Blood Cancers and Lymphoma

Question 1

Peripheral blood smear

Answer 1

PelgerHuët cells - dysplastic change which are abnormal appearing neutrophils having only two nuclear lobes

Question 2

Dysplasia associated with myelodysplastic syndromes

Answer 2

PelgerHuet cells
Hypersegmented PMNs
Hypo/hypergranular cells

RBCs - presence of ringed sideroblasts (seen w/ prussian blue), megaloblastoid erythroid precursors, and mishapen erythroid precursors w/ nuclear budding

Megakaryocytes may be abnormal and only have a single nuclear lobe or multiple separate nuclei (prawn ball megakaryocytes)

Question 3

How are myelodysplastic syndromes classified?

Answer 3

Based on # of blasts present w/i marrow

WHO classification:

<5% blasts - MDS is either refractory anemia (RA) or RA w/ ring sideroblasts (RARS)

5-20% blasts in marrow - RA w/ excess blasts (RAEB)

> 20% blasts in marrow = acute leukemia

Question 4

5q- syndrome

Answer 4

myelodysplastic syndrome which is characterized by megakaryocytes that are uniformly small and monolobated

Question 5

Sxs of acute leukemia

Answer 5

Fever (secondary to infection), easy fatigability (due to anemia), and bleeding (due to thrombocytopenia)

Both ALL and AML are characterized by a decrease in mature forms of cells and increase in immature forms (blasts which have immature chromatin with multiple nucleoli)

Question 6

Acute myelogenous leukemia

Epidemiology

Answer 6

Typically adults between ages of 15-39

Risk Factors:
-Akylating chemo
-Radiation
-Myelodysplastic syndromes
-Myeloproliferative neoplasms
-Down syndrome

Question 7

CD markers for Pt w/ acute myelogenous leukemia

Answer 7

Myeloid markers:
CD13

CD33

Blast markers:

CD34

CD117

Myeloperoxidase (MPO) = stain to differentiate AML from ALL

Question 8

Auer rods in AML

Answer 8

Abnormal lysosomal structures (primary granules) considered pathognomonic of myeloblasts

Stain red with MPO

Question 9

Acute promyelocytic leukemia (APL)

Answer 9

APL is also characterized by the
translocation t(15;17), which results in the fusion of the retinoic acid receptor α (RARA) gene on chromosome 17 to the PML unit on chromosome 15

produces an abnormal retinoic acid receptor such that physiologic levels of retinoic acid no longer activate it.

Treatment for APL is with large doses of vitamin A derivatives, such as all-trans-retinoic acid, which inhibits the proliferation of cells of acute myeloid leukemia.

Question 10

What subtype of acute myelogenous leukemia is associated with gingival infiltrates?

Answer 10

Acute monocytic leukemia

Question 11

What subtype of acute myelogenous leukemia is associated with marked fibrosis of the bone marrow

Answer 11

Acute megakaryocytic leukemia is associated with acute myelofiborisis

Acute megakaryocytic leukemia is
associated in children younger than 5 years of age with Down syndrome.

Special stains for megakaryocytes include stains for von Willebrand factor and stains for GpIb/IIIa (on platelets).

Question 12

Acute lymphoblastic leukemia (ALL)

Answer 12

Primarily disease of children and young adults

Lymphoblasts stain positively for TdT (nuclear enzyme)

ALL is associated with CNS infiltration (distinguishes from AML) where malignant lymphoblasts are protected from chemotherapy by the BBB

Pt’s with ALL may be given prophylactic radiation to head

Also, acute lymphoblastic leukemia is associated with Down syndrome after the age of 5

Question 13

Immunologic classification of acute lymphocytic leukemia

Answer 13

Most of ALL are B-cell origin:

Lymphoblasts express CD19

Few cases are T-cell origin:

Lymphoblasts lack CD19 but instead express T-cell Ags (CD3 and CD7)

CD markers for T cells are CDs less than 10

Many cases of T-ALL involve a mediastinal mass (which may press on the esophagus causing dysphagia) and are clinically similar to cases of T-cell lymphoblastic lymphoma.

Question 14

Pro B-cell acute lymphoblastic leukemia

Answer 14

+TdT (marker for immature cells)

Lacks CD10/cytoplasmic μ/surface Ig

Question 15

Common B-ALL

Answer 15

+TdT and +CD10

CD10 is called CALLA - common ALL antigen

Question 16

Pre-B-ALL

Answer 16

Characteristic translocation t(1;19)

+cytoplasmic μ chains

-TdT and -surface Ig

May be + for CD10

Question 17

Mature B-ALL

Answer 17

Cells have surface Ig

Lack TdT/CD10/ and cytoplasmic μ

Mature B-ALL is the leukemic form of Burkitt’s lymphoma

-Similarly malignant cells have cytoplasmic vacuoles that stain positively with the oil red O lipid stain

Question 18

Prognosis with ALL

Answer 18

The presence of CALLA (CD10) is a marker of a favorable prognosis, as is the presence of t(12;21), which is the most common chromosomal rearrangement in childhood B-ALL.

t(9;22) is associated with a poor prognosis. Most children with ALL achieve complete remission with
chemotherapy.

Question 19

____ is the most common leukemia and is similar in may aspects to small lymphocytic lymphoma (SLL)

Answer 19

Chronic lymphocytic leukemia (CLL)

If Pt presents w/ blood findings first = CLL

If they present w/ lymph node findings first = SLL

Question 20

What sxs are associated w/ chronic lymphocytic leukemia?

Answer 20

CLL has an indolent course - disease is associated w/ long survivial in many cases

Sxs that may develop are related to anemia or infections - malignant cells are non-functional

Lymphadenopathy or splenomegaly may be noted

Minority of Pt - disease may transform into prolymphocytic leukemia or a large cell immunoblastic lymphome (Richters syndrome)

Question 21

Richter’s syndrome (transformation)

Answer 21

CLL transformation into immunoblastic lymphoma

Question 22

Prolymphocytic leukemia

Answer 22

Can be transformation from CLL

Characterized by massive splenomegaly and a markedly increased leukocyte count consisting of enlarged lymphocytes having nuclei with mature chromatin and nucleoli

Question 23

What leukemia is associated with warm AIHA?

Answer 23

CLL - warm autoimmune hemolytic anemia is characterized by finding spherocytes in the peripheral blood

Question 24

Tx of B-CLL

Answer 24

Rituximab - mAb against CD20 (B cell marker)

Drug is associated w/ increased risk of progressive multifocal leukoencephalopathy (demyelinating disease of CNS caused destruction of oligodendrocytes secondary to reactivation of JC virus)

Question 25

Hairy cell leukemia

Answer 25

(HCL) - indolent type of mature B-cell leukemia found most often in older males Signs: Pancytopenia (due to leukemic infiltration of marrow) Splenomegaly (most common sign) - leukemic cells infiltrating red pulp (unusual because leukemias preferentially infiltrate white pulp) | These neoplastic cells proliferate in spleen = splenectomy

Question 26

Peripheral smear of HCL Pt blood

Answer 26

Numerous lymphocytes w/ cytoplasmic projections Cells stain for acid phosphatase and rx'n is refractory to Tx w/ tartaric acid (tartrate-resistant acid phosphatase [TRAP]) Hairy cells also express pan-B-cell markers (CD19 and CD20) and monocyte marker CD11c Hairy cells are negative for CD5 and CD10

Question 27

What does aspiration of marrow in Pt w/ HCL show?

Answer 27

Dry tap But biopsy shows proliferation of malignant cells w/ fried-egg appearance

Question 28

Tx of HCL

Answer 28

Purine analogs like **cladribine** (2-CDA = first-line Tx) Also **pentostatin** (also purine analog) These drugs are **resistant to breakdown by adenosine deaminase** (enzyme that is deficient in the AR form of SCIDs) - inhibits nucelotide metabolism and leads to the accumulation of toxic amounts of dexyadenosine ## Footnote Adenosine deaminase (ADA) is an enzyme that converts adenosine to inosine. ADA inhibition results in the metabolism of deoxyadenosine through an alternate pathway, which is toxic to lymphocytes.

Question 29

What stain differentiates AML from ALL?

Answer 29

Myeloperoxidase Myeloblast stain + Lymoblasts are -

Question 30

What translocation is associated with acute promyelocytic leukemia?

Answer 30

t(15;17) 17 - retinoic acid receptor alpha (RARA) gene 15 - promyelocytic leukemia (PML) gene

Question 31

What increases risk for disseminated intravascular coagulation (DIC) in Pt's w/ acute promyelocytic leukemia (APL)?

Answer 31

The abnormal promyelocytes seen in APL contain **numerous primary granules** - increases risk of DIC

Question 32

Staining of lymphoblasts from Pt w/ acute lymphoblastic leukemia (ALL)

Answer 32

Stain positive for terminal deoxynucleotidyl transferase (TdT) Negative for myeloperoxidase

Question 33

What translocation is associated w/ a poor prognosis for Pt's w/ acute lymphoblastic leukemia (ALL)?

Answer 33

t(9;22)

Question 34

What factor(s) are associated w/ a favorable prognosis for Pt's w/ acute lymphoblastic leukemia?

Answer 34

Translocation t(12;21) and presence of CD10 (CALLA)

Question 35

Why do Pt's w/ acute lymphoblastic leukemia sometimes receive prophylactic radiation to their head?

Answer 35

ALL is associated w/ CNS infiltration, where malignant lymphoblasts are protected from chemotherapy by the BBB

Question 36

Peak incidence of acute lymphoblastic leukemia

Answer 36

Between ages 2-5 Also is associated in Pt's with Down syndrome after age 5 ## Footnote Down syndrome before age 5 is associated with acute megakaryocytic leukemia

Question 37

What subtype are most cases of acute lymphoblastic leukemia?

Answer 37

B-cell origin (B-ALL) Express CD10 and CD19

Question 38

Signs of hairy cell leukemia

Answer 38

Pancytopenia Dry tap of marrow Massive splenomegaly | Splenomegaly is most common sign w/ infiltration of red pulp

Question 39

Strongest evidence of lymphoma malignancy

Answer 39

Monoclonal lymphocytic proliferation ## Footnote Benign lymph node enlargement is associated w/ a polyclonal proliferation of lymphocytes

Question 40

What is the most common indolent non-Hodgkin lymphoma?

Answer 40

**Follicular lymphoma** - B-Cell origin and characterized by painless waxing and waning lymphadenopathy in an older adult

Question 41

Histological characterization of follicular lymphoma

Answer 41

Neoplastic nodule that obscure (efface) the normal lymph node arhitecture Follicle in follicular lymphoma do not contain tingible-body macrophages and are not surrounded by mantle zones

Question 42

What translocation is associated w/ follicular lymphoma?

Answer 42

**t(14;18)** - causes BCL2 overexpression and inhibition of apoptosis

Question 43

Most common type of non-Hodgkin lymphoma in adults

Answer 43

**Diffuse large B-cell lymphoma** Agressive (high-grade) type of lymphoma w/ a poor prognosis Tumor cells have a high proliferative index and stain positively for CD20 Also associated w/ alteration in Bcl-2 proteins

Question 44

Primary CNS lymphoma

Answer 44

Associated w/ advanced HIV infection (secondary EBV infection)

Question 45

Primary effusion lymphoma

Answer 45

Associated w/ advanced HIV infection (secondary HHV-8 infection)

Question 46

Burkitt lymphoma

Answer 46

High-grade B-cell lymphoma associated with **t(8;14) resulting in MYC overexpression** - produces a nuclear protein whose Fx is to activate transcription

Question 47

Histopathology of Burkitt lymphoma

Answer 47

Sheets of malignant small, non-cleaved lymphocytes forming a starry-sky appearance due to macrophages engulfing apoptotic cells

Question 48

African type of Burkitt lymphoma

Answer 48

Endemic form and typically involves the maxilla or madible - especially of the young child ## Footnote Associated w/ EBV

Question 49

American type of Burkitt lymphoma

Answer 49

Nonendemic and commonly involvees the abdomen, such as bowel, ovaries, or retroperitoneum ## Footnote Associated w/ EBV if Pt is immunosuppressed (i.e. HIV)

Question 50

Gastric MALT lymphoma

Answer 50

Type of **marginal zone lymphoma** associated w/ *H. pylori* infection and **t(11;18)**

Question 51

Marginal cells

Answer 51

Normally located in marginal zone of the spleen (area where T and B cells first enter spleen)

Question 52

Mantle cell lymphoma

Answer 52

Characteristically associated w/ **t(11;14)** - involves the cyclin D1 gene (on 11) and Ig heavy chain locus (on 14) - results in overexpression of cyclin D1 (CCND1 or bcl-1) Non-Hodgkin B cell lymphoma that originates from B-cells normally found in the mantle zones (normally located immediately outside of the follicle) ## Footnote **Small cleaved cells that stain + for CD5. CD19, and CD20** In contrast to CLL/SLL that are negative for CD23

Question 53

Hodgkin lymphoma

Answer 53

Bimodal age group distribution: young adults and adults older than 50 sxs: fever, night sweats, and weight loss Characterized by the proliferation of Reed-Sternberg cells - usually present w/ focal, nontender lymphadenopathy in a young adult

Question 54

Reed-Sternberg cells

Answer 54

Malignant cells in Hodgkin lymphoma Stain positively for **CD15 and CD30** Appear as large binucleated cells w/ an owl-eye appearance in a background of reactive lymphocytes in a biopsy of lymphoid tissue

Question 55

What is the most common subtype of Hodgkin lymphoma

Answer 55

**Nodular sclerosis Hodgkin lymphoma** Characterized morphologically by the presence of **lacunar cells** (a variant of RS cells w/ a clear space surrounding the nucleus)

Question 56

Hypercalcemia in individuals w/ Hodgkin lymphoma

Answer 56

May result from **paraneoplastic secretion of gamma-interferon by activated T-cells** - activates Vit D by **increasing the expression of 1alphahydroxylase** in malignant lymphocytes and macrophages | This same mechanism causing hypercalcemia can be seen with sarcoidosis

Question 57

Sézary syndrome

Answer 57

The **leukemic form of mycosis fungoides** characterized by finding CD4+ cells with cerebriform nuclei (Sezary cells) in the peripheral blood. May be associated w/ a generalized pruritic erythematous rash - red-man syndrome ## Footnote Mycosis fungoides is not associated w/ hypercalcemia

Question 58

Mycosis fungoides

Answer 58

**Malignancy of CD4+ T-cells** Skin biopsy shows atypical lymphocytes w/ markedly convoluted nuclei infiltrating the epidermis May form characteristic intraepidermal clusters known as **Pautrier microabscesses** | Sezary syndrome

Question 59

What malignancy of CD4+ T-cells is endemic in Southern Japan and parts of the Caribbean?

Answer 59

**Adult T-cell leukemia/lymphoma** - mostly affects CD4+ T-cell subset which have a predilection for the skin (cutaneous T-cell lymphomas) Characterized by hypercalcemia and poor prognosis ## Footnote The cause of ATLL is infection with **HTLV-1**, a virus that infects CD4-positive T-cells. Examination of the peripheral smear will show abnormal hyperlobated lymphocytes, called flower cells. The prognosis of ATLL is poor.

Question 60

Langerhans cells

Answer 60

APCs found in the skin - possess characteristic racquet-shaped intracytoplasmic granules known as **Birbeck granules (pentilaminar bodies)** ## Footnote Histological markers: CD1a (mediates Ag presentation) S-100 (tumor marker for cells derived from the neural crest)

Question 61

Hand-Schüller-Christian disease

Answer 61

Langherhans cell histiocytosis (**multifocal LCH**) that is characterized by the clinic triad: **Bone lesions** (particularly the calvarium and base of skull) **DM I** **Exophthalmos** Lesions are result of proliferations of LC's - lesions around hypothalamus lead to **decreased ADH production** and **signs of DM insipidus** Poor prognosis | Usually begins between the second and sixth years of life

Question 62

Letterer-Siwe disease

Answer 62

Acute disseminated LCH Affects young children (<3 y/o) **Cutaneous lesions that resemble seborrhea, hepatosplenomegaly, and lymphadenopathy** LC's infiltrate the marrow which leads to anemia, throbocytopenia, and recurrent infections Usually rapidly fatal, intensive chemotherapy 50% of Pt's may survive 5 years

Question 63

Eosinophilic granuloma

Answer 63

**Unifocal Langerhans cell histiocytosis (LCH)** Seen in older patients Usually unifocal - most often affecting the skeletal sytem (usually ribs) Lesions are granulomas that contain mix of lipid-laden Langerhans cells, macrophages, lymphocytes, and eosinophils Excellent prognosis

Question 64

What lymphoma is defined by finding hallmark cells upon histological exam?

Answer 64

Anaplastic large cell lymphoma (ALCL) | T-cell lymphoma ## Footnote Hallmark cells may have nuclei w/ a horsehoe-like or embryo-like appearance Malignant cells are strongly + for **CD30**

Question 65

Anaplastic large cell lymphoma is associated with what gene mutation?

Answer 65

Mutations involving the **ALK gene**

Question 66

What is the most common cutaneous T-cell lymphoma

Answer 66

Mycosis fungoides (MF) Primarily affects the skin - but extracutaneous spread to lymph nodes, spleen, liver, and lungs is common

Question 67

Stages in the involvement of skin w/ mycosis fungoides

Answer 67

1. Generalized pruritic erythematous rash 2. Formation of plaques 3. Formation of large tumor nodules ## Footnote Early in the disease a skin biopsy will reveal a bandlike infiltrate in the upper dermis composed of atypical lymphocytes with markedly convoluted nuclei. These PAS-positive cells will infiltrate the epidermis (epidermotropism) and may form characteristic intraepidermal clusters known as Pautrier’s microabscesses.

Question 68

Type of lymphoma that histologically shows popcorn-cells

Answer 68

Popcorn-cells = variant Reed-Sternberg cells called the lymphohistiocytic cells (L&H) - only seen in the lymphocyte predominant subtype

Question 69

What class of lymphoma presents with contiguos spread to adjacent node groups

Answer 69

Hodgkin lymphoma - therefore early Tx w/ radiation therapy is possible

Question 70

How is the classification of Hodgkin lymphoma defined?

Answer 70

Based on the inflammatory response

Question 71

Classic Hodgkin Lymphoma

Answer 71

1. Nodular sclerosis HL 2. Mixed cellularity HL 3. Lymphocyte-rich HL 4. Lymphocyte depletion HL (worst prognosis) | Nodular sclerosis is most common subtype of HL ## Footnote Nodular slerosis is most common in females

Question 72

Which forms of Hodgkins Lymphoma are associated w/ EBV?

Answer 72

1. Mixed cellularity HL 2. Lymphocyte-rich HL 3. Lymphocyte depleted HL

Question 73

Types of B-cells in normal germinal centers

Answer 73

1. Centroblasts - large non-cleaved lymphocyte that have a nucleolus and usually lack a nuclear cleft 2. Centrocytes - lack a nucleolus and have irregular or cleaved nuclei (small cleaved lymphocytes)

Question 74

Buttock-cells

Answer 74

Malignant centrocytes (small cleaved cells) that are found within the peripheral blood **Associated w/ non-Hodgkin's lymphomas**

Question 75

Is BCL2 expressed in reactive germinal centers?

Answer 75

**No** - the product of BCL2 is located on the outer mitochondrial membrane, ER, and nuclear envelope - it inhibits apoptosis by blocking bax channels and by binding and sequestering apoptosis activating factor 1 (Apaf-1) Interfers w/ apoptosis mechanism that involves cyt c being released from mitochondria via bax channels (cyt c binds and activates Apaf-1 which stimulates caspase cascade and promotes apoptosis)

Question 76

Follicular form of non-Hodgkin's lymphoma

Answer 76

Nodular (follicular) nHL results from neoplastic proliferation of B-cells dervided from germinal centers Express CD19, CD20, and CD10 (CALLA), and surface Ig

Question 77

How do nodules seen w/ follicular lymphoma histologically differ from germinal centers?

Answer 77

1. Increased numbers (crowding) of nodules 2. Location in both cortex and medulla 3. Uniform size 4. Composition (a monotonous proliferation of cells that lack tingible-body macrophages Follicles are not surrounded by mantle zones (unlike normal reactive germinal centers)

Question 78

Lymphoblastic lymphoma

Answer 78

high-grade NHL lymphoma that frequently involves the bone marrow and peripheral blood **Malignant cells in most cases are T-cells** - clinical picture similar to that of T-cell acute lymphoblastic leukemia T-cell lymphoblastic lymphomas occurring in the thoracic cavity of young Pt's usually arise in the mediastinum and have a particularly aggressive clinical course w/ rapid growth

Question 79

Treatment for acute promyelocytic leukemia is with large doses of what?

Answer 79

All-trans-retinoic acid ## Footnote Treatment for acute promyelocytic leukemia is with large doses of all-trans-retinoic acid (a vitamin A derivative).

Question 80

What cells stain positive for terminal deoxynucleotidyl transferase (TdT) and negative for myeloperoxidase?

Answer 80

Lympoblasts ## Footnote Testing for acute lymphoblastic leukemia vs acute myeloblastic leukemia

Question 81

Malignant cells of chronic lymphocytic leukemia have what markers?

Answer 81

* The malignant cells of CLL are most often of B-cell origin and express CD19, 20, 21, and 23, along with the T-cell marker CD5.

Question 82

which is the most common type of lymphoma in adults in the United States, is characterized by malignant lymphocytes that have a high proliferative index and stain positively for CD20?

Answer 82

Diffuse large cell lymphoma

Question 83

Answer 83

Burkitt lymphoma

Question 84

Answer 84

Sezary syndrome

Question 85

Answer 85

Follicular lymphoma

Question 86

What condition would you see marginal cells in the lymph node?

Answer 86

Toxoplasmosis lymphadenitis

Question 87

Answer 87

Follicular lymphoma - resulting from overexpression of BCL2 (located on chromosome 18) ## Footnote BCL2 = B-cell lymphoma protein - antiapoptotic protein Also - the TCR gene and heavy chain genes are located on chromosome 14

Question 88

Answer 88

Question 89

Answer 89

Small cleaved lymphocyte - aka buttock cell

Question 90

Diagnosis

Answer 90

**Burkitt lymphoma** Tingible macrophages - present but there is no follicle (distinguishes between follicular lymphoma/hyperplasia and Burkitt's lymphom)

Question 91

Answer 91

Reed-Sternberg cells - characteristic of Hodgkin lymphoma

Question 92

Answer 92

Lacunar cells are diagnostic of nodular slcerosis

Question 93

Answer 93

| Specifically Han-Schuller Cristian disease ## Footnote Lytic lesions in the skull of a child = Langerhan cell histiocytosis in an adult = multiple myeloma

Question 94

What type of T cells infiltrate the skin?

Answer 94

CD4+ T cells

Question 95

Answer 95

Question 96

Which one of the following is characterized histologically by neoplastic nodules that obscure the normal lymph node architecture? A) Burkitt lymphoma B) Follicular lymphoma

Answer 96

B) Follicular lymphoma

Question 97

Burkitt lymphoma is a high-grade B-cell lymphoma that is associated with t(8;14), which results in overexpression of what?

Answer 97

c-MYC ## Footnote Burkitt lymphoma is a high-grade B-cell lymphoma that is associated with t(8;14), which results in MYC overexpression, the product of which is a nuclear protein whose function is transcription activation.

Question 98

What RBC abnormality is seen in multiple myeloma?

Answer 98

Rouleaux formation (grouped erythrocytes w/ stacked-coin appearance)