Chapter 13: White Blood Cells Flashcards
What CDs are makers of HSC and ALL white blood cells?
HSC - CD34
WBC - CD45 (leukocyte common antigen)
What is HSC location throughout development?
3rd week –> yolk sac
3rd month –> liver
4th month –> bone marrow (puberty –> ONLY AXIAL)
Where is EPO generated from and what are its two production modes?
- generated by KIDNEY (peritubular capillary lining)
- released relative to Po2
contantly Hb >10 or logarithmically Hb <10
What is the normal % of T Cells in the peripheral blood?
80%
What is the most common cause of agranulocytopenia?
DRUG TOXICITY
- inc. susceptibility to bacterial or fungal infection, since it is a reduction in the number of neutrophils
What do infections occurring due to agranulocytosis look like (2)? When does serious infection normally occur?
- infections with ulcerating necrotizing lesions of mouth (agraun. angina)
- deep lesions w/dark necrotic membranes (Candida/Aspergillus)
serious infection occurs w/neutrophil count <500
How is Agranulocytosis treated?
broad spectrum antibiotics and GCSF to stimulate granulocyte production
When will LAP (Leukocyte alkaline phosphatase) be elevated vs normal?
Elevated –> leukemoid reactions
Normal –> leukemia
What is the effect of Sepsis on neutrophils morphology (2) specifically?
appearance of toxic granulations (abnormal, dark azurophilic granules) and Dohle bodies (dilated endoplasmic reticulum)
Acute Nonspecific Lymphadenitis:
What is the difference between Localized, Systemic, and Mesenteric forms?
L: from direct microbiological draining
S: from bacteriemia and viral infections (usually kids)
M: mesenteric LN enlargement (looks like appendicitis)
Where is Chronic Nonspecific Lymphadenitis commonly seen in? What does the lymph node look like?
- commonly occurs in inguinal and axillary LNs
- LNs are nontender without acute inflammation or tissue drainage
What development in nonlymphoid tissue can chronic immune reactions lead to, and what is the common cytokine required?
- leads to Tertiary Lymphoid Organs
- chronic gastritis (H. pylori) and Rhematoid arthritis lead to MALToma’s
- lymphotoxin required for Peyer Patch formation
What are 3 common causes of follicular hyperplasia and what are Tingible-body macrophages?
CC: rheumatoid arthritis, toxoplasmosis, early HIV
TBM = macrophages that have eaten apoptotic B Cells
What is a common cause of Paracortical Hyperplasia, and what happens when these reactions become exuberant?
- T cell mediated response like that to infectious mononucleosis (EBV)
- exuberant rxns cause immunoblasts to encroach on B-cell follicles, leading to sinusoidal/endothelial hypertrophy
- if immunoblasts (large, activated T-cells) are numerous, need special studies to exclude neoplasm from the differential
Sinus Histocytes (Reticular Hyperplasia)
- inc. in number and size of cells lining lymphatic sinusoids (expansion/distension)
- nonspecific, though seen in LNs draining carcinoma of the breast
Hemophagocytic Lymphohistiocytosis:
What is it and what is its pathogenesis? What is it most commonly caused by?
- aka “Macrophage Activating Syndrome” –> cytopenias and symptoms of systemic inflamm dur to macrophage activation
- macrophages and CD8+ cells destroy peripheral and marrow cell lineages, while releasing mediators that suppress hematopoiesis
- infection is most common trigger (EBV especially)
Hemophagocytic Lymphohistiocytosis:
What does it look like clinically and how can it be treated?
- acute febrile illness and hepatosplenomegaly with anemia/thrombocytopenia
- inc. LFTs/TG (hepatitis) and DIC may be present
Treatment: immunosuppressive drugs and mild chemo
- only about 50% survive (may have sequelae)
Myeloid Neoplasms
What is the difference between Acute Myeloid Leukemia, Myelodysplastic Syndrome, and Chronic Myeloproliferative Disease?
AML: blasts accumulate in bone marrow suppressing normal hematopoiesis (MOST SEVERE)
MDS: ineffective hematopoiesis, causing peripheral blood cytopenias (more severe than MPD)
CMD: inc. production of one or more adult myeloid elements leads to inc. peripheral blood counts
less severe types can evolve over time into more aggressive forms of disease
What kinds of cancer do these viruses lead to:
- HTLV1
- EBV
- KSHV/HHV8
- HIV
- adult T-cell leukemia/lymphoma (ATLL)
- Burkitt lymphoma, Hodgkins, other B-cell lymphoma
- paracortical response to B cell infection in Burkitt
- B-cell lymphoma (malignant pleural effusions)
- B-cell lymphoma
What is the difference in spread of Hodgkins vs Non-Hodgkins lymphoma?
Hodg: spreads in an orderly fashion, staging useful
- distinctive pathological features, unique treatment
NonHodg: spreads widely and is less predictable
Acute Lymphoblastic Leukemia (ALL):
What is it, who does it commonly affect, and what is its pathogenesis between T and B cells?
- immature lymphoblast neoplasm (mostly B-ALL)
- affects hispanics > white > blacks and is the MOST COMMON cancer/leukemia of childhood (< 15)
- B cells: 90% t(12;21) translocation (ETV6/RUNX1)
- also LOF in PAX5, E2A, RBF
- T cells: GOF in NOTCH1
Acute Lymphoblastic Leukemia (ALL):
What is the morphology and how can you tell this neoplasm apart from Acute Myeloid Leukemia?
- hypercellular bone marrow with “starry sky” appearance due to macrophages eating tumor cells
- scant basophilic cytoplasm with large nuclei
- ALL stains MPO (-) and TdT (+), while AML is MPO (+) and TdT (-), also more likely to cause NERVE PALSIES than AML
Acute Lymphoblastic Leukemia (ALL):
What does it look like clinically (4) and how is it treated?
- mass effect, “storm-onset” (onset in days to weeks), fatigue, fever, bleeding (due to cytopenia), and NEUROLOGICAL problems (nerve palsies, headaches, vomiting)
Treat: aggressive chemo (95% remission, 75-85% cured)
Acute Lymphoblastic Leukemia (ALL):
What is the difference between a good prognosis and bad prognosis?
Good: age 2-10, low WBC count, HYPER-DIPLOIDY, and t(12;21) translocation
Bad: age < 2, t(9;22) translocation (seen in adolescence w/WBC count >100,000)
What are common B and T cell markers that can be checked for when determining the kind of lymphoid neoplasm?
B cell: CD 10, 19, 20
- very immature will be CD 10 (-)
T cell: CD 1, 8
- very immature will be CD 3, 4, 8 (-)
What are the three “T’s” of T-cell ALL?
presents Teenaged males as a Thymic mass (mediastinal) and has Thymocytes
- also see splenomegaly
Chronic Lymphocytic Leukemia (CLL):
What is it, who does it affect, and what chromosomal anomalies does it show?
- most common leukemia of adults in Western World
- affects males (2:1) that are 60 yo in Western countries
- translocations are RARE, has deletion 13q14.3 (microRNA 15/16) and 11q, 17q
PNEUMONIC: 11, tr12, 13q14, 15, 16, 17
Chronic Lymphocytic Leukemia (CLL):
What is the morphology and immunophenotype? What are 3 indicators of BAD prognosis?
M: develop proliferation centers (large lymphocytes gather in aggregates - mitotically active); promylocytes if LN is involved (Small Lymphocytic Lymphoma)
I: CD 5, 19, 20, 23 (B cell prolif. w/CD5 = CLL)
B: 11q, 17p deletions, ZAP70(+), NOTCH1 mutations
Chronic Lymphocytic Leukemia (CLL):
What are the clinical aspects and treatments for patients?
C: asymptomatic –> nonspecific signs (hepatosplenomegaly and lymphadenopathy), monoclonal Ig spike may be preset
- can cause hypogammaglobulinemia (low IgG)
T: gentle chemo, immunotherapy (CD20), BTK inhibitors, HSC transplant (median survival 4-6 yrs)
Richter Syndrome and CLL
- tendency of CLL/SLL to transform to diffuse B-cell lymphoma
- rapidly enlarging mass within LN or spleen
- BAD (survival < 1 yr)
Follicular Lymphoma:
What is it, what is its pathogenesis (translocation?), and what is its morphology (3 places)?
- LN tumor causing obliteration of architecture and is the most common indolent form NHL in the US
P: germinal centers; associated with t(14;18) BCL2/IgH
- devoid of apoptotic cells do to BCL2 blockage
- MLL2 (histone methyltransferase mutation)
M: diffuse proliferation of centrocytes/centroblasts
- also lymphoid aggregates in bone, spleen white pulp, and hepatic portal triads
Follicular Lymphoma:
What is its immunophenotype and what is its clinical presentation? What two types of cancer can it progress to?
I: CD10, 19, 20 (+) and CD5 (-)
- also BCL6/BCL2 (+)
C: painless presentation in middle-age w/generalized lymphadenopathy; INCURABLE; “waxing-waning” course with 7-9 yr survival –> PALLITATE
**can transform to Diffuse Large B-cell Lymphoma (30-50%) or Burkitt Lymphoma
Diffuse Large B-cell Lymphoma (DLBCL):
What is it, what is its pathogenesis, and what other mutations can it have (2 major)?
- most common form of NHL (median 60 yo)
P: 3q27 mutation involving BCL6 (inhibits GC diff., growth arrest, and apoptosis)
- also see t(14;18) with BCL2 (anti-apoptosis) –> not normal to see BCL2 and BCL6
- also see Myc mutations
Diffuse Large B-cell Lymphoma:
What does it look like, what is its immunophenotype, and where is it located?
M: massive cells with ROUND-OVAL nucleus, diffuse growth pattern (rapidly enlarging mass)
I: CD19, 20 (+)
L: can arise anywhere in the body, but common at Waldeyer Ring (oropharyngeal tonsils/adenoids)
- can go extranodally to GI/skin/bones (rare)/brain
Diffuse Large B-cell Lymphoma:
What does it look like clinically and what finding leads to a worse outcome?
C: aggressive and rapidly fatal without treatment
- 60-80% remission, 40-50% cured
WO: Myc translocation = treat like Burkitt Lymphoma
What is the difference between Immunodeficient-associated Large B-cell Lymphoma and Primary Effusion Lymphoma?
- both are DLBCL subtypes
I = severe T-cell immunodeficiency from EBV B-cell inf.
P = malignant pleural or ascitic effusion
- tumor cells have no cell markers
- infected with KSHV/HHV8
Burkitt Lymphoma:
What is its pathogenesis (translocation?), morphology, and immunophenotype?
P: t(8;14) translocation - Myc/IgH
- can also have t(2;8) or t(8;22) light chains
- FASTEST GROWING TUMOR (doubles 36 hrs)
M: high mitotic index (Tingible-body MO) and “starry sky” pattern
- if BM - royal blue cytoplasm w/clear cyto vacoules
I: CD 10, 19, 20; BCL6 (+)/BCL2 (-), MYC (+)
What is the difference between Sporadic, African (endemic), and HIV-associated Burkitt Lymphoma?
S: t(8;14) w/mass of ileocecum and peritoneum
- 15-20% EBV infection
A: t(8;14) w mandible mass and or abdominal masses
- all patients have EBV
H: t(8;14) and 25% of pts have EBV
Burkitt Lymphoma:
What does it look like clinically?
- 30% of NHL in the United States
- very aggressive, but responds well to intense chemo; children/young adults are usually cured
What are Plasma Cell Neoplasms (dyscrasias)? What are M components and Bence-Jones proteins?
- neoplastic plasma cells that typically secrete monoclonal Igs
- M component = monoclonal Ig in blood (not urine)
- BJ proteins = excess light chains passed in urine
What is the most common plasma cell dyscrasias and what is the most common plasma cell malignancy?
PCD = Monoclonal Gammopathy of Uncertain Significance (MGUS)
PCM = Multiple Myeloma
Multiple Myeloma:
- What is it, who is at risk, and what is the CRAB pneumonic for symptoms?
- MOST COMMON plasma cell neoplasm
- causes bony destruction of the skeleton (pain via pathologic fractures –> hypercalcemia/renal failure)
- affects 60-75 yo males of African descent
C (hyperCalcemia), R (renal failure), A (acquired immune problems), B (bone lytic lesions)
What is the difference between Solitary and Smoldering myeloma?
Solitary - single mass in bone/soft tissue
- almost always progresses to multiple myeloma
Smolder - lacks signs/symptoms with HIGH plasma M
- no lytic bone lesions, 75% progress to MM in 15 yrs
- middle ground between MM and MGUS
Multiple Myeloma:
How does the tumor survive and what is the morphology of the bone lesions?
S: IL-6 (plasma cell growth) –> high = BAD prognosis
- MIP1a inc. NFkB (RANKL) activating osteoclasts
- leads to inc. bone resorption
M: in axial skeleton
- 1-4 cm punches with soft, gelatinous red tumor masses
Multiple Myeloma:
What is the morphology of the neoplastic cells (FM) and what is their immunophenotype?
M: M protein causes Rouleaux formation (RBC “sticks)
- Flame cells: red cytoplasm; degraded proteins
- Mott cells: grape-like cytoplasmic droplets
may have Russell (cytoplasmic) or Dutcher (nuclear) bodies of fibrils, crystalline rods, and globules
I: CD138 (+) and CD56 (+)
What are the two most common causes of death for Multiple Myeloma pts? What are two types of light chains that can be deposited as amyloids, causing amyloidosis?
- infections (dec. prod. of normal Igs)
- renal failure
- due to Bence-Jones Proteinuria
- excreted light chains are toxic to renal tubular cells
- due to Waldernstrom Macroglobulinemia
- excess IgA/IgG –> hyperviscous blood
amyloidosis –> lambda 3 and 6 light chains
Multiple Myeloma:
What does marrow involvement give rise to and what are treatment options for patients (4)?
M: require BM exam; normal RBC anemia, moderate leukopenia/thrombocytopenia
T: survival 4-7 years, NO CURE
- proteasome inhibitors: degrade proteins
- thalidomide, HSC transplant prolongs life
- biphosphonates inhibit bone resorption
Lymphoplasmacytic Lymphoma:
What is it, what is its pathogenesis (translocation?), and what is its morphology?
- B-cell neoplasm of adults (6-7th decade) where substantial fraction of tumor cells terminally differentiate (vs CLL)
- acquired MYD88 mutation (inc. growth/survival)
M: MAST CELL hyperplasia with Russell (cytoplasm) and Dutcher (nuclear) PAS(+) bodies
Lymphoplasmacytic Lymphoma:
What is its immunophenotype, how does it present clinically (4), and what are treatment options?
I: CD20 (+), usually IgM (+) –> IgM will match surface Ig
C: nonspecific signs, no bone lesions, lymphadenopathy/hepatosplenomegaly in 50%
- cold agglutinins –> autoimmune hemolysis (10%)
T: NO CURE, low dose chemo/immunotherapy, median 4 yr survival
What is Waldernstrom Macroglobulinemia?
- high IgM lvls lead to hyperviscosity blood symptoms
- retinopathy, neuro symptoms, spontaneous bleeds
- Cryoglobulinemia causes Raynauds phenomenon at low temperatures
Mantle Cell Lymphoma (MCL):
What is it, who is at risk, and what is its pathogenesis?
- tumor cells that look like normal mantle zone B cells
- Naive B cell origin
- presents in males (5th-6th decade)
P: t(11;14) cyclin D/IgH (overexpression of G1 - S phase progression)
Mantle Cell Lymphoma (MCL):
Where are tumors usually found, what is its morphology, and what is its immunophenotype?
What tells it apart from CLL?
- can have extranodal involvement (bone, spleen, liver, gut); causes lymphomatoid polyposis (bowel polyps)
- for a large “mantle zone” around a small germinal center (Follicular has NO GC)
- inc. Cyclin D1, CD 5, 19, 20 (+)
- no Ig hypermutation (Naive B cells)
- no CD23 (differentiates from CLL)
Mantle Cell Lymphoma (MCL):
What is the clinical outcome and what are possible treatment options?
- painless lymphadenopathy, poor prognosis with median survival of 3-4 yrs; death via organ dysfunction
- chemo is NOT helpful
Marginal Zone Lymphoma:
What is it and where does it normally occur at?
- tumors from MEMORY B-cells located in lymph nodes, spleen, and extranodal tissue
- called MALTomas (arise in tissue affected by chronic inflammation) –> thyroid (Hashi), salivary glands (Sjog), stomach (H.Py)
- usually localized but can spread late in course
Marginal Zone Lymphoma:
What is its pathogenesis? What 3 translocations are specific for Marginal Zone Lymphomas?
- monoclonal B-cells that rely on antigen stimulated Th cells
- t(11;18), t(14;18), and t(1;14) –> specific for EXTRANODAL marginal zone lymphomas (MALTomas)
- can transform to large B-cell lymphoma
Hairy Cell Leukemia:
What is it, who is at risk, and what is its pathogenesis?
- rare w/”hair-like” projections from leukemic cells
- MEMORY cell origin
- middle-aged (55) white males (5:1)
P: BRAF activating mutation (valine–>glutamate)
- downstream of RAS in MAPK signaling
Hairy Cell Leukemia:
What does it look like and what is its immunophenotype?
M: fine, hair-like projections; kidney-shaped nuclei
- tumor cells trapped in ECM (no Aspiration)
- heavily infiltrated splenic Red Pulp (no white)
I: CD11c, 19, 20, 25, 103 (+)
- Annexin A1, TRAP, and surface IgG (+)
Hairy Cell Leukemia:
How does it present clinically and what are treatment options?
- massive splenomegaly (NO hepatomegaly or lymphadenopathy)
- pancytopenia from marrow involvement/spleen sequestration (inc. infection mycobact. kansasii)
T: exceptionally sensitive to gentle chemo (long lasting remission), BRAF inhibitors (excellent response if fail chemo)
EXCELLENT PROGNOSIS
Peripheral T-cell Lymphoma:
What is it and what is it immunotype?
- mature T cell tumor
I: CD2, 3, 5 (+) –> requires immunotyping
- has aB or yd TCRs
Peripheral T Cell Lymphoma:
What is its morphology and how does it present clinically (5)?
- diffuse through LN with mixed sized malignant T-cells
- infiltrate of reactive cells (possible neoangiogenesis)
C: general lymphadenopathy +/- pruritis, eosinophilia, fever, weight loss
- worse prognosis than B-cell types, CURE RARE
Anaplastic Large Cell Lymphoma:
What is it and what is its pathogenesis? What is its immunophenotype (2)?
What rearrangement is pathognomonic for it?
- T-cell lymphoma w/GOOD prognosis
P: ALK rearrangement on chromosome 2p23
- not expressed on normal lymphocytes
- pathognomonic
I: CD30 (+), CD8 cell is anaplastic
Anaplastic Large Cell Lymphoma:
What is its morphology and how does it present clinically?
M: horshoe nuclei and voluminous cytoplasm (HALLMARK CELLS)
- surround venules; mimic metastatic carcinoma
C: common in kids/young adults
- chemotherapeutic cure = 75-80%
- ALK (-) adults = worse prognosis
Adult T-cell Leukemia/Lymphoma (ATLL):
What is it, what is its pathogenesis, and what is its morphology?
- CD4 neoplasm via HTLV-1 (Japan, Caribbean, W. Africa)
P: HTLV-1 produces Tax protein = NFkB activation
M: multi-lobulated nuclei (Clover/Flower cells)
Adult T-cell Leukemia/Lymphoma (ATLL):
How does it present clinically (5) and what is its prognosis?
C: skin lesions, general lymphadenopathy, hepatosplenomegaly, peripheral blood lymphocytosis, hypercalcemia
P: rapidly progresses, fatal in months to 1 yr despited chemo
Mycosis Fungoides/Sezary Syndrome:
What is it and how do they work? What are their markers (3)?
- tumor of CD4+ helper cells that homes to skin
MF: premycotic, plaque, tumor
- neoplastic T-cells with cerebriform appearance
- late disease goes to LNs and bone marrow
SS: rarely progresses to tumefaction
- generalized exfoliative erythroderma
markers: CLA (+), CCR4/CCR10 (+)
- median 8-9 yr survival
Large Granular Lymphocytic Leukemia:
What are the two variants, what is their morphology, and how do they present?
- either T cell (CD3/indolent) or NK (CD56/common/agg)
- STAT3 mutation; large w/blue cytoplasm & azurophilic granules
C: neutropenia/anemia (tho low marrow involvement), mild lymphocytosis and splenomegaly and rhematoid disorders (“FELTY SYNDROME”)
Extranodal NK/T-cell Lymphoma:
What is it, what is its immunophenotype, and how does it present clinically?
- destructive nasopharyngeal mass (ischemic necrosis); arises from EBV infected cell (seen in Asia)
- no CD21 or CD3, no TCR rearrangements; only NK cell markers
C: highly aggressive; likes radiation but not chemo
- poor prognosis in advanced disease
When does Hodgkins Lymphoma usually present and what are the classical cells used to diagnose it?
- usually occurs at age 32, and is treated with radiation and chemotherapy (curable in most cases)
- Reed-Sternberg cells
What is the difference between Classical Hodgkins Lymphoma and Lymphocyte predominance Hodgkins Lymphoma pathogenesis?
C: acquired mutations and EBV
- Ig genes (VDJ/Somatic Hyper) but aren’t expressed
- NF-kB activation via LMP1 (upregulation)
LP: express B-cell markers and no EBV
- Reed Steinberg cells that express B-cell markers
Nodular Sclerosis Hodgkins Lymphoma
- most common for (70%); adolescents/young adults
- EXCELLENT prognosis
- Lacunar cells, collagen bands that divide LNs, NO EBV
- PAX5, CD15/30 (+)
- usually in cervical, supraclavicular, mediastinal LNs
Mixed Cellularity Hodgkins Lymphoma
- 2nd most common, male predominance (biphasic dist)
- night sweats, weight loss, prognosis very good
- Reed Sternberg (70% EBV) w/mononuclear variants
- PAX5, CD15/30 (+)
Lymphocyte Rich Hodgkins Lymphoma
- reactive lymphocytes w/occasional residual B follices
- excellent prognosis
- 40% of cases are EBV+
- PAX5, CD15/30 (+)
Lymphocyte Depletion Hodgkins Lymphoma
- least common, elderly (HIV) in industrialized countries
- worst prognosis
- scarce lymphocytes with EBV in 90% of cases
- PAX5, CD15/30 (+)
do immunophenotype to see if it is in fact Large cell non-hodgkins lymphoma
Lymphocyte Predominance Hodgkins Lymphoma
- males < 35 w/cervical or axillary lymphadenopathy
- excellent prognosis, even with inc. recurrence
- “popcorn” cells with small lymphocytes/macrophages
- CD20, BCL6 (+) and CD15/30 (-); NO EBV
What is the common progression of Hodgkins Lymphoma and what is its prognosis?
nodal disease –> splenic –> hepatic –> marrow/tissues
- tumor stage is MOST important prognostic factor
- AntiCD30 produce excellent response in pts failing conventional methods (NOT in Predominance type)
What are the four stages of Hodgkins Lymphoma staging?
Stage 1
Stage 2
Stage 3
Stage4
S1: single LN or extra-lymphatic organ/site
S2: involvement of 2+ LNs on SAME SIDE of diaphragm
- localized involvement of extra-lymphatic organ
S3: LNs on BOTH sides of diaphragm w/o OR with localized involvement of extra-lymphatic organ
S4: diffuse involvement of 1+ extra lymphatic organs or sites +/- lymphatic involvement
What is Acute Myeloid Leukemia? What are the 2 most common chromosomal rearrangements?
- accumulation of at least 20%+ immature myeloid blasts in the bone marrow (confirm with MPO test)
- peaks after 60 yo; causes anemia, thrombocytopenia, neutropenia
t(8;21) - RUNX1 disrupted
inv(16) - CBFB disrupted
normally bind to form factor for normal hematopoiesis
What are the differences between AML Classes?
Class I
Class II
Class III
Class IV
C1: favorable prognosis (t(8;21)/inv(16)), intermediate prognosis (t(15;17) - APML), poor prognosis (t(11;q23))
C2: AML w/MDS features, poor prognosis
C3: therapy-related, very poor prognosis
C4: all AML’s that lack features of other classes
- intermediate prognosis
What subtype of AML has the t(15;17)? What does this translocation cause and how can it be treated?
Acute Promyelocytic Leukemia
- may exhibit early, significant life-threatening bleeding (DIC once established is often fatal)
PML-RARa fusion protein interferes with terminal differentiation of granulocytes
- treat with all-trans retinoic acid/arsenic trioxide
What is the difference between AML myeloblast morphology and monoblast morphology?
Mye: peroxidase (+) azurophilic granules, Auer rods
- common in AML w t(15;17)
- voluminous cytoplasm, 2-4 nucleoli
Mono: peroxidase (-), nonspecific esterase (+)
- no Auer rods, folded/lobulated nuclei
What are the clinical symptoms of AML?
anemia, fatigue, neutropenia
- fever due to opportunistic infection of oral cavity, skin, lungs, kidneys, bladder, colon
- tumors can be localized soft-tissue masses (w/o systemic treatment will progress to full disease)
What is the prognosis of AML?
- 60% remission with chemotherapy (5 yrs - 70-85%)
- 80% of t(15;17) cured w/all-trans retinoic acid
- t(8;21), inv(16) w/o KIT mutant –> good prog w/chemo
AMLs following MDS/genotoxic therapy/older adults have dismal prognosis (Transplant HSC)
Myelodysplastic Syndromes (MDS):
What is it and how is it caused? What does it look like?
- clonal stem cell disorders w/maturation defects due to ineffective hematopoiesis
- characterized by thrombocytopenia
cause: transformation occurs most rapidly/frequently in t-MDS or appears 2-8 yrs after genotoxic therapy
M: disordered differentiation of myeloid lineages
MDS Erythroid, Granulocyte, and Megakaryocyte Lineage effects?
E: ring sideroblasts (iron-laden macrophages)
- maturation similar to B12/folate deficiency
- misshapen nuclei
G: dec. secondary granules, Dohle bodies, Pseudo-Pelger-Huet bodies (neutrophils with only two nuclear lobes)
M: cells w/single nuclear lobe or multiple separate lobes (pawn balls)
What is the clinical difference between Primary MDS and t-MDS? How are they treated?
P: avg. 70 yrs and survive up to 5+ yrs
- pancytopenia; 10-40% progress to AML
- COD: infection and bleeding
t: appears 2-8 yrs after genotoxic treatment (survive 4.8 months = TERRIBLE prognosis)
- cytopenias are severe, progression to AML rapid
Treat
- HSC transplant in young patients, older ones get antibiotics/transfusions
What are Chronic Myeloproliferative Disorders?
- mutated active tyrosine kinases causing growth factor independence (does NOT impair differentiation)
- inc. production of one+ mature blood elements (pancytosis of everything) but bleeding because platelets are abnormal
- neoplastic stem cells tend to home to secondary hematopoietic organs
Chronic Myelogenous Leukemia (CML):
What is it and what is its morphology? What is a characteristic finding of it?
- MOST COMMON myeloproliferative disorder (chimeric BCR-ABL gene driven by t(9;22) Philadelphia chromo)
- inc. granulocytic precursors (basophils/eosinophils) and inc. platelets and normal erythroid precursors
- *Sea-Blue Histiocytes are characteristic finding**
- wrinkled macrophages w/green-blue cytoplasm
Chronic Myelogenous Leukemia (CML):
How does it present clinically (4) and how is it diagnosed?
C: 50-60 yos (male predominance)
- HUGE spleen (extramedullary hematopoiesis)
- LUQ pain or splenic infact
- fatigue/weight loss/anorexia/hyper-metabolism
D: detect BCR-ABL w/PCR, LAP is low
- worse prognosis w/o Philadelphia Chromosome
Chronic Myelogenous Leukemia (CML):
What is the prognosis and treatment for it?
- pt lives 3 years w/o treatment
- accelerated phase –> blast phase (acute leukemia)
T: 90% remission with Gleevec (BCR-ABL inhibitor)
- HSC transplant for younger (75% cure)
Polycythemia Vera (PCV):
What is it and what is its pathogenesis?
- inc. RBCs due to point mutation in JAK2 (slight inc. in platelets)
- Valine –> phenylalanine at residue 617 (acts independent of GF)
- constitutively active JAK2 affects JAK-STAT pathway decreasing the requirements of EPO
Polycythemia Vera (PCV):
What is the difference between the Early Phase and Spent Phase? What are sequelae of disease (2)?
E: organomegaly (congestion) and basophilia/large platelets
S: late in course: extensive marrow fibrosis and hepatosplenomegaly (extramed. hematopoiesis)
Sequelae: inc. risk of thrombosis, hyperuricemia (high cell turnover –> GOUT)
Polycythemia Vera (PCV):
What are clinical and lab findings of disease?
C: uncommon adult disease, prone to have thrombosis and bleeding, venous circulation congests (hyperviscosity), deoxygenated blood in periphery longer –> HA, dizziness, HTN
Pruritis after taking a hot shower
L: greatly inc. hematocrit, inc. hemoglobin, IRON DEFICIENCY due to chronic bleeding, inc. WBC/platelets
Polycythemia Vera (PCV):
What is the prognosis of disease?
- if untreated = death within months
- ALL transformation rare
- phlebotomy extends survival to 10+ years
Essential Thrombocytosis:
What is it, what are its important mutations, and what is its prognosis?
- elevated platelet counts w/o polycythemia or marrow fibrosis (inc. megakaryocytes) - diagnosis of exclusion
mutations: Activation JAK2 (50%)
P: insidious (long asymptomatic phase), survival 12-15 years
Essential Thrombocytosis:
What are clinical findings and treatment of disease?
C: adults > 60; organomegaly, thrombosis/hemorrhage
- DVT, portal and hepatic vein thrombosis, MI
- Erythromelalgia: small artery occulsion
- burning/throbbing of hands/feet
T: gentle chemo to suppress thrombopoiesis
Primary Myelofibrosis:
What is it, what is its mutation, and what is its pathogenesis?
- obliterative marrow fibrosis (identical to spent phase of other disorders) –> LEAST COMMON; collagen deposition by non-neoplastic fibroblasts
Mutation: Activating JAK2 or MPL mutation, also calreticulin
P: inappropriately released PDGF/TGFb, extramedullary hematopoiesis, anemia
Primary Myelofibrosis:
What is the morphology of the spleen and blood (3)? What are common lab findings of disease?
Spleen: splenomegaly, red-gray/firm
Blood: DaCRYocytes (tear drop-shaped cells damaged during release from fibrotic marrow, abnormally large platelets, basophilia
Labs: normocytic, normochromic anemia w/leukoerythroblastosis (WBC/platelets variable)
Primary Myelofibrosis:
How does it present clinically, what is the prognosis of disease, and how can it be treated?
C: patient > 60 yo w/LUQ fullness and hyperuricemia
- night sweats, fatigue, weight loss (inc. metabolism)
- diagnose with BONE MARROW BIOPSY
P: survive 3-5 years
T: JAK2 inhibitors for splenomegaly, HSC transplant for younger
Langerhans Cell Histocytosis:
What is it, what is its immunophenotype (5), and what are common mutations seen in it?
- proliferative macrophage/dendritic cell disorders
- BIRBECK granules in cytoplasm (“tennis racket” shaped containing langerin)
I: HLA-DR, S100, CD1a (+) and CCR6+CCR7
M: BRAF activating mutation (similar to hairy cell)
Multifocal Multisystem Langerhans Cell Histocytosis:
What is it, how does it present clinically (2), and what is its treatment/prognosis?
- malignant Langerhans proliferation in kids < 2 yo (can be seen in adults)
- Letterer-Siwe Disease
- SEBORRHEIC eruption over trunk/scalp, destructive osteolytic bone lesions, anemia/thrombocytopenia/recurrent infections
T: intensive chemotherapy (rapidly fatal, 5 yr survival 50%)
Unifocal Unisystem Langerhans Cell Histocytosis:
What is it and how does it present clinically? What does biopsy reveal?
- benign Langerhans proliferation in medullary cavity of bone (adolescents)
- eosinophilic granuloma
- pathologic fracture/pain/tenderness
- biopsy: Langerhans cells with numerous eosinophils
Mutifocal Unisystem Langerhans Cell Histocytosis:
What is it and how does it present clinically?
What is the Hand-Schuller-Christian Triad?
- benign Langerhans proliferation in young children
- multiple erosive bone masses that can extend into soft tissue (diabetes insipidus in 50% due to pituitary stalk involvement)
- treat with chemo or spontaneous regression
HSCT: calvarial bone defects, diabetes insipidus, exophthalmos
Pulmonary Langerhans Cell Histocytosis:
What is it?
- reactive proliferation of Langerhans cells with nodules/cysts in middle and upper lung lobes
- seen in adult smokers (pulmonary disease may regress with cessation); 40% due to BRAF mutations
Spleen Functions:
- Phagocytosis
- Ab production
- Hematopoiesis
4: Sequestration of formed blood elements
- MO eat undeformable RBCs, remove Heinz/Howell Jowel bodies, and remove bacteria/particles
- antibody-secreting plasma cells in red pulp sinuses; make Abs against bacterial polysaccharides/auto-Abs against self-Ags
- used during development, but can be an extramedullary site in certain disease states
- enlargement can cause holding of 80-90% of bloods platelets; can cause thromobcytopenia/leukopenia
What condition does asplenia make a patient more susceptible to and what 4 microbes should they be vaccinated against? (PMHN)
What is the “dragging” sensation experienced in the LUQ?
- inc. risk of sepsis due to incapsulted bacteria
- vaccinate against: pneumococci, meningococci, H. influenzae, and Neiserria
- due to splenomegaly, discomfort from eating due to pressure on stomach
What is Nonspecific Acute Spenitis?
- reactive enlargement of spleen
- acute congestion of red pulp may encroach on lymphoid follicles (white pulp necrosis - hemolytic streptococcus)
Congestive Splenomegaly:
What is it, what causes it, and what is its morphology?
- caused by chronic venous outflow obstruction (from intrahepatic disorder affecting portal drainage)
- causes cirrhosis and leads to portal/splenic vein hypertension
M: gray-red to deep red surface, firm, thick and fibrous
Splenic Infact:
What does it look like and what commonly causes it?
- occluded major splenic artery (no collaterals); common site of emboli from the heart
M: pale, wedge-shaped, subcapsular, fibrous capsule (BLAND) OR suppurative necrosis w/depressed scars (SEPTIC due to infective endocarditis)
Spleen Neoplasms and Congenital Abnormalities
primary neoplastic involvement RARE, when it does happen it is usually benign
CA: hypoplasia MORE common than complete absence
- check for accessory spleen when doing splenectomy, because it could nullify the treatment if not removed too
Splenic Rupture:
What commonly precipitates it and what 4 things are common predisposing factors? (MMTL)
- commonly precipitated by BLUNT TRAUMA
PFs: Malaria, infective Mononucleosis, Typhoid fever, Lymphoid neoplasm
unlikely to rupture chronically due to reactive fibrosis of capsule
DiGeorge Syndrome:
What is it and what problems can it cause?
- thymic hypoplasia/aplasia due to problems w/3rd and 4th pharyngeal pouches
- hypocalcemia, chromosome 22q11 deletion (cardiac defects, abnormal face, cleft palate, thymic hypoplasia)
Thymic Follicular Hypoplasia:
What is it and what causes it?
- B-cell proliferation in thymus (germinal centers)
- most common in myasthenia gravis (65-75%)
or other autoimmune disorders
What is a Thymoma and what are its 3 histological subtypes?
- tumor of thymic epithelial cells (squamous cells) containing benign immature T-cells (THYMOCYTES)
- usually seen in adults > 40, rare in kids
Subtypes:
Benign: cytologically benign and non invasive
Malignant: cyto benign but invasive (NO ATYPIA)
Malignant: malignant (CELLULAR ATYPIA)
Noninvasive Benign Thymoma:
Where is it commonly located and how does it present clinically (2)
- common in anterior superior mediastinum (can impinge upon structures),
- tumors w/medullary epithelial cells are usually NONINVASIVE
pts present with impingement (40%), mysathenia gravis (30-45% of pts have thymoma)
- thymocytes from thymomas generate long-lived CD4/CD8 cells (inc. association with autoimmunity)
What are the two types of Malignant Thymoma?
Type 1: Invasive Thymoma
- 20-25%; tumor cytologically bland/locally invasive
- minimal invasion/excision = 90% 5 yr survival
- extensive invasion = 50% 5 yr survival
Type 2: Thymic Carcioma
- 5%; fleshy, invasive masses metastasize to lungs
- most SQUAMOUS CELL CARCINOMAS
- 2nd: lymphoepithelioma-like carcinoma
What does lymphoepithelioma-like carcinoma look like?
sheets of cells with indistinct borders
- resembles nasopharyngeal carcinoma
- EBV genomes found in 50%
