Medical 199

c. Classification of CLL

i. B-CLL (95% of cases) have B-cell markers, such as CD 19 and CD20 ■ One T-cell marker is also present: CD5

• Also important is that the cells are CD23 positive and CD 10 negative ii. T-CLL (5% of cases) have T-cell markers d. Histology of affected lymph nodes reveals only diffuse pattern (not nodular), but proliferation centers are also present e. Peripheral blood findings i. Increased numbers of normal-appearing lymphocytes ii. Numerous smudge cells ("parachute cells") are present; smudge cells result from the feet that the neoplastic lymphocytes are unusually fragile f. Bone marrow findings: numerous normal-appearing neoplastic lymphocytes g. Clinical characteristics of CLL

i. CLL is the most indolent of all of the leukemias ii. Mean age at time of diagnosis is 60

iii. The malignant cells are nonfunctional —> patients develop hypogammaglobulinemia —» increased risk of infections iv. CLL is associated with warm autoimmune hemolytic anemia (AIHA) (10% of cases), which will cause spherocytes to be observed in peripheral blood v. CLL rarely transforms into a worse disease, such as prolymphocytic leukemia or large cell lymphoma (Richter syndrome)

Hairy cell leukemia a. Indolent disease of older men b. Lymphocytes have "hairlike" cytoplasmic projections ("dry tap" with bone marrow aspiration)

c. Diagnostic stain: positive tartrate-resistant acid phosphatase (TRAP)

d. Physical exam: a markedly enlarged spleen (splenomegaly) due to infiltrate of red pulp by malignant cells e. Treatment with 2-chlorodeoxyadenosine (2CDA), which inhibits adenosine deaminase (ADA) and increases levels of toxic deoxyadenosine

Follicular lymphomas a. The most common form of non-Hodgkin's lymphoma (NHL) in the United States b. All follicular lymphomas are derived from B-lymphocytes c. Characteristic translocation is t(14;18)

i. Chromosome 14 has immunoglobulin heavy-chain genes ii. Chromosome 18 has bcl-2 (activation of bcl-2 inhibits apoptosis by blocking the bax channel)

d. Clinical features i. Commonly present with disseminated disease (more advanced stage)

ii. Has a better prognosis than diffuse lymphomas iii. Doesn't respond to therapy (unlike the more aggressive diffuse lymphomas)

iv. Up to half of cases will progress to a diffuse large-cell NHL

e. Classification i. Follicular small cleaved (<20% large cells in follicles)

ii. Small cleaved cells are also called centrocytes iii. Small cleaved cells in peripheral smear are called "buttock cells"

iv. Follicular mixed small and large cells (20-50% large cells, which are also called centroblasts, in the follicles)

v. Follicular large cell (>50% large cells in the follicles)

4. Diffuse large B-cell lymphoma a. The Working Formulation divides the diffuse lymphomas into diffuse small cleaved, diffuse mixed small cleaved and large cell, and diffuse large cell b. Common features i. Composed of large cells with a diffuse growth pattern ii. May present at extranodal sites: CNS, stomach, etc.

iii. Aggressive, rapidly proliferating tumor iv. May respond to therapy c. Special subtypes i. I mm uno deficiency-associated B-cell lymphomas (these are often infected with EBV)

ii. Body-cavity large B-cell lymphomas (some of these are associated wjth human herpes virus (HHV]-8)

5. Small noncleaved lymphoma (Burlatt lymphoma)

a. Micro i. Medium-sized lymphocytes with a high mitotic rate ii. "Starry-sky" appearance is due to numerous reactive tingible-body macrophages (phagocytosis of apoptotic tumor cells)

b. Characteristic t(8;14) translocation i. Chromosome 14 has immunoglobulin heavy-chain genes ii. Chromosome 8 has oncogene c-myc c. African type is the endemic form i. Involvement of mandible or maxilla is characteristic ii. Associated with EBV

d. American type is nonendemic form i. Commonly involves the abdomen (such as bowel, retroperitoneum, or ovaries)

ii. High incidence in AIDS patients

6. Mantle cell lymphoma (MCL)

a. Synonym: intermediate differentiated lymphocytic lymphoma b. MCL is not in the original working classification c. Most cases of small-cleaved NHL in die Working Formulation are, in feet, mande cell lymphoma d. The tumor cells arise from mande zone B-lymphocytes (positive for CD 19, CD20, and CD5; negative for CD23)

e. Characteristic translocation t(ll;14)

i. Chromosome 11 has bcl-1 (cyclin D)

ii. Chromosome 14 has immunoglobulin heavy-chain genes

7. Marginal zone lymphoma (MALToma)

a. May arise inside or outside lymph nodes (extranodal)

b. Associated with mucosa-associated lymphoid tissue: MALTomas c. Begins as reactive polyclonal reaction and may be associated with previous autoimmune disorders d. Remains localized for long periods of time Plasma cell neoplasms (multiple myeloma)

a. Multiple myeloma is the most common primary tumor arising in bone of adults b. Lab i. Increased serum protein with normal serum albumin ii. M spike: monoclonal immunoglobulin spike

iii. Twenty percent express Bence-Jones proteins, which are light chains that are small and can be filtered into urine c. Histology i. Bone marrow has increased numbers of plasma cells (>20% is characteristic)

ii. Peripheral blood may show rouleaux ("stack of coins")

d. Multiple lytic bone lesions due to the osteoclastic activating factor (OAF)

i. OAF is IL-6 (increased amounts of IL-6 are associated with a poorer prognosis because survival of myeloma cells is dependent on IL-6).

ii. Lytic bone lesions cause hypercalcemia, bone pain, and increased risk of fracture e. Complications i. Increased risk of infection, the most common cause of death ii. Renal disease, such as myeloma nephrosis iii. Amyloidosis (10% of patients) due to amyloid light (AL) chains f. Plasmacytoma: solitary aggregates —> plasma cells, which may be located i. Within bone: precursor lesions to later develop into myeloma ii. Outside bone (extramedullary): usually found within the upper respiratory tract and are not precursor lesions for myeloma g. Monoclonal gammopathy of undetermined significance (MGUS)

i. Old name was benign monoclonal gammopathy ii. M protein is found in 1-3% of asymptomatic individuals over the age of 50 (the incidence increases with increasing age)

iii. About 20% of these individuals will develop a plasma cell dyscrasia in 10-15 years Lymphoplasmacytic lymphoma (Waldenstrom macro globulin emia)

a. Synonym: small lymphocytic lymphoma with plasmacytic differentiation b. Waldenstrom's macroglobulinemia (WM) is a cross between multiple myeloma and small lymphocytic lymphoma (SLL)

i. Like myeloma, WM has an M spike (IgM)

ii. Like SLL (unlike myeloma), the neoplastic cells infiltrate many organs, such as lymph nodes, spleen, and bone marrow iii. Unlike multiple myeloma (MM), there are no lytic bone lesions, and serum calcium levels do not increase c. Russell bodies (cytoplasmic immunoglobulin) and Dutcher bodies (intranuclear immunoglobulin) may be present d. May have hyperviscosity syndrome (because IgM is a large pentamer)

i. Visual abnormalities due to vascular dilatations and hemorrhages in the retina ii. Neurologic symptoms include headaches and confusion iii. Bleeding and cryoglobulinemia due to abnormal globulins, which precipitate at low temperature and may cause Raynaud phenomenon

Peripheral T-Cell and Natural Killer Cell Neoplasms

1. Peripheral T-cell lymphoma, unspecified a. This is a "wastebasket" diagnostic category

2. Adult T-cell leukemia/lymphoma (ATLL)

a. ATLL is a malignant T-cell disorder (CD4-T cells) due to HTLV-1 infection that is found in Japan and the Caribbean b. Clinical symptoms: skin lesions, hypercalcemia, enlarged lymph nodes, liver, and spleen c. Micro: hyperlobated "4-leaf clover" lymphocytes in the peripheral blood

3. Mycosis fungoides (MF) and Sezary syndrome (SS)

a. MF is a malignant T-cell disorder (post-thymic CD4 cells) but has a better prognosis than ATLL

b. Clinical: generalized pruritic erythematous rash (no hypercalcemia)

c. Sequence of skin changes (stages): inflammatory eczematous —» plaque stage -h> tumor nodule stage d. Micro reveals atypical PAS-positive lymphs in epidermis (epidermotropism); aggregates of these cells are called Pautrier microabscesses e. Cerebriform Sezary cells in peripheral blood: Sezary syndrome (which is also associated with a generalized exfoliative skin rash)

Hodgkin Disease (HD)

1. Hodgkin versus non-Hodgkin lymphomas a. Characteristics of HD that are different from NHL

i. Clinically, HD may present similar to infection (with fever)

ii. Spread is contiguous to adjacent node groups (unlike non-Hodgkin's lymphomas)

iii. Classification is based on inflammatory response and not malignant cell iv. No leukemic staLe v. Extranodal spread uncommon

2. Hodgkin disease a. The malignant cell is the Reed-Sternberg (RS) cell i. "Owl-eye" appearance: symmetric (mirror image) bilobed nucleus with prominent central nucleoli surrounded by clear space ii. RS cells are positive for CD15 (Leu-Ml) and CD30 (Ki-1)

iii. Except for lymphocyte predominate HD in which the malignant cells stain for B-cell markers and have negative CD15 and CD30

b. Classification of HD

i. LP (lymphocyte predominant) type; has L-H cells (popcorn cells) and are negative for CD15 and CD30

ii. Mixed cellularity; has eosinophils and plasma cells (increased number of eosinophils is related to IL-5 secretion)

iii. Lymphocyte depleted (LD); has few lymphocytes, and there are many RS cells iv. Nodular sclerosis (NS)

■ This is the most common subtype

• The only type more common in females

■ Lymph node has broad collagen bands

■ RS variant: Lacunar cells (clear space surrounding cell) c. Clinical characteristics i. Bimodal age group distribution (late 20s and >50)

ii. Usually patients present with painless enlargement of lymph nodes.

iii. B-cell symptoms: fever (that comes and goes = Pel-Ebstein fever), weight loss, night sweats iv. Bad prognosis is direcdy proportional to the number of RS cells present and inversely proportional to the number of lymphocytes v. Survivors of chemotherapy and radiotherapy have increased risk for non-Hodgkin lymphoma or acute leukemia

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