surrounding red blood cells.
         o   Reactive, or atypical lymphocytes are lymphocytes that become large as a result of antigen
             stimulation
- Case
         o   In a young, previously healthy individual without evidence of bone marrow suppression on the
             CBC (e.g. marked anemia, thrombocytopenia or neutropenia), the most likely cause for atypical
             lymphocytes in the peripheral blood is a viral infection.
         o   Mononucleosis, is the viral illness most commonly associated with significant expansion of
             lymphoid tissues throughout the body, lymphocytosis and an increased percentage of atypical
             lymphocytes on the smear.
         o   The atypical lymphocytes in the peripheral blood are, primarily, virus-specific cytotoxic T-cells
             responding to the EBV infected B-cells.
         o   The EBV-infected B-cells are in the circulation as well (up to 20% of circulating Bs may contain
             virus during acute phase) but most are in the expanded lymphoid tissues.
         o   The lymphoid organ expansion is due to both the mitogenic action of the EBV virus on infected B-
             cells and the reactive T- and B-cells trying to clear infected cells.
         o   Splenic rupture is a rare complication of infectious mononucleosis.
         o   The "classic" criterion-- at least 50% lymphocytes and at least 10% atypical lymphocytes in the
             presence of fever, pharyngitis and adenopathy--is useful but hardly specific.
         o   Serologic confirmation is required, most commonly a "monospot" (heterophile antibody)
             determination is sufficient for confirmation.
         o   If negative and index of suspicion is high then detection of EBV capsid antigens may be necessary
         o   If heterophile antibodies or viral capsid antigens are negative then, if not considered previously:
         o   Streptococcal pharyngitis and other viral pharyngitides are consideration (one wouldn't expect
             the systemic lymphadenopathy and splenomegaly seen in this case).
         o   Acute cytomegalovirus infection, toxoplasmosis and acute HIV infections can produce systemic
             lymphoid tissue expansion; however, lymphopenia is more common than lymphocytosis.
         o   If the atypical lymphocytes were, in fact, blast forms (a morphologic distinction that can be
             difficult in some cases) then precursor B-cell or T-cell neoplasms would be considerations (usually
             associated with evidence of bone marrow suppression).



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Leukocytes and Inflammation
- Granulocytes
             o Primary granules (azurophilic, red/magenta) appear before the secondary granules
             o Secondary granules are specific
                       Basophilic: peroxidase, heparin, histemine, etc
                       Eosinophilic: major basic protein
                       Neutrophilic (weak staining): lysozyme and other proteases
- Case
             o Diff
                       WBC=20, 000                   -10,000
                       Neutrophils 80%               50-60%
                       16,000                        1800-7000          absolute count
                       Bands 10%                     0-10%
                       2,000                         0-1000             absolute count
                       Lymphocytes 10%               30-40%
                       2000                          1500-4000          absolute count
             o Diff WBC count descriptive terms
                       Leukocytosis (WBC count is too high)
                       Neutrophilic leukocytosis (Neutrophilia, too many neutrophils)
                       Left shifted maturation (too many young neutrophils)
                       Absolute lymphocyte count within reference range
                       What is the most likely cause?
                               Bacterial infection
                                        o Leukocytosis (WBC count is too high)
                                        o Neutrophilic leukocytosis (Neutrophilia, too many neutrophils)
                                        o Left shifted maturation (too many young neutrophils)
                                        o Absolute lymphocyte count within reference range
- Neutrophilia. Four segmented and two band neutrophils are seen in this low-oil magnification view of the
  peripheral blood; most often due to acute bacterial infection
- Abnormal neutrophils in leukocytosis
             o Neutrophilic Leukocytosis, reactive
                       Expect cytoplasmic vacuoles, granules, Dohle bodies
                       Expect left shift
                       Bacterial infection is the most common cause
             o Leukemoid Reaction (suggestive of a leukemia)
- Abnormal granulocytes
             o Dohle body
                       Single or multiple blue grayish blue inclusions of variable size and shape
                       Round or elongated
                       Remnants of free ribosomes or rough ER
                       Seen with toxic granules and vacuoles
             o Abnormal Neutrophils: Segmented and band neutrophils with toxic change (examples shown in
                 panels B and D) have less condensed chromatin than their normal counterparts and bluer
                 cytoplasm due to retention of ribosomal RNA. Focal basophilia appears as pale blue spots, called
                 Dohle bodies, that represent aggregated ribosomes and whorls of rough endoplasmic reticulum.
                 Many cells with toxic change are frothy or vacuolated cytoplasm, which represents degranulation
                 of lysosomes. Specific granules are less visible than in normally matured cells.
             o Reactive changes in neutrophils. Neutrophils containing coarse purple cytoplasmic granules (toxic
                 granulations) and blue cytoplasmic patches of dilated endoplasmic reticulum (Döhle bodies,
                 arrow) are observed in this peripheral blood smear taken from a patient with bacterial sepsis.
             o Döhle bodies appear as a small, light blue-gray staining area in the cytoplasm of the neutrophils.
                 They are found in poisoning, burns, infections, and following chemotherapy.



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- Abnormal granulocytes
               o Hypersegmented neutrophil
                          More than the usual 3 to 4 lobes
                          Nucleus has six or more lobes
                          Larger than normal
                          Vitamin B12 or folate deficiency
                          Dysplastic syndromes
               o Hypersegmented neutrophil along with macro-ovalocytes in a case of pernicious anemia.
                    Compare the size of the RBCs to the lymphocyte at the lower left center, macrocytic rbcs are just
                    as large or larger than the nucleus of the lymphocyte
               o This is a hypersegmented neutrophil in a patient with megaloblastic anemia. There are 8 lobes
                    instead of the usual 3 or 4. Such anemias can be due to folate or to B12 deficiency.
- Blasts
               o Blasts are abnormal mononuclear cells that do nor normally circulate in the peripheral blood.
               o Blasts are immature cells that reside in the BM.
               o The typical morphologic description is “nondescript.”
               o The typical appearance is shared by lymphoblasts, myeloblasts, and circulating lymphoma cells
               o The presence of Auer rods which results from the fusion of primary granules is virtually
                    pathognomonic of myeloid differentiation
- The myeloblast is the first stage of the granulocytic series that is identifiable by light microscopy. It may be
  difficult to distinguish myeloblasts from other blasts in the peripheral blood unless one uses special stains or
  infers their identity from the presence of other immature cells of the same line. A myeloblast can be
  distinguished from a promyelocyte by its lack of cytoplasmic granulation.
- Lymphoblasts are 12-20 µm in diameter with a round to oval nucleus, sometimes eccentric in location. The
  nucleus to cytoplasm ratio is about 4:1 and the periphery of both the nucleus and the cell may be irregular in
  outline.
- Abnormal granulocytes
               o Auer rod
                          Pink or red, round or rod shaped cytoplasmic inclusions
                          Aggregated azurophilic granules
                          Seen in acute non-lymphocytic leukemia (leukemia of granulocytic cells)
                          Acute promyelocytic leukemia has the most granules
                          Auer rods are elongated, bluish-red rods composed of fused lysosomal granules, seen in
                              the cytoplasm of myeloblasts, promyelocytes and monoblasts and in patients with acute
                              myelogenous leukemia.
               o Leukoerythroblastic reaction
                          Immature red and white blood cells
                          Due to abnormal infiltrates in the bone marrow
                          Space occupying lesions in the bone marrow-metastasis and granulomas
                          Requires bone marrow sampling
                          Here is a granuloma in a bone marrow biopsy, a potential myelophthisic process, “space
                              occupying lesion.” Granulomas in marrow tend to be small and poorly formed. Multiple
                              cultures and special stains are done to determine if there is an infectious etiology, such
                              as a mycobacterial or fungal infection.
                          The marrow spaces between the trabecular bone are filled with cohesive clusters of
                              dark blue cells and smaller groups of these cells replacing normal hematopoietic cells.
                              This is metastatic breast carcinoma. A bone marrow biopsy can confirm the diagnosis.
                          A leukoerythroblastic reaction is a stressed bone marrow –has nucleated red blood cells
                              and immature granulocytic cells. A leukoerythroblastic picture indicates severe
                              disruption of the marrow and requires BM sampling.
                          Nucleated rbcs and myelocytes are present. This usually (but not always) indicates that
                              the bone marrow has been infiltrated or replaced by such things as secondary cancer or
                              fibrosis.


                                                           8
Leukocytosis – Reactive
- Lymphocytosis
              o Is it a child or an adult?
                       Young children normally have a lymphocytosis
              o Is it self limiting or presistnet?
                       Viral infection is self limiting
                       Leukemia is not.
- Case: 62 year old man with lymphocytosis due to an acute viral infection; reactive, and self limiting
- Consider the next case #3: the lymphocytosis is persistent, not self limiting and is not associated with a known
  viral infection
              o The patient is a 50-year-old white man who presented for evaluation of lymphocytosis. The
                  lymphocytosis was detected on a complete blood cell count (CBC) obtained during a routine
                  physical exam.
              o The patient is a 50-year-old white man who presented for evaluation of lymphocytosis. The
                  lymphocytosis was detected on a complete blood cell count (CBC) obtained during a routine
                  physical exam 6 months ago. The physician has monitored the patient but the lymphocytosis
                  persists. There is no clinical evidence for infection, inflammation, etc.
                       Lymphocytosis: The patient reports feeling well without any new complaints. He is
                            relatively active and denies any new fatigue. The physical examination reveals a well-
                            developed man in no acute distress. No adenopathy or organomegaly noted. The
                            patient has no peripheral edema.
                                  WBC is increased and absolute count of lymphocytes is increased
                       Final Diagnosis Case #3: 50 year old with persistent lymphocytosis due to a chronic
                            leukemia. These mature lymphocytes are increased markedly in number. They are
                            indicative of chronic lymphocytic leukemia, a disease most often seen in older adults.
                            This disease responds poorly to treatment, but it is indolent.
Leukemias
- Granulopoiesis and Leukocyte Maturation
              o Myeloblast
              o Promyelocyte (primary, nonspecific granules)
              o Myelocyte (secondary granules)
              o Metamyelocyte
              o Band cell
              o Mature granulocyte (neutrophil, eosinophil, or basophil)
- Neoplastic Diseases of White Cells
              o Leukemias: neoplasms arising in bone marrow cells; neoplastic cells may circulate in the blood
                  and 2º colonize other tissue
- Neoplastic Proliferations Classified by Cell Type
              o Lymphocytic
              o Myelogenous (Myeloid) are the granulocytic cell (neutrophils, basophils, and eosinophils) and
                  other cells from the myeloid stem cell
              o ( megakaryocytes and monocytes)
- Leukemia Based on Cell Maturation
              o Acute Leukemia: accumulation of immature cells in bone marrow and blood
                       Myelogenous
                       Lymphocytic
              o Chronic Leukemia: accumulation of immature and mature cells (terminally differentiated) in bone
                  marrow and blood, but mature cells predominate
                       Myelogenous (Myeloid)
                       Lymphocytic
              o Acute Myeloblastic Leukemia, Immature cells predominate, especially blasts
              o Chronic Myelogenous Leukemia, mature cells predominate, although immature cells are present



                                                        9
              o   Acute myelogenous leukemia (AML) with predominates of myeloblasts and chronic myelogenous
                  leukemia (CML) with all stages of maturation, but primarily matured granulocytes.
              o Acute myelogenous leukemia (AML) with predominates of myeloblasts
              o NOTE: No myelocytes, metamyelocytes, band forms even though this is the bone marrow!
              o Chronic myelogenous leukemia (CML) with all stages of maturation, but primarily matured
                  granulocytes. There are too many cells, differentiation from myeloblasts to segmented
                  neutrophil continues, but the mature cells (meta, bands, and segs predominant)
-   Bone marrow cells terminology
              o Myeloid (Myelogenous)
                         Granulocytic Cells
                                  Neutrophils, Eosinophils, and Basophils
                         Mononuclear-Phagocytic Cells
                                  Monocytes and Macrophages
                         Thrombocytes/Megakaryocytes
              o Lymphocytes
                         T and B Cells
-   Diff WBC case
              o 54 yo has splenomegaly and persistent leukocytosis
              o Peripheral blood differential white blood cell count and bone marrow aspirate differential cell
                  count exhibit cells that are similar in distribution.
              o So the cells from the bone marrow show differentiation; thus THIS is NOT ACUTE Leukemia
              o 32%         Neutrophils (50 – 60%)
              o 30%         Bands (0 – 9%)
              o 20%         Lymphocytes (20-50%)
              o 10%         Metamyelocytes
              o 5%          Myelocytes
              o 2%          Promyelocytes
              o 1%          Blasts
              o Bone Marrow Aspirate and Peripheral Blood have same distribution of Granulocytes
-   Case 4
              o Peripheral blood has left shifted
                  neutrophil maturation so that peripheral blood has same distribution of granulocytes as bone
                  marrow
              o This is consistent with a chronic leukemia rather than acute leukemia, because the cells are
                  differentiating along the usual maturation line but more mature cells are present than immature
                  cells
-   Case
              o 54 yo man has fatigue (cardiac and/or renal disease, anemia) and mucosal bleeding (platelets or
                  clotting factor)
              o CBC shows neutrophilia and bi-cytopenia (platelets and red blood cells)
              o 5%          Neutrophils (30 – 70%) (so few segmented neutrophils, because the myeloblast is in a
                  maturation arrest)
              o 5%          Bands (0 – 10%)
              o 20%         Lymphocytes (20-50%)
              o 10%         Metamyelocytes
              o 10%         Myelocytes
              o 20 %        Promyelocytes
              o 30%         Blasts (predominant cell; it is not differentiating the way it should, “maturation arrest”)
              o Acute leukemia has “maturation arrest”
              o Left Shifted Maturation Without Neutrophil Maturation (to a significant number of segmented
                  neutrophils) is consistent with an acute leukemia or myelophthisic anemia




                                                           10
             o  This is an acute leukemia: Blasts: The fine, highly dispersed nuclear chromatin stains a light
                reddish-purple, and one or two pale blue or colorless large nucleoli are visible. The cytoplasm is
                usually agranular and deeply to moderately basophilic.
           o Peripheral Blood: This is an acute leukemia: These are immature myeloblasts with many nucleoli.
                A distinctive feature of these blasts is a linear red "Auer rod" composed of crystallized azurophilic
                granules. These findings are typical for acute myelogenous leukemia (AML).
- Leukemia – Diff Dx
           o A 44 year old man has a persistent disorder that shows a peripheral blood leukocytosis with a
                predominance of mature neutrophils, few myelocytes, metamyelocytes, and promyelocytes.
                Myeloblasts are not identified. The bone marrow shows a similar pattern of hyperplastic
                granulocytic cells showing maturation.
           o 32%          Neutrophils (50 – 60%)
           o 30%          Bands (0 – 9%)              60% Mature Neutrophils
           o 20%          Lymphocytes
           o 10%          Metamyelocytes
           o 5%           Myelocytes
           o 2%           Promyelocytes
           o 1%           Blasts
           o What is the most likely diagnosis?
                      Chronic Leukemia: accumulation of mature cells (terminally differentiated) in bone
                          marrow and blood
                                Myelogenous (Myeloid): Segmented neutrophils> banded neutrophils>
                                   myelocytes>myelocytes, promylocytes, and myeloblasts
                      Chronic Myelogenous Leukemia: Early myeloid cells such as myeloblasts, myelocytes,
                          metamyelocytes, and nucleated red blood cells are commonly present in the blood
                          smear, mimicking the findings in the bone marrow. The presence of the different
                          midstage progenitor cells differentiates this condition from the acute myelogenous
                          leukemias, in which a leukemic gap (maturation arrest) or hiatus exists that shows
                          absence of these cells.
           o Acute leukemia: no maturation




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