Maintenance of hematopoietic tissues
- nurse cells = macrophages that supply iron to RBCs in BM
- leukoerythroblastosis = abnormal release or immature precursors into peripheral blood
- normal fat:hematopoietic elements = 1:1
Leukopenia
- neutropenia, lymphopenia
- neutropenia is most common granulocytopenia
Neutropenia
- more common
- severe infections when neutrophil count <500/mm3
- agranulocytosis = clinically significant reduction in neutrophils
- inadequate or ineffective granulopoiesis
o suppression of HSCs
o suppression of committed granulocytic precursors by drugs (most common)
o disease states with ineffective hematopoiesis
o rare congenital conditions (Kostmann syndrome = impairment of granulocytic differentiation
- accelerated removal or destruction of neutrophils
o immunologically mediated injury
o splenomegaly
o increased peripheral utilization
- clinical: infection, malaise, chills, fever, weakness, fatique
Lymphopenia
- HIV
- treatment with steroids, cytotoxis drugs
- autoimmune disorders
- acute viral infections
Leukocytosis
- increased WBCs in blood
- mechanisms:
o increased production, increased release from marrow stores
o decreased margination
o decreased extravasation into tissues
- types:
o neutrophils – acute bacterial infections, tissue necrosis
o eosinophils – allergic, parasitic, drugs, certain malignancies, collagen vascular
o basophils – myeloproliferative
o monocytosis – chronic infections, IBD
o lymphocytosis – chronic infections, viral infections, pertussis
- reactive changes in sepsis or severe inflammatory disorders
o Döhle bodies (patches of dilated ER; sky-blue cytoplasmic puddles_
o toxic granules
o cytoplasmic vacuoles
- leukemoid reaction = in severe infections, many immature granulocytes appear in blood simulating a myeloid leukemia
Lymphadenitis
- activation of resident immune cells leads to morphologic changes in lymph nodes
Acute nonspecific lymphadenitis
- lymph nodes painful, red, engorged
- in cervical region most often due to infections of teeth or tonsils
- in axillary or inguinal regions most often from infections in extremities
- systemic viral or bacterial infections (children) cause acute generalized lymphadenopathy
- overlying skin red
Chronic nonspecific lymphadenitis
- nontender
- follicular hyperplasia
o caused by humoral immune response
o germinal centers have B cells with dark zone (centroblasts) and light zone (centroytes)
o tingible-body macrophages
o caused by RA, toxoplasmosis, early HIV
- Paracortical hyperplasia
o T cell-mediated resonse
o acute viral infections (mono)
- Reticular hyperplasia (sinus histiocytosis)
o increase in cells lining lymphatic sinusoids
o prominent in lymph nodes draining breast CA
o macrophages and dendritis cells
- chronic immune rxns can cause organized collections in non-immune tissues
Neoplastic proliferation of white cells
- lymphoid neoplasms = B cells, T cells, NK cells orgin
- myeloid neoplasms = acute myeloid leukemias, myelodysplastic, myeloproliferative
- histiocytosis = macrophages, dendritic cells, Langerhans cells
White cell neoplasia etiology and pathogenetic factors
- translocations are most common chromosomal abnormality in white cell neoplasm
o mutated genes play critical roles in development, growth, or survival of normal counterparts of malignant cells
§ MALTomas = B-cell lymphoma or MALT1/BCL10 constitutively activating NF-kB
o oncoproteins created by genomic aberrations often block normal maturation
§ BCL6 needed for germinal centers but turn off for maturation
o proto-oncogenes often activated in lymphoid cells by errors that occur during antigen receptor gene rearrangement and diversification
- inherited genetic factors
o Bloom, Fanconi, Down, ataxia teleangectasia and type I NF
- viruses (HTLV-1, EBV, HHV-8)
- chronic immune stimulation (H.pylori, celiac, HIV)
- iatrogenic factors (radiation therapy)
- smoking (AML)
Lymphoid neoplasms
- clinical:
o enlarged lymph nodes
o involvement of extranodal sites
o suppression of normal hematopoiesis
o secretion of circulating factors
o pain due to bone destruction
- histologic examination required for Dx
- most of the time, antigen receptor gene rearrangement precedes transformation (all daughter cells share same antigen receptor gene configuration)
- majority are B cell origin (85-90%)
- often associated w/ immune abnormalities
- neoplastic B and T cells tend to behave like their normal counterparts (T cells to skin; B cells to germinal centers)
- Hodgkin lymphoma spreads in orderly fashion
Acute lymphoblastic leukemia/lymphoma
- neoplasms of pre-T or pre-B cells (lymphoblasts)
- 85% are B-ALLs
- T-ALLs less common; present as thymic lymphomas in adolescent males (lymphadenopathy and splenomegaly)
- ALL is most common CA of childhood
- must be distinguished from AML bc of differing responses to chemo (ALL myeloperoxidase negative)
- TdT +, starry sky, hypercellular
ALL molecular pathogenesis
- 90% have numerical or structural chromosomal changes (hyperploidy)
- many of chromosomal aberrations seen in ALL dysregulate expression and function of txn factors required for normal B and T cell development
o 70% of T-ALLs have GOF in NOTCH1
o many B-ALLs have LOF in PAX5, EBF, E2A
- clinical:
o abrubt stormy onset
o symptoms of bone marrow suppression
o mass effect (bone pain, lymphadenopathy, splenomegaly, hepatomegaly, testicular enlargement)
o CNS manifestations (HA, vomiting, nerve palsies)
ALL prognosis
- worse prognosis:
o under 2 years (MLL gene translocations)
o presentation in adolescence or adulthood
o peripheral blast counts >100,00
o presence of particular cytogenic aberrations (Ph chromosome)
§ Ph chromosome is t(9:22) with constitutively active BCR-ABL
o “2 adolescents in Philadelphia stole >$100,000”
- favorable prognosis:
o 2-10 years of age
o low WBC count
o hyperploidy
o trisomy of 4,7,10
o presence of t(12:21)
CLL/SLL
- most common leukemia of adults in the western world
- proliferation centers pathognomic
- 2:1 male predominance; median age= 60 years
- smudge cells
- tumor cells express CD19/20 and low expression of IgM/D
- translocations are rare
- most common are deletions of 13q14.3, 11q, 17p, and trisomy 12q
- clinical:
o often asymptomatic at Dx
o nonspecific (fatigue, weightloss, anorexia)
o generalized lymphadenopathy
o hepatosplenomegaly
o disrupted normal immune fxn (hypogammaglobinemia, autoantibodies à anemia, thrombocytopenia)
o variable course/prognosis
o tendency to transform to more aggressive tumors
§ prolymphocytic (most common)
§ diffuse large B-cell lymphoma (Richter syndrome)
Follicular lymphoma
- most common form of indolent NHL
- arises from germinal center B cells
- middle age; male=female
- strongly assoc. w/ chromosomal tlc involving BCL2
- centrocytes (small cleaved cells) and centroblasts
- hallmark is t(14:18) à overexpression of BCL2 (blocks apoptosis)
- clinical:
o painless
o generalized lymphadenopathy
o indolent waxing, waning course
- histologic transformation in 30-50% (most commonly to diffuse large B-cell lymphoma)
Diffuse large B-cell lymphoma
- most common form of NHL
- slight male predominance; median age= 60 years
- large cell size; diffuse growth pattern
- express CD19/20
- dysregulation of BCL6
- 10-20% of tumors have t(14:18)
- oncogenic herpesviruses
o immunodeficiency-associated large B-cell lymphoma
§ occurs in setting of T-cell immunodeficiency (advanced HIV infection)
§ most infected w/ EBV
o primary effusion lymphoma
§ presents as malignant pleural or ascetic effusion in pts with advance HIV infection or elderl
§ KSHV/HHV-8
- clinical:
o rapidly enlarging mass at nodal or extranodal site (Waldeyer ring commonly affected)
o aggressive
o rapidly fatal without treatment
Burkitt lymphoma
- 3 subsets:
o African (endemic)
o sporadic (nonendemic)
o aggressive subset in HIV pts
- high mitotic index & numerous apoptotic cells
- “starry sky” pattern
- translocations of c-MYC on chromosome 8 t(8,14)
- all endemic tumors are infected with EBV
- clinical:
o most present as tumor at extranodal site
§ endemic = mandible, ab viscera
§ sporadic – ileocecum, peritoneum
Plasma cell neoplasms (dyscrasias)
- secrete monoclonal Ig or Ig fragment
- most common & deadly is multiple myeloma
- often synthesize excess light or heavy chains w/ complete Igs
- monoclonal Ig in blood = M component
- free light chains excreted in urine (Bence-Jones proteins)
Monoclonal gammopathies
- multiple myeloma
- Waldenstrom macroglobulinemia
o high IgM
o hyperviscosity
- heavy-chain disease
- primary or immunocyte-associated amyloidosis
- monoclonal gammopathy of undetermined significance
o most common plasma cell dyscrasia
o asymptomatic
o M protein < 3
Multiple myeloma
- multifocal involvement of skeleton
- men; African descent; elderly (65-70 years)
- Ig genes in myeloma cells show evidence of hypermutation
- proliferation and survival of myeloma cells dependent on several cytokines (particularly IL-6)
- Factors produced by neoplastic plasma cells mediate bone destruction
o myeloma-derived MIP1α upregulates RANKL by bone marrow stromal cells
o causes hypercalcemia and pathologic fractures
- many have rearrangements involving the Ig heavy-chain gene on chromosome 14q32
- presents as destructive plasma cell tumors (plasmacytomas) of axial skeleton
- bone lesions appear as punched-out defects, 1-4 cm in dm
- plasmablasts, bizarre multinucleated cells
- flame cells with fiery red cytoplasm
- Mott cells w/ multiple grapelike cytoplasmic droplets
- other inclusions (fibrils, crystalline rods, globules)
- Russell bodies (cytoplasmic), Dutcher bodies (nuclear)
- rouleaux formation characteristic (high lvl of M proteins causes red cells in peripheral blood smears to stick to one another in linear arrays)
- Bence Jones proteins contribute to myeloma kidney
- clinical:
o bone resorption (fractures, chronic pain)
o hypercalcemia (neurologic, renal problems)
o recurrent bacterial infections
o renal insufficiency
o SPE M protein
o anemia (normocytic normochromic)
Solitary myeloma (plasmacytoma)
- solitary lesion of bone or soft tissue
- progress to multiple myeloma
Smoldering myeloma
- middle ground between multiple myeloma and MGUS
- 75% progress of multiple myeloma
MGUS
- most common plasma cell dyscrasia
- 1% develop symptomatic plasma cell neoplasm (usually multiple myeloma) per year
- early stage of myeloma development
Lymphoplasmacytic lymphoma
- B-cell neoplasm of older adults
- 6th or 7th decade of life
- most commonly, plasma cell component secretes monoclonal IgM à hyperviscosity syndrome (Waldenstrom macroglobulinemia)
- mast cell hyperplasia
- Russel and Dutcher bodies
- clinical:
o weakness, fatigue, weight loss
o lymphadenopathy, hepatosplenomegaly
o anemia, auto-immune hemolysis caused by cold agglutinins
o hyperviscosity syndrome (visual impairment, neurologic problems, bleeding, cryglobulinemia)
- incurable, plasmapheresis
- most common cytogenic abnormality is deletion involving chromosome 6q
Mantle cell lymphoma
- tumor cells closely resemble normal mantle zone B cells that surround germinal centers
- small lymphocytes with cleaved nuclear contours
- most commonly presents with painless lymphadenopathy
- express high levels of cyclin D1 from t(11:14)
Marginal zone lymphoma (maltomas)
- often arise in areas of chronic inflammation (H. pylori, Sjögren disease, Hashimotos)
- remain localized for long time
- may regress if inciting agent removed
- continuum between reactive lymphoid hyperplasia and full-blown lymphoma
- up-regulations of BCL10/MALT1
Hairy Cell leukemia
- middle-aged; white males; median age 55
- rare distinctive B-cell neoplasm
- leukemic cells have fine hairlike projections
- pale blue cytoplasm with
- dry tap
- express CD19/20, surface IgG
- massive splenomegaly is most common (often only) sign
- pancytopenia, infections
Peripheral T-cells and NK-cell neoplasms
- peripheral T-cell lymphoma, unspecified
o variably sized malignant T cells
o more common in Asia
o infiltrate of reactive cells (eosinophils and macrophages)
o present with generalized lymphadenopathy, eosinophilia, pruritus, fever, and weight loss
o worse prognosis than mature B-cell neoplasms
- anaplastic large-cell lymphoma
o ALK positive on chromosome 2p23
o horse-shoe shaped nuclei with voluminous cytoplasm (hallmark cells)
o children or young adults
o soft tissues
o very good prognosis
- adult T-cell leukemia/lymphoma
o neoplasm of CD4+ T cells
o only in adults infected by human T-cell leukemia retrovirus type 1 (HTLV-1)
o skin lesions, lymphadenopathy, hepatosplenomegaly, peripheral blood lymphocytosis, hypercalcemia
o cloverleaf or flower cells
o tumor cells have HTLV-1 provirus
o rapidly progressive (fatal within months to a year)
- mycosis fungoides/Sezary Syndrome
o tumor of CD4+ helper T cells that home to skin
o neoplastic cells have cerebriform appearance due to marked infolding of nuclear membrane
o Sezary syndrome = generalized exfoliative erythroderma
o express adhesion molecule CLA and chemokine receptors CCR4 and CCR10
- large granular lymphocytic leukemia
o T-cell and NK-cell variants
o mainly in adults
o large lymphocytes with abundant blue cytoplasm and few course azurophilic granules
o T-cell variant
§ present with lymphocytosis and splenomegaly
§ CD3+
§ more indolent
o NK-cell variant
§ CD3-, CD56+
§ more aggressive
o neutropenia and anemia dominate clinical picture
o increased rheumatologic disorders
o Felty syndrome = RA, splenomegaly, and neutropenia
- Extranodal NK/T cell lymphoma
o destructive nasopharyngeal mass
o surrounds and invades BVs à ischemic necrosis
o large azurophilic granules
o highly assoc. with EBV
o highly aggressive
Hodgkin lymphoma
- arises in a single node or chain of nodes and spreads 1st to anatomically contiguous lymphoid tissues
- staging is very important in guiding therapy
- average age at Dx = 32 years
- Reed-Sternberg cells
- WHO classification:
o nodular sclerosis
o mixed cellularity
o lymphocyte-rich
o lymphocyte depletion
o lymphocyte predominance (non-classical)
- classical types are PAX5+, CD15/30+
- activation of NF-KB is common in classical (usually from EBV infection)
- clinical:
o most commonly present as painless lymphadenopathy
o fever, night sweats, weight loss
o cutaneous anregy
o nodal à splenic à hepatic à marrow + other tissues
o increased risk of developing secondary CA:
§ myelodysplastic syndromes
§ AML
§ lung CA
Nodular sclerosis
- most common HL
- lacunar variant of RS cells
- deposition of collagen bands that divide involved lymph nodes into circumscribed nodules
- male=female
- lower cervical, spraclavicular, mediastinal lymph nodes
- prognosis excellent
Mixed-cellularity
- involved lymph nodes diffusely effaced by heterogenous cellular infiltrate of T cells, eosinophils, plasma cells, benign macrophages mixed with RS cells
- RS and mononuclear variants plentiful
- EBV in 70% of cases
- more common in males, older age, advanced tumor stage
Lymphocyte-rich
- uncommon
- reactive lymphocytes make up most of cellular infiltrate
- RS and mononuclear variants cells present
- EBV in 40% of cases
Lymphocyte depletion
- abundance of RS cells or their pleomorphic variants
- paucity of lymphocytes
- EBV in >90% of cases
- mostly in elderly and HIV pts
Lymphocyte predominance
- “nonclassical”
- lymphocytic and histiocytic variants (L&H)
o “popcorn cell”
o express B-cell markers typical of germinal-center B cells (CD20 and BCL6)
- males, <35 years old
- present with cervical or axillary lymphadenopathy