CANCER Flashcards by Nick Yetter

Angioimmunoblastic T-cell Lymphoma Presentation and Morphology

Clinical Presentation: rapidly progressive critical illness, diffuse lymphadenopathy, hepatosplenomegaly, skin rash, cold autoimmune hemolytic anemia, evidence of immunocompromise

Normal Counterpart: Follicular T-helper cells (involved sites: lymph nodes, spleen, liver, BM and skin)
Morphology: will see enlarged lymph node b/c of expanded paracortex
Reactive will see expansion of small paracortical vessels and immunoblast, microscopic examination is not always helpful

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Angioimmunoblastic T-cell Lymphoma: Immunophenotyping

CD3+, CD4+ and CD10+
CD10: usally a marker of B-cells in germinal center, presence in paracortex on these T cells can lead toward diagnosis
CD21: residual FDC network, should be absent if there is not a germinal center, but with this lymphoma they are present and staining for CD21+ can help diagnose

Picture: L-CD3 and R-CD10

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Angioimmunoblastic T-cell Lymphoma: Genetics and Clinical Course

Complex Karyotypes: mult chromo loss/gain, mult deletions, no pattern has emerged
Clinical Course: Aggressive, median survival >3yrs

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Periperipheral T-cell Lymphoma Not otherwise specified (NOS): Clincal presentation and features

~30% T cell lymphomas

Clinical presentation: (1) Diffuse lymphadenopathy (2) B symptoms (fever, night sweats, weight loss) (3) paraneoplastic features (eosinophilia, pruritis, hemolytic anemia)
Normal counter part: unclear

-Involved sites: any where, except usually NOT blood stream

Usual Themes: expanded paracortex, effacement of normal architecture

Variations: Distinct subsets of atypical cells or clusters of “epitheloid histocytes” usually near the cortex (paracortical, picture)

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Periperipheral T-cell Lymphoma Not otherwise specified (NOS): Immunophenotype and Clinical Course

Immunophenotype:

expected; CD3, 5, 7, and 4 or 8/
Usually see; loss of one or more of the above
Variants: “double +” (CD4+, CD8+)

–Unexpected markers: CD20 (B-cell marker), CD56 (macrophage/monocyte marker), CD30 (R/S cell marker)

Genetics: no pattern has emerged
Clinical Course: aggressive 5 yr survival 20-30%

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Typical Organ Distribution of CLL

-Chronic lymphocytic leukemia

See mostly in the PB and some in the BM and lymph nodes

If blood is primary site use: leukemia
If not use lymphoma
If there is more lymph node involvement it could be called a SLL (small lymphocytic LYMPHOMA)

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CLL Facts/Presentation

Presentation: lymphocytosis in older males (high familial incidence)
Malignancy of Memory B-cells, see more PB (CLL) involvment and see small lymphocytes with little cytoplasm and “SMUDGE CELLS”
Cells have already been through a germinal center rxn/class switching and express IgG
Pseudofollicular: looks like germinal center (reactive) in germinal center, but is actually a proliferative center, Ki67 should be over expressed in these

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CLL: Genetics and Markers

Genetics: 80%: del13q14.3>trisomay 12>del11q (MLL gene), del17p (p53)

Immunophenotype: Light chain restricted (kappa or lambda) CD20-weak, CD5+ and CD23+

Key clinical predictors: immunopheno; ZAP-70+ (bad), CD38+ (bad), markers of somatic hypermutation state (means more or les differ)

Genetics: 17p deletion (p53/bad) and 13q deletion (good)

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Plasma Cell Neoplasms, Types

Monoclonal gammaopathy of uncertain significant (MGUS), mild form, usally asymptomatic can progress to myeloma

-Myeloma: more severe form associated with multiple lytic bone lesions

Involved sites: BM>>>PB

See Rouleaux (row of coins) on peripheral smear from protein production
Almost always presents in elderly (aquired mutations)

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Diagnosis of Plasma Cell Neoplasms

Serum Protein Electrophoresis (SPEP): can show abundence of Igs (not light chain only)

-Immunofixation electrophoresis (IFE): can determine if monoclonal and will show light chain restrictive

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Plasma Cell Neo Morphology

See a lot of cytoplasm and an eccentric nucleus, usually have clumpy chromatin and prominent golgi apparatus
Will look like bone is being eaten away in places (osteoclasts)

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General Plasma Cell Neoplasms

Immunophenotype: CD38++++, CD138++++, CD19-, CD20-; light chain restricted
Genetics: Translocation of IgH (chromo 14) in about 2/3 of cases, Trisomes of ODD # chromo are common
MGUS: 1%/yr progress to mult myeloma
Mult Myeloma: median survival 3-4 years

Predictors of worse outcome: t(4;14)-FGFR3, t(14;16)-C-MAF, t(14;20)-MAFB, del17p (p53 region) and Serum beta 2 microglobulin (all these are usually not found but when they are it is a poor prognosis

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Follicular Lymphoma

Presentation: lymphadenopathy in older individuals, can involve BM and PB
Results from failure of germinal B-cells to apoptose (b/c of Bcl-2 over expression-anti-apoptotic)
t(14;18)-Bcl-2 w/ IgH promoter
Immunopheno: CD19+, CD10+ (germ cen), Bcl-2 (90%), BCL-6 (85%)

–BCL-2 staining will not be seen in a reactive center reaction

Will like a germinal center but will lack: polarity (Iarge cells at one end and smaller cells at the other end) and tingible body macrosphages (sign of rapid turn over, no cells are apoptosing)
Clinical Course: (1)30% will progress to diffuse large B-cell lymphoma (2) Quite variable, depends on stage, grade, cytogenetics

–Grade 1 will have mostly centrocytes (small dark cells) and Grade 3 will have mostly Centroblasts (larger cells)

PICTURE: Darker staining center is abnormal and the lighter stained center is normal

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Grade 1 Follicular Lymphoma

-Most centrocytes, smaller than centroblasts

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GRADE 3 FOLLICULAR LYMPHOMA

MOSTLY CENTROBLASTS (LARGER)

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DIFFUSE LARGE B-CELL LYMPHOMA

“garabage” category of B-cell lymphomas
Clinical presentation: Rapidly growing adenopathy, ELDERLY, 40% present with extranodal disease (GI, BM, other)
IMMUNOPHENO: CD19+, CD20+, CD10+ (30-60%)
Genetics: t(v, 3q27)(v, BCL-6) ~30%, t(14;18) (BCL-2)~20-30% and others may occur
Clinical course: depends on stage, generally have a more acute course
KEY PREDICTORS: BM involvement and BM appearnace (concordant vs discordant), can see follicles w/o germinal centers, big cells with mitotic figures, generally

Hodkin Lymphoma Pathophysiology

Cannot be killed (NFkB or EBV or other anti-apoptotic mutation), similar to Follicular lymphoma, B-cells which went into germinal centers and did not die.
Classical: do have Ig rearrangement, but do not express Ig w/n cell or on their surface (cripple Ig promoter/transcription factor mutation) (strom-it has a “shaved head”)
Nodular: express surface Igs and other B-cell markers

AML with AUER RODs

t(8;21) Runx-1-Run1T1 Mutation

Clinical Presentation: younger patients/kids

Auer rods: crystalization of granule contents (excess myeloperoxidase production)

Immunophenotype: CD34+, CD13+, CD33weak

Prognosis: good response to chemo

APL: PML-RARA

t(15;17) fusion of PML (trans factor) with RARA (retinoic acid receptor)

Class II mutation: Inhibits granulocyte differentiation
TREATMENT: All Trans Retinoic Acid (ATRA), induces cell differentiation of the blasts to granulocytes (CLINICAL REMISSION)
CLINICAL PRESENTATION: DIC, SEVERE THROMBOCYTOPENIA***
Morphology: AUER RODS in stacks (faggot cells)*** sometimes see Bi-nuclear appearance

Immunophenotype: Weak/absent: CD34, HLA-DR, CD13+, CD33+

Prognosis: good if diagnosis is made

AML: CBFB-MYH11

inv(16) or t(16;16)

Class II mutant, clinical presentation: younger patients/kids
Morphology: Myelomonocytic* (mixed granulocyte-monocyte feats), Increased Eosinophils in blood and marrow (not known why)
Immunophenotype: CD34+, CD117+ (blasts); CD13+, CD33+ (granulocytes); CD14+, CD11b+ (monocytes)

Prognosis: GOOD; optimal with high dose CYTARABINE

AML w/ Normal Cytogenetics

40-50% of AML cases

-Any age group

Morphology: undifferentiated or variable granulocytic or monocytic/monoblastic

Immunophenotype: blast markers (CD34, CD117)+, can show any lineage markers
Prognosis: have to look at molecular genetics, pairing of mutation will determine
For some BM transplant doesnt help (NPMN! or CEBPA+, FLT3-ITD-, 60% 4-yr survival)
for other it will (FLT3-ITD+ or NPM1-, CEBPA-, FLT3-ITD-, ~29% 4-yr survival)

ALL (Acute Lymphoblastic Leukemias)

TdT: important for VDJ recombination and marker of B and T cells

CD19,CD10 and uCD20 are markers of B cells, can also express myeloid markers (CD13, CD33)
Can also express CD34 (GENERAL BLAST MARKER*****)

ALL: BCR-ABL1

t(9;22), proliferation activator (class I), diff from the mutation found in CML which is a class II mutation and prevents maturation of the cell, and have similar cytogenetics
Clinical Presentation: Older adults (25% of all cases)

Morphology: Big agranular blasts, hard to tell ir myeloid or lymphoid

Immunophenotype CD10+, CD19+, TdT+

Prognosis: Poor

ALL: MLL rearranged

t(v;11q23), or t(11;19) Class II mutation, also found in AML

Clinical Presentation: most common leukemia in kids

Morphology: big agranular blasts

Immunophenotype: CD10-, CD19+, TdT+

Prognosis: Poor

ALL, Mutations that made St. Jude Famous

- t(12;21); TEL-AML1 (ETV6-RUNX1), class II (inhibits differentition) - Clinical Presentation: Kids, 25% of pediatric B-ALL Morphology: big agranular blasts Immunophenotype: TdT+, CD34+, CD20- Prognosis: 90% cure rate

ALL: T-ALL

- Common motif for lymphoid malignancies: oncogene\>\>\>\>Ig or TCR promoter - Clinical Presentation: Kids 25% of pediatric T-ALL, often wih thymic mass\*\* Morphology: Big agranular blasts Immunophenotype: TdT+, CD3+, CD5+, can express myeloid or B-cell antigens as well Prognosis: High Risk: more intense chemotherapy regime, pretty good survival rate

Myeloproliferative Disease

Definition: Chronically proliferating clones which differentiate to circulating blood cells Chronic Myelogenous Leukemia (CML): shows blast profile CMML (myelodysplastic/myelomonocytic): hybrid b/t myelocytes and granulocytes -Can also see Chronic: eosinophilic, neutrophilic or mastocytosis leukemia. Need to differentiate from a Reactive condition --Best indicator if prominence of mature to immature cells is out of order, "Myeloid Bulge" (more blasts than more mature cells)

Myeloproliferative Diseases of Erythroid and Megs Lineages

Polycythemia Vera, elevated RBC count (erythroid lineage) - Essential thromboythaemia/Primary myelofibrosis: elevated platelet count (meg lineage) - Can progress to AML

CML that is Undectable

Cryptic Translocation, Cannot see with Routine Cytogenetics -Will progress to AML (can be myeloid or lymphoid) PHASES: chronic, accelerated, acute -Can also confuse with sepsis, get a BM

Mastocytosis

--Usually presents as benign cutaneous lesions in kids (itchy) that goes away by itself -Release of histamine can cause systemic symptoms that confuse clinician Morphology: Aggregates of blank looking cells, round or spindle shapes, s/t with eosinophils Immunophenotype: Tryptase+, CD117+, CD25+ Treatment: Imatinib Prognosis: highly variable

Polycythemia Vera

- Jak2 mutation in \>95% of cases-detectable in PB leukocytes - Clinical presentation: Thromboisis?hypertension/stroke or MI. increased RBC # Morphology: hypercellular marrow, erythroid hyperplasia, increased Megs -Immunophenotype: no known features Prognosis: \>10yr survival is common, can progress to myelofibrosis MDS, acute leukemia Epo will usually be low, one way to differ between neoplastic and reactive

Essential Thrombocythemia

Jak2 mutation in ~50% of cases-detectable in PB -Clinical Presentation: Thrombosis, increased platelets, can also be due to Fe deficiancy, infecion or chronic inflammation, can also have bleeding and splenomegaly Morphology: Increased Megs (very abnormal and tend to cluster) Immunopheno: not known, can not put Meg through flow cytometry (too fragile) -Prognosis: \>10yr survival is common, can progress to myelofibrosis MDS, acute leukema

Primary Myelofibrosis

Jak2 mutation ~50%, disputed diagnostic criteria -Morphology: increased Megs, bizarre shapes, clusting and fibrosis (TEAR DROPS?) No known immunopheno Prognosis: usually shorter survival than ET, can progress to marrow failure, acute leukemia -Cells of bone marrow will relocate to spleen and liver: Extra-medullary hematopoiesis Treatment: supportive care, blood transfusions, splenectomy are dangerous (pts too old, will bleed) and HSCT is curative but high mortality rate b/c pts are old as hell

Myelodyisplasias

- Usually present as unexplained cytopenia, bicytopenia or pancytopenia - see poorly functioning clones, mostly in elderly (\>70) 5 major adult forms (best to worst prognosis): (1) Refractory cytopenia with unilineage dysplasia (2) refractory anemia with ring sideroblasts (3) myelodysplastic syndrome with isolated del(5q) (4) refractory cytopenia with multilineage dysplasia (5) refractory anemia with excess blasts -Accumulation of several mutations over time in different mutations

Refractory Cytopenia with Unilineage Dysplasia

Clinical pres: unexplanined cytopenai Morphology: weird looking precursors: binucleation or irregular nuclei, can show fibrosism high or low cellularity, megaloblastoid features Prognosis: surival unclear, rarely progresses to AML

Refractory Anemia with Ring Sideroblasts

- Nonspecific cytogenetic abnormalities (trisomes, monosomes) may be present - Morphology: ring sideroblasts usually with dyspoietic feats (in red cell series only) --Iron granules form ring around nucleus -Prognosis: rarely progresses to AML

MDS with Isolated del(5q)

- All the Megakaryocytes are MONOCUCLEAR - Clinical pres: Anemia often severe, usually elderly - Morph: megs are mononuclear - Prognosis: good median survival; treatable with LENALIDOMIDE, 10% progress to AML

Refractory Cytopenia with multilineage dysplasia

- Two or more lineages show dysplastic changes - Clinical pres: Anemia often severe: usually elderly - Morph: Granulocytes dont granulate normally (if affected), nuclei dont lobulate normally Prognosis: Median survival 30 months, 10% progress to AML in 2 years