Mature Lymphoid Neoplasms

Chronic Lymphocytic Leukemia incidence

most common adult leukemia
4.7/100,000 in US
90% of patients are over 50
66% are voer 60 (median age - 70 years)
male to female ratio - >2:1

Chronic Lymphocytic Leukemia pathogenesis

no relationship to radiation but hereditary predisposition
can be preceeded my immunologic disease and 10% autoimmune (DAT)
95% have B-cell clone and 5% T-cell clone
leukemic B-cells are non-functional (decreased Ig, decreased Ab, lost memory, secondary response and DTH)
normal T-cells

Chronic Lymphocytic Leukemia early symptoms

fatigue and reduced exercise tolerance
lymphadenopathy
splenomegaly
25% discovered on routine exam or lab (WBC count)

Chronic Lymphocytic Leukemia late symptoms

worse fatigue/anemia
recurrent and persistent infections (decreased Ab)
bruising/bleeding from decreased platelet count end stage
jaudice, fever, weight loss
bone tenderness and edema

Chronic Lymphocytic Leukemia lab findings

high WBC
monotonous lymphs within patients
heterogeneous between patients
smudge cells (fragile lymphs)
50% hypogammaglobulinemia and 5-10% monoclonal spike
increased cryoglobulins
mild anemia
normal platelet count early
thrombocytopenia in end stage
low frequency of blast transformation

Chronic Lymphocytic Leukemia cell surface markers

strong CD 5, CD19, CD23
no or dim FMC-7 (to rule out PLL where CD20 is strong)
negative - sIg (unless mature B cell)
LEF1+ (Lymphocyte enhancer binging factor 1)
clonal Ig light chain

Chronic Lymphocytic Leukemia prognosis

mean survival is 10 years post diagnosis
83% survive > 5 years, 10-15% survive > 10 years
33% die of other cancers - poor prognosis for IgHV

Chronic Lymphocytic Leukemia stage A

observe only
lymphocytosis w/o anemia and thrombocytopenia
<3 nodes involved

Chronic Lymphocytic Leukemia stage B

observe unless symptatic
lymphosytosis w/o anemia and thromocytopenia
> 3 nodes involved

Chronic Lymphocytic Leukemia stage C

treat
lymphocytosis with anemia and thrombocytopenia
> 3 nodes involved

Chronic Lymphocytic Leukemia treatment

no treatment → mild chemo → CVP or CHOP
reduce symptome by reducing tumor burden
advanced disease (treat for remission) CVP or CHOP

B-Cell prolymphocytic Leukemia incidence

rare but aggressive
usually de-novo but can follow CLL

B-Cell prolymphocytic Leukemia clinical features

prominent splenomegaly
minimal lymphadenopathy

B-Cell prolymphocytic Leukemia lab findinds

marked lymphocytosis ( > 55% prolymphocytes = PLL)
anemia and thrombocytopenia
PLL morphology
parge, moderately abundant blue cytoplasm
moderately condensed cytoplasm with single prominent nucleolus

B-Cell prolymphocytic Leukemia laboratory testing

strong sIg
variable CD5
strong CD20 (FMC-7)
absent CD23
often del(17p)

B-Cell prolymphocytic Leukemia treatment and prognosis

aggressive, poor response to chemo, poor prognosis

Hairy cell leukemia incidence

uncommon but affects men 7:1 over women

Hairy cell leukemia clinical features

insidious, abnormal cells in RES, splenomegaly, fatigue

Hairy cell leukemia lab findings

high WBC early that declines as fibrosis develops
pancytopnia
hairy cells in blood and bone marrow (round or oval nucleus, reticular chromatin with inconspicuous nucleoli, moderate cytoplasm with hairy projections)
fibrotic marrow (hypo and hyper sellular sites, hairy cells in BM)

Hairy cell leukemia lab testing

TRAP positive
acid phosphatase is + in all cells but mature B cells
substrate + acid phos + hexazotized pararosaniline = red color
add tartrate first and red disappears in non H.C

Hairy cell leukemia treatment and prognosis

must be distinguished from CLL to effectively treat
HCL does not respond to CLL therapy
splenectomy and interferon
Purine analog
mena survival is 5-6 years on alpha interferon and 5-10 years with purine analog

monoclonal Gammopthay

a group of disordrs characterized by proliferation of a single clone of plasma cells that produce a homogenous monoclonal protein

malignant monoclonal gammopathies

multiple myeloma
plasmacytoma
malignant lymphptoliferative disease (waldenstrom’s macroglobulinemia)
heavy cahin disease
amyloidosis

monoclonal gammopathies of undetermined significance

benign
non-monoclonal malignant
Bi-clonal gammopathies

overt multiple myeloma pathogenesis

multiple mutations in HSC → proliferation of malignant plasma cells → produces monoclonal IgG or IgA → renal failure, respiratory involvement, infection, hyperviscosity

multiple myeloma clinical features

weakness and fatigue (anemia)
bone pain and bone loss (moth eaten appearance on X-ray
renal insufficiency
infactions
ringing ears, ocular, CHF
bleeding
organ dysfunction

multiple myeloma peripheral blood

normo/normo anemia
rouleaux
increased ESR
normal WBC and platelet early then decreased
plasma cells

multiple myeloma bone marrow

hypercellular with normal megakaryocytes
elevated and abnormal plasma cells (in sheets)
russel bodies (red), flame cells (IgA), mott cells (grapes)
eventual cytopenias as plasma cell numbers increase

multiple myeloma special testing

serum protein electrophoresis
bence-jones protein
chemistry tests (increased BUN, creatinine, uric acid, serum protein)
radiologic tests to visualiz fractures

multiple myeloma treatment

dialysis for renal failure
plasmapheresis for hyperviscosity
transfusions for BM failure
antibiotics for infections
radiation for plasmacytoma or bone pain
chemotherap + TX
otherwise melphalan and predisone
borezomib (proteosome inhibitor)

smoldering multiple myeloma

MM that does not progress → can terminate in MM

plasma cell leukemia

when plasma cells enter circulation

non-secretory myeloma

immature plasma cells that are very invasive
no abnormal Ab production

plasmacytoma

mass of plasma cells in BM, respiratory tract

Waldenstrom’s macroglobulinemia pathogenesis

multiple mutations in HSC → proliferation of plasmacytoid lymphs → produces monoclonal IgM → renal failure → respiratory → hyperviscosity syndrome

Waldenstrom’s macroglobulinemia clinical features

weakness and fatigue
weight loss
bleeding
hepatosplenomegaly and lymphadenopathy
hyperviscosity syndrome (tinnitis, blurred vision, CHF)

Waldenstrom’s macroglobulinemia peripheral blood

normo/normo anemia
rouleaux/increased ESR
increased plasmacytoid lymphs and monos

Waldenstrom’s macroglobulinemia bone marrow

hypocellular
increased plasmacytoid lymphs
increased mast cells

Waldenstrom’s macroglobulinemia special testing

SPE (gamm spike)
immunoelectrophoresis/immunofixation electrophoresis (IgM)
Bence-jones protein

Waldenstrom’s macroglobulinemia treatment

chemo (reduce tumor burden)
Targeted therapy (rituximab, bortezomib, ibrutinib, acalabrutinib)
plasmapheresis

Waldenstrom’s macroglobulinemia prognosis

mean survival = 5-10 years and improving
potential cure with SCT

heavy chain disease pathogenesis

same as MM but malignant plasma cells make heavy chains

gamma chain disease

rare but first reported, older men, fatigue, fever
anemia, increased gamma heavy chains in serum and urine
asymptomatic then death shortly after diagnosis

alpha chain disease

most common, young adults, mediterranean
normal SPE - slight broad band at alpha 2 or beta
melphalan, cyclophosphamide, prednisone (usually fatal)

Mu chain disease

very rare, with CLL, Abn lymphs, normal SPE, treat like CLL

delta chain disease

very rare, resembles MM, monoclonal gamma spike, no light chaisn

amyloidosis

a waxy, starchy looking substance that is a gelled immunoglobulin-like protein that deposits in tissues and causes organ malfunction

primary amyloidosis

idopathic and associated with plasma cell dysrasis

secondary amyloidosis

associated with TB, RA, ulcerative colitis, bronchitis, osteomyelitis

heredofamilial amyloidosis

inherited mediterranean family with abnormal transthyretin

trasthyretin

transport protein for T4 and Retinol (Vit A)

Isolated Organ amyloidosis

hemodialysis
brain (alzheimer’s alpha 4-beta-protein)
diabetes (procalcitonin)

calcitonin

hormone that regulates calcium metabolism

amyloidosis clinical features

amyloid infiltration of tissues causing failure
clinical - tongue, skin
pathologic - liver, spleen, joints, GI, renal, cardiac

amyloidosis lab findings

amyloid biopsied tissue
stains with congo red or metachromatic stains

amyloidosis treatment

chemotherapy and immunosuppression but usually unseccessful

amyloidosis prognosis

relentless progression to death

monoclonal gammopathy of undetermined significance

incidental finding of monoclonal spike on SPE without cause or symptoms

monoclonal gammopathy of undetermined significance lab findings

monoclonal spike with 9.2 g.dL total protein
<2 g/dL monoclonal protein
<5% plasma cells in BM

monoclonal gammopathy of undetermined significance prognosis

11% progress to monoclonal gammopathy

cryoglobulinemia

increase in cryoglobulin in serum
cause by hep C, plasma cell dyscrasis, and, autoimmune disseases

cryoglobulinemia type I

monoclonal
IgM Waldenstrom’s, IgG multiple Myeloma

cryoglobulinemia type II

mixed with 2 or more monoclonal Abs
lymphoma, CLL, malignancies

cryoglobulinemia type III

polyclonal
hep C, HIV, EBV, CMV, or collagen vascular disease

cryoglobulinemia clinical features

cold intolerance, renal disease, vascular occlusions (clummped cryoglobulins)

cryoglobulinemia la findings

increased cryoglobulins, cold abs, abnormal UA

cryoglobulinemia treatment

treat underlying disease
plasmapheresis
protect from cold

lymphoma

asymptomatic, asymetrical enlargement of a group of lymph nodes cause my neoplastic grwoth of lymphoid cells that destorys the lymph node architecture
cance of lymphocytes that occurs in lymph nodes

Hodgkin’s lymphoma incidence

one third of lymphomas
bimodal incidence
frequency is 2.6-3.6/100,000/year for women/men
multiple mutations in HSC and associated with EBV

Hodgkin’s lymphoma clinical features

cervial lymph node → swelling, fever, sweats, eight loss, itching, LN pain → supraclavicular → mediastinal
splenomegay in 65% but can affect any organ
less aggressive than non-hodgkin’s
lymph node issue not a BM issue

Hodgkin’s lymphoma early disease lab findings

mild normo/normo anemia
increased monos, eos, platelets, large atypical lymphs
increased ESR

Hodgkin’s lymphoma advanced disease lab findings

granulocytosis, tocis granulation and large platelets
AIHA, +DAT and abnormal liver and renal function tests

Hodgkin’s lymphoma diagnostics

abnormal lymph node → aspirate → not reactive
abnormal lymph in PB
Reed-sternberg cell (DIAGNOSTIC)(unknown origin, large, bilobulated nucleus, owl-eye appearance)

Hodgkin’s lymphoma stage I

1 group of LN above or below diaphram (usually cervical)

Hodgkin’s lymphoma stage II

2 groups of LN on same half of body (cervical.supraclavicular)

Hodgkin’s lymphoma stage III

2 groups of LN on different halves of body
a - no fever, night sweats, or weight loss
b - fever, night sweats and weight loss

Hodgkin’s lymphoma stage IV

extra-nodal involvement (outside LN)

Hodgkin’s lymphoma treatment

radiotherapy: IIa, IIIb, IV (does not melt with radiation)
MOPP

prognosis

80% of stages I and II have long term survival
70% of stage III has > 10 year survival
Stage IV - poor prognosis

Non-Hodgkin’s lymphoma

etiology unknown
multiple mutations in lymphoid stem cell

Non-Hodgkin’s lymphoma incidence

3% of new caners each year
slight male preponderance

Non-Hodgkin’s lymphoma pathogenesis

multiple mutations in lympoih stem cell
cancer of lymphocytes in lymph nodes
usually of B-cell origin

Non-Hodgkin’s lymphoma clinical geatures

nuch more aggressive
enlarged lymph nodes anywhere in the body
NHL tents to spread to extra nodal sites

Non-Hodgkin’s lymphoma diagnosis

usually treat as infectious but LN aspiration if >2 weeks
pathologist must examine Ln aspiration

working formulation

Non-Hodgkin’s lymphoma classification
Low - intermediate - high
based on morphology of cells and lymph node pattern

REAL classification

Non-Hodgkin’s lymphoma classification
B vs T cell
combines lymphomas, plamsa cell dyscrasias, lymphocytic leukemias, hairy cell leukemia

WHO classification

Non-Hodgkin’s lymphoma
Mature B - includes CLL, PLL, HCL, MM, WM
Mature T and NK - mycosis fungoides (Sezary syndrome)
modgkin’s lymphoma

Non-Hodgkin’s lymphoma treatment

CHOP
radiation - melts

Non-Hodgkin’s lymphoma

2/3 of lymphomas
multiple mutations in lymphs in LN
can affect any lumph node
more aggressive than HL
WHO - Mature B and T/NK cell types
Melts with radiation
Treat with SHOP
poorer prognosis compared to HL

Mycosis Fungoides classification and incidence

cutaneous T-cell lymphoma
2% of lymphomas that primarily affect older men

Mycosis Fungoides pathogenesis

T-helper mutation in skin _. malignant → accumulate in skin → rash → skin tumors → Sezary syndrome → lung, spleen, liver, kidney → 12-15 month survival after Sezary syndrome

Mycosis Fungoides lab findings

Szary cells in circulation (clefted lymphocytes)
CD2,3 (Pan t-cell marker)
CD4 (Th cell marker)

Mycosis Fungoides treatment and prognosis

treat with topical chemo, radiation, phototherapy
skin lesion progresses in 2-10 years
treat with chemo → survival is 12-15 months after Sezary syndrome