medical 195

Reactive Proliferations of White Blood Cells 1. Leukocytosis a. Increased neutrophils (neutrophilia)

i. Increased bone marrow production is seen with acute inflammation associated with pyogenic bacterial infection or tissue necrosis ii. Increased release from bone marrow storage pool may be caused by corticosteroids, stress, or endotoxin iii. Increased bands ("left shift") in peripheral blood is characteristic iv. Reactive changes include Dohle bodies (aggregates of rough endoplastic reticulum [RER]), toxic granulations (prominent granules), and cytoplasmic vacuoles of neutrophils v. Increased leukocyte alkaline phosphatase (LAP) is useful to differentiate benign reactions from neoplastic chronic myelocytic leukemia (CML) (which has decreased LAP)

b. Increased eosinophils (eosinophilia) are seen with i. Allergies and asthma (type I hypersensitivity reaction)

ii. Parasites iii. Drugs (especially in hospitals)

iv. Certain skin diseases v. Certain cancers (adenocarcinomas)

c. Increased monocytes (monocytosis) are seen with i. Certain chronic diseases, such as some collagen vascular diseases and inflammatory bowel disease (IBD)

ii. Certain infections, especially TB

d. Increased lymphocytes (lymphocytosis) are seen with i. Acute (viral) diseases ii. Chronic inflammatory processes e. Infectious mononucleosis (IM) is an example of a virus disease causing Lymphocytosis i. Most common cause is Epstein-Barr virus (EBV) (a herpesvirus) but less commonly due to other viruses (heterophile-negative IM is most likely due to cytomegalovirus [CMV])

ii. Sequence of events

■ EBV invades B-lymphocytes via CD21 (CR2) receptors • Cytotoxic (CD8) T-lymphocytes respond against invaded B-cells and form atypical lymphocytes (Downey cells), which are enlarged lymphocytes that have abundant cytoplasm that is condensed peripherally ("ballerina skirt" appearance); they are similar in appearance to monocytes, hence the name "mononucleosis"

■ Atypical lymphocytes are found in the peripheral blood and T-cell areas of lymph nodes (paracortex) and may cause misdiagnosis as Hodgkin disease histologically (therefore, don't biopsy a lymph node!)

iii. Antibody production: heterophil antibodies (antibodies against other species such as red cells of sheep and horses) are the basis of the Paul-Bunnell reaction used as the monospot test (may be negative first week, so need to repeat test).

iv. Clinical infectious monocytosis

• Age groups ("kissing disease") include adolescents and young adults

• Symptoms (classic triad): fever, sore throat (see gray-white membrane on tonsils), arid lymphadenitis (posterior auricular nodes); fourth sign is hep-atosplenom egaly

• Mono is an acute, self-limited disease that usually resolves in 4-6 weeks v. Complications include hepadc dysfunction, splenic rupture, and rash if treated with ampicillin

2. Lymphadenopathy a. Acute nonspecific lymphadenitis i. Tender enlargement of lymph nodes ii. Focal involvement is seen with bacterial lymphadenitis

• Histology: may see neutrophils within the lymph node

■ Note: cat-scratch fever (due to Afipia felis) causes stellate microabscesses iii. Generalized involvement of lymph nodes is seen with viral infections (see reactive T cells immunoblasts in lymph nodes and peripheral blood)

b. Chronic nonspecific lymphadenitis i. Nontender enlargement of lymph nodes ii. Follicular hyperplasia involves B-Iymphocytes and may be seen with rheumatoid arthritis, toxoplasmosis, and early HIV infections iii. Paracortical lymphoid hyperplasia involves T cells and may be seen with viruses, drugs (Dilantin), and systemic lupus erythematosus (SLE)

iv. Sinus histiocytosis involves macrophages and, in most cases, is nonspecific. An example is lymph nodes draining cancers.

Lymphoid Neoplasms

1. General definitions, characteristics, and classifications a. Acute leukemias i. Peripheral blood has decreased mature forms and increased immature forms called blasts, which have immature chromatin with nucleoli ii. Bone marrow has increased immature cells (blasts); the diagnostic criteria is > 30% blasts in the bone marrow iii. Acute symptoms are secondary to marrow failure, which can produce decreased RBCs (causing anemia and fatigue), decreased WBCs (permitting infections and fever), and decreased platelets (inducing bleeding)

b. Non-Hodgkin lymphoma classifications i. The Revised European-American classification of Lymphomas (REAL)

• Precursor B-cell neoplasms (immature B cells)

• Peripheral B-cell neoplasms (mature B cells)

• Precursor T-cell neoplasms (immature T cells)

■ Peripheral T-cell neoplasms (mature T cells)

ii. The Working Formulation divides non-Hodgkin lymphomas into three categories based on the prognosis (low-grade, intermediate-grade, and high-grade)

iii. Rappaport is an old classification (developed 1966) that is based on the microscopic appearance of tumor cells

• The size of the tumor cells was classified as eidier lymphocytic or histiocytic, and the tumor growth pattern was nodular or diffuse

• Well differentiated cells were similar to lymphocytes; poorly differentiated cells were angulated (cleaved) or had nucleoli

C. Precursor B-Cell and T-Cell Neoplasms

1. Acute lymphoblastic leukemia (ALL)

a. Lymphoblasts are positive for terminal deoxytransferase (TdT) (which is determined by using a nuclear stain), PAS, and acid phosphatase b. The French-American-British (FAB) classification of ALL (no longer employed)

i. LI: small homogeneous blasts (85% of cases of ALL)

ii. L2: larger, heterogeneous (pleomorphic) blasts with nuclear clefts iii. L3: (<1% of cases) large blasts with cytoplasmic vacuoles that stain with oil red O (leukemic form of Burkitt lymphoma)

c. The immunologic classification of ALL (at present preferred)

i. B-celi lineage; classification is based on presence or absence of cytoplasmic or surface markers

• Surface immunoglobulin (slg) present: mature B-ALL (a.k.a. FAB L3, the leukemic form of Burkitt's lymphoma)

■ Cytoplasmic U present: pre-B-ALL

■ Early pre B-ALL is the most common type of ALL and is seen primarily in children

■ Symptoms are due to marrow involvement and pancytopenia ii. T-cell lineage (T-ALL) is associated with mediastinal mass in young (adolescent) adult male (think "T" = thymus = mediastinal)

2. Lymphoblastic lymphoma a. The majority of cases are T cells and are aggressive and rapidly progressive b. Clinical; young males with mediastinal mass (think thymus)

c. The leukemic phase of lymphoblastic lymphoma is similar to T-ALL

D. Peripheral B-Cell Neoplasms

1. Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL)

a. CLL is very similar to SLL, which is also called well differentiated lymphocytic lymphoma (WDLL)

i. If patients present with blood findings ~ CLL, whereas patients who present with lymph node findings = SLL.

ii. Note: lymph node involvement is also common (50%) with CLL

b. Small lymphocytic lymphoma (SLL)

i. SLL is a proliferation of small B-lymphocytes, which have B-cell markers and one T-cell marker (CDS), like B-CLL

Clinical Correlate

ALL is associated with infiltration of the CNS and testes (Sanctuary sites). Prophylactic radiation and/or chemotherapy to the head is recommended because malignant cells in brain are protected from chemotherapy by the blood-brain barrier.

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