Pbl Exam 10 Case 2

Front 1

1. What are the 2 broad categoies of white blood cell disorders?

Back 1

1. Proliferative disorders, in which there is an expansion of leukocytes. Proliferations of white cells can be reactive or neoplastic.

2. Leukopenias, which are defined as a deficiency in WBCs.

Front 2

2. What is leukopenia and lymphopenia?

Back 2

An abnromally low white cell count (leukopenia) usually results from reduced numbers of neutrophils (neutropenia, granulocytopenia).

Lymphopenia is less common; in addition to congenital immunodeficiency diseases, it is most commonly observed in specific settings, such as advanced HIV infection, following therapy w/glucocorticoids or cytotoxic drugs, autoimmune disorders, malnutrition, and certain acute viral infections.

Front 3

3. What is the pathogenesis of neutropenia or agranulocytosis?

Back 3

A reduction in circulating granulocytes will occur if there is: (1) reduced or ineffective production of neutrophils or (2) accelerated removal of neutrophils from the circulating blood.

Front 4

4. Inadequate or or ineffective granulopoiesis is observed in what 4 settings?

Back 4

1. Suppression of myeloid stem cells, as occurs in aplastic anemia
2. Suppression of committed granulocytic precursors due to exposure to certain drugs
3. Disease states associated w/inefective granulopoiesis, such as megaloblastic anemia
4. Rare inherited conditions (such as Kostmann syndrome) in which genetic defects in specific genes result in impaired granulocytic differentiation

Front 5

5. Accelerated removal or destruction of neutrophils occurs with which 3 settings?

Back 5

1. Immunologically mediated injury to the neutrophils, which may be idiopathic, associated w/SLE, or produced by exposure to drugs

2. Splenic sequestration, in which excessive destruction occurs secondary to enlargement of the spleen

3. Increased peripheral utilization, as may occur in overwhelming bacterial, fungal, or rickettsial infections

Front 6

6. Which cause is responsible for most of the significant neutropenias (agranulocytoses)?

Back 6

Drugs. B/c such drugs cause a generalized suppression of the bone marrows, production of erythrocytes and platelets is also affected.

The roster of drugs includes aminopyrine, chloramphenicol, sulfonamides, chlorpromazine, thiouracil, and phenylbutazone.

Front 7

7. What are the different toxic effects of the drugs on the neutropenias (i.e. chlorpromazine vs. thiouracil)?

Back 7

The neutropenia induced by chlorpromazine and related phenothiazines may result from a toxic effect on granulocytic precursors in the bone marrow.

In contrast, agranulocytosis following administration of aminopyrine, thiouracil, and certain sulfonamides likely stems from immunologically mediated destruction of mature neutrophils thru mechanism similar to those involved in drug-induced hemolytic anemias.

Front 8

8. What is the are the anatomic alterations in neutropenia?

Back 8

When neutropenia is caused by excessive destruction of mature neutrophils, the marrow is usually hypercellular owing to the presence of increased numbers of granulocytic precurosrs. Hypercellularity is the rule in neutropenias associated w/ineffective granulopoiesis, as occur sin megaloblastic anemias and myelodysplastic syndrome.

Agranulocytosis caused by agents that suppress or destroy granulocytic precursors is understandably associated w/marrow hypocellularity.

Front 9

9. What is a common consequence of agranulocytosis?

Back 9

Infections (most often bacterial or fungal) are a common consequence of agranulocytosis. Ulcerating necrotizing lesions of the gingiva, floor of the mouth, buccal mucosa, pharynx, or anywhere w/in the oral cavity (agranulocytic angina) are quite characteristic.

These ulcers are typically deep, undermined, and covered by gray to green black necrotic membranes from which numerous bacteria or fungi can be isolated.

*The neutropenic pt is at high risk for deep fungal infections caused by Candida and Aspergillus.

Front 10

10. What is the clinical course of neutropenia?

Back 10

The symptoms and signs of neutropenias are related to bacterial or fungal infections. They include malaise, chills, and fever, followed in sequence by marked weakness and fatigability.

In severe agranulocytosis w/virtual absence of neutrophils, these infections can be overwhelming and cause death w/in a few days.

***The most serious infections occur w/counts below 500 per mm^3.

Front 11

11. What is leukocytosis?

Back 11

Leukocytosis refers to an increase in the number of blood leukocytes.

It is a common reaction to a variety of inflammatory states and is sometimes the first indication of neoplastic growth of leukocytes.

Front 12

12. What are the 4 factors that influence the peripheral blood leukocyte count?

Back 12

1. The size of the myeloid (for granulocytes and monocytes) and lymphoid (for lymphocytes) precursors and storage cell pools in the bone marrow, circulation, and peripheral tissues
2. The rate of release of cells from the storage pool into the circulation
3. The proportion of cells that are adherent to blood vessel walls at any time
4. The rate of extravasation of cells from the blood into the tissues

Front 13

13. What happens when there is an infection?

Back 13

In acute infection, there is a rapid increase in the egress of mature granulocytes from the bone marrow pool, which is roughly 50x the size of the peripheral blood marginal pool.

The release of IL-1, TNF, and other inflammatory cytokines stimulates bone marrow stromal cells and T cells to produce increased amts of colony-stimulating factors (CSFs), which enhance the proliferation and differentiation of committed granulocytic progenitors, and over several days, cause a sustained increase in neutrophil production.

Front 14

14. What are Dohle bodies?

Back 14

Dolhle bodies are patches of dilated endoplasmic reticulum that appear as sky-blue cytoplasmic "puddles" in smears stained w/Wright-Giemsa stain.

Front 15

15. Where are Dohle bodies seen?

Back 15

In sepsis or severe inflammatory disorders (such as Kawasaki disease), leukocytosis is often accompanied by morphologic changes in the neutrophils, such as toxic granuloations, Dohle bodies, and cytoplasmic vacuoles.

Toxic granules are coarse and darker than the normal neutrophilic granules and are believe to represent abnormal azurophilic (primary granules).

Front 16

16. In which 2 situations is it difficult to distinguish between reactive leukocytosis and leukocytosis caused by leukemia?

Back 16

Particularly in children, acute viral infections can produce the appearance of activated lymphocytes in the peripheral blood and marrow that resemble neoplastic lymphoid cells.

At other times, particularly in inflammatory states and severe chronic infections, many immature granulocytes appear in the blood, simulating a picture of myelogenous leukemia (called a leukemoid reaction).

Front 17

17. What is acute nonspecific lymphadenitis?

Back 17

Lymph nodes undergo reactive changes whenever they are challenged by microbiologic agents, cell debris, or foreign matter introduced into wounds or into the circulation. Acute lymphadenitis is most often seen in the cervical region due to microbial drainage from infections of the teeth or tonsils and in the axillary or inguinal regions secondary to infections in the extremities.

Similarly, acute lymphadenitis often occurs in the mesenteric lymph nodes draining acute appendicitis.

Front 18

18. What is the morphology of acute nonspecific lymphadenitis?

Back 18

Macroscopically, the nodes become swollen, gray-red, and engorged. Histologically, there is prominence of the lymphoid follicles, w/large germinal centers containing numerous mitotic figures. Macrophages often contain particulate debris of bacterial origin or derived from necrotic cells. When pyogenic organisms are the cause of the reaction, the centers of the follicles may undergo necrosis; indeed the entire node can sometimes be converted into a suppurative mass.

The cells lining the sinuses become hypertrophied and cuboidal and often undergo hyperplasia.

Front 19

19. What is the clinical course of acute nonspecific lymphadenitis?

Back 19

Clinincally, nodes w/acute lymphadenitis are enlarge db/c of the cellular infiltration and edema. As a consequence of the distention of the capsule, they are tender to touch. When abscess formation is extensive, they become fluctuant.

The overlying skin is freq red, and sometimes penetration of the infection to the skin surface produces draining sinuses, particularly when the nodes have undergone suppurative necrosis.

Front 20

20. What is chronic nonspecific lymphadenitis?

Back 20

Chronic immunologic reactions can produce several different alterations depending on the underlying stimulates.

They are: follicular hyperplasia, marginal zone B-cell hyperplasia, paracortical lymphoid hyperplasia, and sinus histiocytosis.

Front 21

21. What is follicular hyperplasia?

1/2

Back 21

Follicular hyperplasia is caused by stimuli that activate humoral immune responses. ***It is distinguished by the appearance of large, round or oblong B cell-rich germinal centers (secondary follicles) surrounded by a collar of small, resting naive B lymphocytes (the mantle zone).***

W/in germinal centers 2 distinct regions are discernible: a dark zone containing proliferating blast-like B cells (centroblasts) and a light zone composed of B cells with irregular or cleaved nuclear contours (centrocytes).

Also present through the follicle are phagocytic macrophages containing nuclear debris (tingible-body macrophages) and an inconspicuous network of follicular dendritic cells.

Front 22

22. What is follicular hyperplasia?

2/2

Back 22

There is often striking hyperplasia of the mononuclear phagocytic cells lining the lymphatic sinuses.

Some specific causes of follicular hyperplasia include RA, toxoplasmosis, and early stages of HIV infection. This form of lymphadneitis may be confused morphologically w/follicular lymphomas.

Front 23

23. What are 3 ways to distinguish follicular hyperplasias from follicular lymphomas?

Back 23

Several features favor reactive follicular hyperplasia:
1. Preservation of the lymph node architecture
2. Marked variation in the shape and size of lymphoid nodules
3. The presence of freq mitotic figures, phagocytic macrophages, and recognizable light and dark zones, all foo which tend to be absent from neoplastic follicles

Front 24

24. What is marginal zone B-cell hyperplasia?

Back 24

Follicular hyperplasia is sometimes accompanied by marginal zone B-cell hyperplasia. In some immune reactions, particuarly those cause dby toxoplasmosis and early HIV infection, marginal zone B cells accumulate in a rim external to the mantle zone of germinal centers.

*These cells have moderately abundant pale cytoplasm and folded or reniform nuclei resembling those of monocytes, leading to the descriptive term monocytoid B cells. They appear to be memory B cells derived from antigen-stimulated germinal center B cells.

Front 25

25. What is paracotical lymphoid hyperplasia?

Back 25

Paracortical lymphoid hyperplasia is caused by stimuli that trigger cellular immune responses. ***It is characterized by reactive changes w/in the T cell regions of the lymph node that encroach on, and sometimes appear to efface, the B-cell follicles.

Such changes are encountered in immunologic reactions induced by drugs (esp Dilantin), in acute viral infections, and following vaccinations.

Front 26

26. What is the morphology of the lymph nodes in paracortical lymphoid hyperplasia?

Back 26

W/in interfollicular regions, activated T cells (immunoblasts) are observed. These cells are 3-4x the size of resting lymphocytes and have round nuclei, open chromatin, several prominent nucleoli, and moderate amts of pale cytoplasm.

Front 27

27. What is sinus histiocytosis (AKA reticular hyperplasia)?

Back 27

Sinus histiocytosis refers to distention and prominence of the lymphatic sinusoids. Although nonspecific, this form of hyperplasia may be particularly prominent in lymph nodes draining cancers, such as CA of the breast.

***The lining lymphatic endothelial cells are markedly hypertrophied, and macrophages are greatly increased in numbers, resulting in expansion and distention of sinuses***

In the setting of CA, this pattern of reaction has been thought to represent host immune response against the tumor or its products.

Front 28

28. What are the 3 categorizes of neoplastic proliferations of white cells?

Back 28

1. Lymphoid neoplasms (leukemias)
2. Myeloid neoplasms (AML, CML, etc..)
3. Histiocytoses (Langerhans cells histiocytoses)

Front 29

29. What is a common feature present in the majority of white cell neoplasms?

Back 29

Nonrandom chromosomal abnormalities, most commonly translocations, are present in the majority of white cell neoplasms.

Front 30

30. What are the specific oncogenic rearrangements in lymphoid neoplasms?

PART 1

Back 30

In lymphoid neoplasms, many oncogenic rearrangements stem from mistakes during the events that occur during antigen receptor gene expression.

The normal Ig and TCR gene diversity in B and T lymphs is produced by DNA breakage and rejoining. B- and T-cell progenitors express a V(D)J recombinase activity that cuts DNA at specific sequences, and many pathogenic rearrangements seen in lymphoid neoplasms are caused by the inappropriate joining of these sites to sequences flanking proto-oncogenes.

Front 31

31. What are the specific oncogenic rearrangements in lymphoid neoplasms?

PART 2

Back 31

Mature, antigen-stimulated B cells undergo differentiation in the germinal centers of lymph nodes. There, Ig genes are further modified by class switching and somatic hypermutation, which are regulated forms of genomic instability. Like V(D)J recombination, class switching proceeds thru a mechanism involving dsDNA breaks, and mistakes during this process may account for some oncogenic rearrangements that are seen in certain B-cell malignancies.

It appears that "misdirected" somatic hypermutation also causes mutations in oncogenes that are implicated in B-cell transformation.

Front 32

32. So why are germinal center B cells much more likely to give rise to lymphomas than are mature T cells?

Back 32

The inherent genomic instability of germinal center B cells might explain why they are much more likely to give rise to lymphomas than are mature T cells, which have fixed, stable TCR genes.

Front 33

33. What are the genetic diseases that promote genomic instability and are at an increase risk of leukemia?

Back 33

Bloom syndrome, Fanconi anemia, and ataxia telangiectasias.

In addition, both Down syndrome and NF1 are associated w/an increased incidence of childhood leukemia.

Front 34

34. What viruses have been associated with white cell neoplasias?

Back 34

1. Human T-cell leukemia virus-1 (HTLV-1)
2. EBV
3. Kaposi sarcoma, human herpesvirus-8 (KSHV/HHV-8)

Front 35

35. Which neoplasms are these viruses associated with?

Back 35

HTLV-1 has been associated only w/adult T-cell leukemia/lymphoma.

In contrast, clonal episomal EBV genomes are found in the tumor cells of a subset of Burkitt lymphoma, 30-40% of cases of Hodgkin lymphoma, many B-cell lymphomas occurring in the setting of T-cell immunodeficiency, and rare natural killer cell lymphomas.

KSHV is uniquely associated w/an unusual type of B-cell lymphoma that presents as a malignant effusion, often in the pleural cavity.

Front 36

36. What are some environmental agents liked to leukemia?

Back 36

The most clear cut associations are those of H. pylori infection w/gastric B-cell lymphoma, and gluten-sensitive enteropathy with intestinal T-cell lymphoma.

Also, HIV infected individuals are at high risk for B cell lymphomas derived from germinal center B cells.

Front 37

37. What are some iatrogenic factors that can cause white cell neoplasms?

Back 37

Ironically, radiotherapy and certain forms of chemo used to treat CA increase the risk of subsequent myeloid and lymphoid neoplasms.

This association is believed to stem from mutagenic effects of ionizing radiation and chemotherapeutic drugs on hematolymphoid progenitor cells.

Front 38

38. What does leukemia mean? Lymphoma?

Back 38

Leukemia is used form lymphoid neoplasms presenting w/widespread involvement of the bone marrow, usually accompanied by the presence of large numbers of tumor cells in the peripheral blood.

Lymphoma, on the other hand, is used to describe proliferations arising as discrete tissue masses.

Front 39

39. What is the one type of lymphoma that is segregated from all other forms?

Back 39

Hodgkin lymphoma is segregated from all other forms, which constitute the NHLs.

Front 40

40. What are plasma cell neoplasms?

Back 40

The plasma cell neoplasms are tumors composed of terminally differentiated B cells.

Such tumors most commonly arise in the bone marrow, only rarely involving lymph nodes or producing a leukemic peripheral blood picture.

Front 41

41. What are the general clinical presentations of the various lymphoid neoplasms?

Back 41

2/3's of NHLs and virtually all cases of Hodgkin lymphoma present w/nontender nodal enlargement (often greater than 2 cm) that can be localized or generalized. The remaining 1/3 of NHLs arise at extranodal sites (e.g., skin, stomach, or brain).

In contrast, the leukemic forms (lymphocytic leukemia) most commonly come to clinical attention owing to signs and symptoms related to suppression of normal hematopoiesis by tumor cells in the bone marrow. Lymphocytic leukemias also characteristically infiltrate and enlarge the spleen and liver. Finally, plasma cell neoplasms involving the skeleton cause local bony destruction and hence often present w/pain due to pathologic fractures.

Front 42

42. What are the 5 categories of lymphoid neoplasms?

Back 42

1. Precursor B-cell neoplasms
2. Peripheral B-cell neoplasms
3. Precursor T-cell neoplasms
4. Peripheral T-cell and NK-cell neoplasms
5. Hodgkin lymphoma

Front 43

43. In most lymphoid neoplasms, what precedes transformation?

Back 43

In most lymphoid neoplasms, antigen receptor gene rearrangement precedes transformation; hence, the daughter cells derived form the malignant progenitor share the same antigen receptor gene config and sequence and synthesize identical antigen receptor proteins (either Ig or TCRs).

Front 44

44. How is this different from normal immune responses?

Back 44

Normal immune responses are polyclonal and thus comprise populations of lymphocytes expressing many different antigen receptors.

As a result, analyses of antigen receptor genes and/or their protein products can be used to distinguish reactive and malignant lymphoid proliferations.

Front 45

45. What is the origin of the majority of lymphoid neoplasms - B or T cells?

Back 45

The majority of lymphoid neoplasms (80-85%) are of B-cell origin, most of the remainder begin T-cell tumors; only rarely are tumors of NK origin encountered.

Most lymphoid neoplasms resemble some recognizable stage of B or T-cell differentiation.

Front 46

46. How do neoplastic B and T cells behave?

Back 46

They tend to recapitulate the behavior of their normal counterparts. Like normal lymphocytes, transformed B and T cells tend to home to particular tissue sites, leading to characteristic patterns of involvement.

For ex, follicular lymphomas proliferate in the B cell areas of the lymph nodes, producing a nodular or follicular pattern of growth, whereas T cell lymphomas typically grow in paracortical T cell zones.

Front 47

47. How do these neoplastic cells spread?

Back 47

Most lymphoid tumors are widely disseminated at the time of Dx. The most notable exception to this rule is Hodgkin lymphoma, which is sometimes restricted to one group of lymph nodes.

Hodgkin lymphoma spreads in an orderly fashion, and as a result staging is of importance in determining therapy. In contrast, the spread of NHL is less predictable, and most pts are assumed to have systemic disease at the time of Dx.

Front 48

48. What is acute lymphoblastic leukemia/lymphoma (ALL)?

Back 48

ALL encompasses a group of neoplasms composed of immature, precursor B (pre-B) or T (pre-T) lymphoblasts.

*The majority of ALLs are precursor B cell tumors that typically manifest as childhood acute "leukemias" w/extensive bone marrow and variable peripheral blood involvement.

The less common precursor T cell ALLs tend to present in adolescent males as "lymphomas" often with thymic involvement.

Front 49

49. Who gets ALL?

Back 49

About 2500 new cases of ALL are Dx each year in the US, most cases occurring in individuals younger than 15 years of age. ALL is almost 2x as common in whites as in nonwhites and is slightly more freq in boys than in girls. The incidence of pre-B ALL is highest at about the age of 4, perhaps b/c the number of normal bone marrow pre-B lymphoblasts (the cell or origin) peak sin early childhood.

Similarly, the peak incidence of pre-T ALL is in adolescence, the age when the thymus reaches its maximal size.

Front 50

50. What is the difference between ALL and AML?

Back 50

Compared to myeloblasts, lymphoblasts have condensed chromatin, inconspicuous nucleoli, and have scant agranular cytoplasm.

However, these distinctions are not absolute, and definitive Dx relies on detection of B and T lymphocyte specific markers with antibodies. In that case, *lymphoblasts (in contrast to myeloblasts) lack peroxidase-positive granules and often contain cytoplasmic aggregates of PAS positive material.*

Front 51

51. ALLs with lymphomatous presentations are mostly of what cell type?

Back 51

ALLs with lymphomatous presentations are mostly of pre-T cell type.

Many pre-T ALLs (50-70%) are associated w/mediastinal masses stemming from thymic involvement, and lymphadenopathy and splenomegaly are also more prevalent in this subtype.

Front 52

52. What is the morphology of ALL?

Back 52

Normal tissue architecture is completely effaced by lymphoblasts having scant cytoplasm and nuclei somewhat larger than those of small lymphocytes. ***The nuclear chromatin is delicate and finely stippled, and nucleoli are either absent or inconspicuous.***

In keeping w/its aggressive growth, the tumor shows a high rate of mitosis, and a "starry sky" pattern can be produced by interspersed benign tingible body macrophages.

Front 53

53. Immunostaining for ALL

Back 53

Immunostaining for TdT, a specialized DNA polymerase that is expressed only by pre-B and pre-T lymphoblasts, is positive in >95% of cases.

Front 54

54. What cell markers are expressed in B-cell ALL?

Back 54

Pre-B ALL cells are arrested at stages preceding surface expression of Ig.

The leukemic blasts almost always express CD19+ and CD10+.

*Early pre-B ALL is distinguished from late pre-B ALL by the absence of cytoplasmic IgM heavy chain.

Front 55

55. What cell markers are expressed in T-cell ALL?

Back 55

Precursor T ALL cells are arrested at early stages of T-cell development. In most cases, the cells are CD1+, CD2+, CD5+, and CD7+

Early pre-T cell tumors are usually negative for CD3, CD4, and CD8, whereas late pre-T cell tumors are positive for these markers.

Front 56

56. What are the genetic abnormalities in ALL?

Back 56

90% of pts w/ALL have numerical or structural changes in the chromosomes of teh leukemic cells. most common is hyperploidy, but also polyploidy, and t(12;21), t(9;22) (Philly chromosome), and t(4;11) tranlocations.

Front 57

57. How do these chromosomal aberrations seen in ALL cause problems?

Back 57

Many if the chromosomal aberrations seen in ALL dysregulate the expression and function of transcription factors required for normal hematopoietic cell development.

These derangements likely interfere w/normal lymphoblast maturation, leading to arrested development and the accumulation of immature progenitors.

Front 58

58. What are the clinical features of ALL?

1/2

Back 58

ALL shares clinical features with AML. An accumulation of neoplastic "blast" cells in the bone marrow and suppresses normal hematopoiesis by physical crowding, competition for growth factors, and other poorly understood mechanisms. This results in anemia, neutropenia, and thrombocytopenia.

Front 59

59. What are the 5 main clinical features of ALL?

2/2

Back 59

1. Abrupt stormy onset
2. Symptoms related to depression of normal marrow function i.e. anemia, fever, bleeding
3. Bone pain and tenderness
4. *Generalized lymphadenopathy, *splenomegaly, and *hepatomegaly caused by neoplastic infiltration
5. *CNS manifestations such as headache, vomiting, and nerve palsies resulting from meningeal spread.

*More common in ALL than in AML

Front 60

60. What is the prognosis for ALL?

Back 60

With aggressive chemo, more than 90% of children w/ALL achieve complete remission, and at least 2/3;s can be considered cured.

Front 61

61. What are the 4 factors that are associated with a worse prognosis in ALL?

Back 61

1. Age under 2
2. Presentation in adolescence or adulthood
3. Peripheral blood blast counts greater than 100,000, which may reflet a high tumor burden
4. The presence of unfavorable cytogenetic aberrations, such as the t(9;22) Philly chromosome

Front 62

62. What factors are associated with a favorable prognosis in ALL?

Back 62

Age of 2-10 years, low white count, an early pre-B phenotype, and hyperploidy or t(12;21).

Front 63

63. What is chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)?

Back 63

These two disorders are morphologically, phenotypically, and genotypically indistinguishable, differing only in the degree of peripheral blood lymphocytosis. Most pts have sufficient lymphocytosis to fulfill the Dx requirement for CLL (absolute lymphocyte count > 4000 per mm^3), which is the most common leukemia of adults in the Western world.

In contrast, SLL constitutes only 4% of NHL. CLL/SLL is much less common in Japan and other Asian countries.

Front 64

64. What is the morphology of the lymph nodes in CLL/SLL?

Back 64

Lymph nodes architecture is diffusely effaced by a predominant population of small lymphocytes 6-12 um in diameter containing round to slightly irregular nuclei w/condensed chromatin and scant cytoplasm.

These cells are mixed w/variable numbers of larger cells called "prolymphocytes" ***In many cases, prolymphocytes gather together focally to form loose aggregates referred to as proliferation centers. When present, proliferation centers are pathognomonic for CLL/SLL.***

Front 65

65. What is the morphology of CLL?

Back 65

In CLL, the peripheral blood contains increased #'s of small, round lymphocytes w/scant cytoplasm. ***These cells are fragile and are freq disrupted in the process of making smears, producing so called "smudge cells".***

Involvement of the bone marrow is observed in all cases of CLL and most cases of SLL, taking the form of interstitial infiltrates and/or non-paratrabecular aggregates of small lymphocytes. Tumor cells usually infiltrate the splenic white and red pulp and the hepatic portal tracts.

Front 66

66. Cell markers for CLL/SLL?

Back 66

CLL/SLL has a distinctive phenotype. The tumor cells express the pan B-cell markers CD19 and CD20. In addition, CD23 and CD5 are present on the tumor cell.

There is also typically low level expression of surface Ig heavy chain and either a kappa or lambda light chain.

Front 67

67. What are the chromosomal abnormalities in CLL/SLL?

Back 67

Chromosomal translocations are rare in CLL/SLL (unusual). The most common findings are deletions of 13q12-14, deletions of 11q, trisomy 12q, and deletions of 17p.

DNA sequencing has revealed that the Ig genes of some CLL/SLL are somatically hypermutated, whereas other are not, suggesting that he cell of origin may be a postgerminal center memory B cell or a naive B cell.

Front 68

68. What is the typical presentation of a pt w/CLL/SLL?

Back 68

Most pts present at ages over 50; a male predominance has been noted. Pts w/CLL/SLL are often asymptomatic. When symptoms appear, they are nonspecific and include easy fatigability, weight loss, and anorexia. Generalized lymphadenopathy and hepatosplenomegaly are present in 50-60% of cases.

The total leukocyte count is variable. Pts can be leukopenic in SLL, while pts with CLL and heavy tumor burdens can have leukocyte counts in excess of 200,000 per mm^3.

Front 69

69. Besides a variable leukocyte count, what else is wrong with the CBC is CLL/SLL?

Back 69

Hypogammaglobulinemia is common and contributes to increased susceptibility to infections.

Conversely, some 10-15% of pts develop autoantibodies directed against RBCs or platelets that produce autoimmune hemolytic anemia or thrombocytopenia. The pathogenic IgGs are produced by non-neoplastic, self-reactive B cells rather than tumor cells, suggesting a systemic defect in immune regulation.

Front 70

70. What is the survival like in CLL/SLL?

Back 70

Overall, the median survival is 4-6 years, but pts with minimal initial tumor burdens can survive for 10 years or more.

***The presence of deletions of 11q and 17p correlates with higher stage disease and portends a worse prognosis.

Front 71

71. What is a feared complication of CLL/SLL?

Back 71

The ability of it to transform into a more aggressive lymphoid neoplasm. ***Most commonly, this takes the form of a prolymphocytic transformation or a transformation to diffuse large B cell lymphoma, so called Richter syndrome.***

Both prolymphocytic and large-cell transformation are usually ominous events, most pts surviving less than 1 year.

Front 72

72. What is follicular lymphoma?

Back 72

Follicular lymphoma is the most ccommon form of NHL is the US. It usuall presents in middle age and afflicts males and females equally. it is less common in Europe and rare in Asian populations.

*The neoplastic cells closely resemble normal germinal center B cells.*

In most cases, a predominantly nodular or nodular and diffuse growth pattern is observed in the lymph nodes.

Front 73

73. What are the two principal cell types observed in lymph nodes in follicular lymphoma?

Back 73

(1) Small cells w/irregular or cleaved nuclear contours and scant cytoplasm, referred to as centrocytes (small cleaved cells)

(2) Larger cells w/open nuclear chromatin, several nucleoli, and modest amts of cytoplasm, referred to as centroblasts.

Front 74

74. What is the peripheral blood involvement in follicular lymphoma?

Back 74

There is lymphocytosis usually under 20,000 per mm^3) in about 10% of pts.

Bone marrow involvement occurs in 85% of pts and characteristically takes the form of paratrabecular lymphoid aggregates.

Splenic white pulp and hepatic portal triads are also freq involved.

Front 75

75. Immunophenotypes for follicular lymphoma?

Back 75

The neoplastic cells resemble normal follicular center B cells, expressing CD19, CD20, CD10, and surface Ig.

(Unlike CLL/SLL, CD5 is not expressed)

****Also, follicular lymphoma cells also express BCL2 protein in more than 90% of cases (normal B cells are BCL2 negative)****

Front 76

76. What is the hallmark of typical follicular lymphoma?

Back 76

A (14;18) translocation that juxtaposes the IgH locus on chromosome 14 and the BCL2 locus on chromosome 18.

This translocation is seen in up to 90% of follicular lymphoma, and leads to overexpression of BCL2 protein. BCL2 is an antagonist of apopotic cell death, and appears to promote the survival of follicular lymphoma cells. In other words, neoplastic follicles are characteristically devoid of apoptotic cells.

Front 77

77. What are the clinical features of follicular lymphoma?

Back 77

Follicular lymphomas tend to present w/painless, generalized lymphadenopathy. Inovvlement of extranodal sites is relatively uncommon.

Although it is incurable, it usually follows and indolent waxing and waning course. The overall median survival is 7-9 years and is not improved by aggressive therapy.

*Histologic transformation to diffuse large B-cell lymphomas occurs in 30-50% of follicular lymphomas.*

Front 78

78. What is diffuse large B-cell lymphoma (DLBCL)?

Back 78

DLBCL is an aggressive lymphoid neoplasm that is rapidly fatal if untreated.

There is a slight male predominance, with a median age of 60. However, the age range is wide, and DLBCL constitutes about 5% of childhood lymphoma.

Front 79

79. What is the common morphologic feature of DLBCLs?

Back 79

A relatively large cell size (usually 4-5x the diameter of a small lymphocyte) and a diffuse pattern of growth.

Front 80

80. What are the other morphologic features of DLBCLs?

Back 80

Most commonly, the tumor cells have a round or oval nucleus that appears vesicular owing to margination of chromatin at the nuclear membrane, but large multilobulated or cleaved nuclei are prominent in some cases. Nucleoli may be 2-3 in number and centrally placed. The cytoplasm is usually moderately abundant and may be pale or basophilic.

More anaplastic tumors may contain multinucleated cells w/large inclusionlike nucleoli that resemble Reed-Sternberg cells.

Front 81

81. Immunophenotype of DLBCLs?

Back 81

These mature B-cell tumors express the B-cell markers CD19 and CD20, and they show variable expression of CD10 and BCL6.

Most have surface Ig, and all are negative for TdT.

Front 82

82. What is the genetic abnormality in DLBCLs?

Back 82

One freq pathogenic event is the dysregulation of BCL6, a DNA-binding transcriptional regulator that is required for the formation of normal germinal centers.

About 30% of DLBCLs contain various translocations that have in common a breakpoints at chromosome 3q27 w/in the BCL6 locus, and tumors lacking 3q27 rearrangement often have acquired mutations in BCL6 promoter sequences.

Front 83

83. So how does this BCL6 mutation or 3q27 rearrangement cause problems?

Back 83

Normally, BCL6 expression is downregulated when B cells leave the germinal center, but both BCL6 promoter mutations or 3q27 rearrangements cause persistent and dysregulated expression of target genes.

**However, tumors with BCL2 rearrangements almost always lack BCL6 rearrangements, suggesting that there are at least 2 unique pathways.

Front 84

84. What are the two subtypes of large B-cell lympomas?

Back 84

1. Immunodeficiency associated large B-cell lymphomas
2. Body cavity large cell lymphomas

Front 85

85. What is immunodeficiency associated large B-cell lymphoma?

Back 85

Immunodeficiency associated large B-cell lymphomas occur in the setting of severe T-cell immunodeficiency.

*The neoplastic B cells are often latently infected w/EBV, which is through to play a critical pathogenic role. Restoration of T-cell immunity may lead to regression of such EBV-positive proliferations.

Front 86

86. What is body cavity large cell lymphoma?

Back 86

Body cavity large cell lymphomas arise as malignant pleural or ascitic effusions, mostly in pts w/advanced HIV infection, but occasionally in HIV-negative elderly adults. The tumor cells often fail to express surface B- or T-cell markers but have clonal IgH gene rearrangements.

***In all cases, the tumor cells are infected with KSHV/HHV8. Among the malignant lymphomas, KSHV has been observed only in this particular subtype.

Front 87

87. What is the clinical course of DLBCLs?

Back 87

In contrast to pts with low grade lymphomas, pts w/DLBCL typically present w/a rapidly enlarging, often symptomatic, mass at a single nodal or extranodal site.

Large B-cell lymphomas can arise at virtually any site such as Waldeyer ring, tonsils and adenoids.

As a group, these are aggressive tumors that are rapidly fatal if untreated. Pts with limited disease fare better than those with widespread disease or a large, bulky tumor mass.

Front 88

88. What are the 3 categories of Burkitt lymphoma?

Back 88

1. African (endemic)
2. Sporadic (nonendemic)
3. A subset of aggressive lymphomas occurring in individuals infected w/HIV

Front 89

89. What is the morphology of Burkitt lymphoma?

1/2

Back 89

Involved tissues are effaced by a diffuse infiltrate of intermediate-sized lymphoid cells, 10-25 um in diameter, containing round or oval nuclei w/coarse chromatin, several nucleoli and a moderate amt of faintly basophilic or amphophilic cytoplasm.

*A high mitotic index is typical, as is apoptotic tumor cell death, accounting for the presence of numerous tissue macrophages with ingested nuclear debris.

Front 90

90. What is the morphology of Burkitt lymphoma?

2/2

Back 90

**These benign macrophages are diffusely distributed among the tumor cells and have abundant clear cytoplasm, creating a characteristic "starry sky" pattern.*

In cases w/bone marrow involvement, the tumor cells in marrow aspirates have slightly clumped nuclear chromatin, 2-5 distinct nucleoli, and royal blue cytoplasm containing multiple, clear cytoplasmic vacuoles.

Front 91

91. Immunophenotype of Burkitt lymphoma

Back 91

These are tumors of mature B cells, expressing surface IgM, monotypic κ or λ light chain, CD19, CD20, and CD10, and BCL6.

Front 92

92. All forms of Burkitt lymphoma are associated with translocations of...?

Back 92

All forms of Burkitt lymphoma are associated with translocations of the c-MYC gene on chromosome 8.

The partner is usually the IgH locus (t(8;14)), but may also be the κ(t(2;8)) or λ(t(8;22)) light chain locus.

Front 93

93. Essentially all endemic Burkitt lymphomas are infected with ______?

Back 93

EBV. Infection precedes cellular transformation.

Front 94

94. What are the clinical features of Burkitt lymphoma?

Back 94

Both the endemic and the sporadic cases are found largely in children or young adults. Most tumors manifest at extranodal sites. Involvement of the bone marrow and peripheral blood is uncommon.

Burkitt lymphoma is very aggressive, but responds well to short term, high dose chemo. Most children and young adults can be cured, but the outcome is more guarded in older adults.

Front 95

95. Main clinical differences btwn endemic vs. sporadic Burkitt lymphoma

Back 95

Endemic Burkitt's often presents as a mass involving the mandible and shows an unusual predilection for involvement of abdominal viscera, particularly the kidneys, ovaries, and adrenal glands.

In contrast, sporadic Burkitt lymphoma most often presents as an abdominal mass involving the ileocecum and peritoneum.

Front 96

96. What is a common feature of plasma cell neoplasms?

Back 96

The common feature of this collection of entities is the proliferation of a B-cell clone that synthesizes and secretes a single homogeneous Ig or its fragments.

In many but not all cases, these proliferations are malignant.

Front 97

97. What is this single homogeneous Ig component in plasma cell dyscrasias?

Back 97

The monoclonal Ig is referred to as an M component, in reference to myeloma. Unlike normal plasma cells, in which the production and coupling of heavy (H) and light (L) chains are tightly balanced, ***Neoplastic plasma cells often synthesize excess L or H chains along with complete Igs.***

Occasionally, only L chains or H chains are produced.

Front 98

98. What is the significance of the free L chains?

Back 98

The free L chains, known as Bence Jones proteins, are small enough to be rapidly excreted in the urine.

Asa result, free L chains are detectable in the blood only in the setting of renal failure or very high levels of synthesis.

Front 99

99. What is the most important plasma cell neoplasm?

Back 99

Multiple myeloma. It is a symptomatic monoclonal gammapathy. It is characterized by multiple masses of neoplastic plasma cells scattered throughout the skeletal system.

Front 100

100. What is Waldenstrom macroglobulinemia?

Back 100

Waldenstrom macroglobulinemia is a syndrome caused by blood hyperviscosity due to high levels of IgM.

It is seen most commonly in adults w/lymphoplasmacytic lymphoma, but it can also occur in association w/tumors morphologically resembling CLL/SLL and with rare IgM-secreting myelomas.

Front 101

101. What is heavy chain disease?

Back 101

Heavy-chain disease is seen in a diverse group of disorders, including CLL/SLL, lymphoplasmacytic lymphoma, and unusual small bowel lymphoma that occurs in malnourished populations (Mediterranean lymphoma).

**The common feature is synthesis and secretion of free H chain fragments.

Front 102

102. What is primary or immunocyte-associated amyloidosis?

Back 102

Primary or immunocyte-associated amyloidosis results from a monoclonal proliferation of plasma cells secreting free L chains (most commonly of λ isotype) that are subsequently processed and deposited as amyloid.

Front 103

103. What is monoclonal gammopathy of undetermined significance (MGUS)?

Back 103

MGUS refers to instances in which M components are identified in the blood of pts having no signs or symptoms.

MGUS is very common in the elderly but progresses to a symptomatic monoclonal gammopathy (most often multiple myeloma) in only a small subset of pts.

Front 104

104. What is multiple myeloma again?

Back 104

Multiple myeloma is a plasma cell neoplasm characterized by involvement of the skeleton at multiple sites. Although bony disease dominates, it can spread to lymph nodes and extranodal sites such as the skin.

Its incidence is higher in men, people of African descent, and older adults.

Front 105

105. The proliferation and survival of myeloma cells are dependent on....?

Back 105

Cytokines, most notably IL-6. IL-6 is produced by neoplastic plasma cells and normal stromal cells in the marrow.

Serum levels of this cytokine are increased in pts w/active disease, and high serum IL-6 levels are associated w/a poor prognosis.

Front 106

106. What cytokines produced by myeloma tumors mediate bone destruction?

Back 106

MIP1α and the receptor activator of NF-κB ligand (RANKL)

Front 107

107. What are the most freq karyotypic abnormalities in multiple myeloma?

Back 107

The most freq karyotypic abnormalities in multiple myeloma are deletions of 13q and translocations involving the Ig heavy chain locus on 14q32.

Common translocation partners with IgH are FGFR3, a gene encoding a type of tyrosine kinase receptor implicated in cell cycle control; cyclin D1 and D3, cMAF, and MUM1/IRF4.

Front 108

108. What are the skeletal lesions like in multiple myeloma?

Back 108

Multiple myeloma presents most often as multifocal destructive bone tumors composed of plasma cells (plasmacytomas) throughout the skeleton. Bones in the axial skeleton are affected most commonly.

Vertebral column 66%
Ribs 44%
Skull 41%
Pelvic 28%

These focal lesions generally begin in the medullary cavity, erode cancellous bone, and progressively destroy the bone cortex, often leading to pathologic fractures.

Front 109

109. What is the morphology of these bone lesions?

Back 109

*The bone lesions appear radiographically as punched-out defects, usually 1-4 cm in diameter* and grossly consist of gelatinous, soft, red tumor masses.

Front 110

110. What is the morphology of the bone marrow in multiple myeloma?

Back 110

Microscopic exam of the marrow reveals an increased number of plasma cells, which usually constitute more than 30% of the marrow cellularity.

The plasma cells can infiltrate the marrow diffusely or be present in sheetlike masses that completely replace normal elements.

*Relatively normal-appearing plasma cells, plasmablasts, with vesicular nuclear chromatin and a prominent single nucleolus, or bizarre multinucleated cells may predominate.*

Front 111

111. What are the morphological variants of multiple myeloma?

Back 111

Such variants include *flame cells*, with fiery red cytoplasm; *Mott cells* having multiple blue grapelike cytoplasmic droplets, and cells containing a variety of other inclusions, including *fibrils*, *crystalline rods*, and *globules*, sometimes *Russel bodies* (cytoplasmic) or *Dutcher bodies* (nuclear).

Front 112

112. What is a rouleaux formation?

Back 112

Commonly, the high level of serum M proteins causes red cells in smears of peripheral blood to stick to one another in linear arrays, a finding referred to as rouleaux formation.

Although characteristic, rouleaux formation is not specific.

Front 113

113. What are the 3 main clinical features of multiple myeloma?

Back 113

1. Infiltration of organs, particularly bones, by the neoplastic plasma cells
2. The production of excessive Ig's, which often have abnormal physicochemical properties
3. The suppression of normal humoral immunity

Front 114

114. Bone resorption in multiple myeloma leads to...?

Back 114

Bone resportion often leads to pathologic fractures and chronic pain. The attendant hypercalcemia can in turn give rise to neurologic manifestations such as confusion, weakness, lethargy, constipation, and polyuria and can contribute to renal disease.

Front 115

115. What are the immunologic problems in multiple myeloma?

Back 115

Decreased production of normal Ig's sets the stage for recurrent infections w/Strep pneumo, Staph aureus, and E. coli.

Front 116

116. What is the renal involvement in multiple myeloma?

Back 116

Renal insufficiency is second to infections as a cause of death. The single most important factor appears to be Bence Jones proteinuria, as excreted light chains are toxic to renal epithelial cells.

*In 99% of pts with multiple myeloma, lab analyses reveal increased levels of Ig's in the blood and/or light chain (Bence Jones proteins) in the urine.

Most myelomas are associated with more than 3 gm/dL of Ig in serum and/or more than 6gm/dL of Bence Jones protein in urine.

Front 117

117. What is the most common serum monoclonal Ig found in multiple myeloma pts?

Back 117

"M protein" IgG.

Excessive production and aggregation of M proteins leads to the hyperviscosity syndrome in approx 7% of pts, most associated w/tumors that secrete IgA or IgG3.

Front 118

118. What is survival like in multiple myeloma?

Back 118

The prognosis is variable but generally poor. Pts w/multiple bone lesions, if untreated, rarely survive for more than 6-12 months, whereas occasional pts with "indolent myeloma" can survive for many years.

Chemo with alkylating agents induces remission in 50-70% of pts, but the median survival is still a dismal 3 years.

Front 119

199. What is solitary myeloma (plasmacytoma)?

Back 119

About 3-5% of plasma cell neoplasms present as a solitary lesion of either bone or soft tissue. The bony lesions tend to occur in the same locations as in multiple myeloma. Extraosseous lesions are often located in the lugns, oronasopharynx, or nasal sinuses. Modest elevations of M proteins in the blood or urine may be found in a minority of pts.

Front 120

120. Can solitary forms progress to multiple forms in solitary myeloma?

Back 120

Progression to classic multiple myeloma is common in pts w/solitary osseous plasmacytoma, whereas extraosseous plasmacytomas disseminate in only a minor fraction of pts.

It appears that the solitary plasmacytoma involving the bones often represent an early stage of multiple myeloma, but progression can take 1-20 years or longer.

Front 121

121. What is monoclonal gammopathy of uncertain significance?

Back 121

M proteins can be identified in the serum of 1% of asymptomatic healthy persons older than 50 years of age and in 3% of individuals older than 70 years of age. This dysproteinemia w/o associated disease is called "monoclonal gammopathy of uncertain significance" MGUS is the most common cause of monoclonal gammopathy.

Approx 1% of pts with MGUS progress to an overt plasma cell dyscrasia (usually multiple myeloma) per year.

*In general, pts with MGUS have less than 3 gm/dL of monoclonal protein in the serum and no Bence Jone proteinuria.

Front 122

122. What is lymphoplasmacytic lymphoma?

Back 122

Lymphoplasmacytic lymphoma is a B cell neoplasm of older adults that usually presents in the 6th or 7th decade of life.

Although similar to CLL/SLL, it differs in that a substantial fraction of tumor cells undergo terminal differentiation to plasma cell. ***Most commonly the neoplastic plasma cells secrete monoclonal IgM, often in amts sufficient to cause a hyperviscosity syndrome known as Waldenstrom macroglobulinemia***

Front 123

123. How is lymphoplasmacytic lymphoma different from multiple myeloma?

Back 123

In contrast to multiple myeloma, heavy and light chain synthesis is usually balanced, and, therefore, complications stemming from the secretion of free light chains (e.g., renal failure and amyloidosis are rare).

Front 124

124. What is the morphology of lymphoplasmacytic lymphoma?

Back 124

Typically, the bone marrow contains a diffuse, sparse to heavy infiltrate of lymphocytes, plasma cells, and intermediate plasmacytoid lymphocytes, often accompanied by a reactive hyperplasia of mast cells.

PAS positive inclusions containing Ig are freq seen in the cytoplasms (Russell bodies) or nucleus (Dutcher bodies) of plasmacytoid cells.

***Tumorous masses causing bony erosions a hallmark of multiple myeloma, are absent.

Front 125

125. Immunophenotype of lymphoplasmacytic lymphoma

Back 125

The lymphocytic component of the tumor cell infiltrate expresses B cell markers such as CD20 and is usually negative for CD5 and CD10, whereas the plasma cell component expresses and secretes a monoclonal Ig.

Front 126

126. What is the most common cytogenetic abnormality in lymphoplasmacytic lymphoma?

Back 126

Deletion involving chromosome 6q.

Front 127

127. What is the presentation like of lymphoplasmacytic lymphoma?

Back 127

The dominant presenting complaints are weakness, fatigue, and weight loss - all nonspecific symptoms. Approx half the pts have lymphadenopathy, hepatomegaly, and splenomegaly. Anemia caused by marrow infiltration is often present and can be exacerbated by autoimmune hemolysis, which is seen in about 10% of pts.

Hemolysis is caused by cold agglutinins, IgM antibodies that bind to RBCs in cold temps.

Front 128

128. What are the 4 additional clinical complaints of pts with high concentrations of IgM?

Back 128

Leads to hyperviscosity syndrome;

Causes:
1. Visual impairment
2. Neurologic problems
3. Bleeding
4. Cryoglobulinemia

Front 129

129. What is the prognosis for lymphoplasmacytic lymphoma?

Back 129

Lymphoplasmacytic lymphoma is an incurable progressive disease. B/c most IgM is intravascular, symptoms caused by high IgM levels (such as hyperviscosity and hemolysis) can be alleviated by plasmapheresis.

Median survival is about 4 years.

Front 130

130. What is mantle cell lymphoma?

Back 130

Mantle cell lymphoma usually presents in the 5th-6th decades of life and shows a male predominance.

***The tumor cells closely resemble the normal mantle zone B cells that surround germinal centers.

Front 131

131. What is the morphology of the tumor cells in mantle cell lymphoma?

Back 131

Tumor cells may surround reactive germinal centers, producing a vaguely nodular appearance at low power, or diffusely efface nodal architecture.

***Typically, the proliferation consists of a homogeneous population of small lymphocytes w/round to irregular to occasionally deeply clefted (cleaved) nuclear contours.***

Front 132

132. How does one distinguish mantle cell lymphoma from follicular lymphoma and CLL/SLL?

Back 132

Large cells resembling centroblasts are usually absent, as are proliferation centers, helping to distinguish mantle cell lymphoma from follicular lymphoma and CLL/SLLL, respectively.

Front 133

133. What is a common symptom at Dx of mantle cell lymphoma?

Back 133

The majority of pts have generalized lymphadenopathy at Dx, w/20-40% having peripheral blood involvement.

Freq sites of extranodal involvement include the bone marrow, splenic white pulp zones, hepatic periportal areas, and the gut. Occasionally, multifocal mucosal involvement of the small bowel and colon produces "lymphomatoid polyposis"; of all forms of NHL, mantle cell lymphoma is most likely to spread in this fashion.

Front 134

134. What is the immunophenotype of mantle cell lymphoma?

Back 134

Mantle cell lymphoma expresses CD19, CD20, moderately high levels of surface Ig heavy chain , and either κ or λ light chain.

It is usually CD5+ and CD23-, which can also help to distinguish it from CLL/SLL.

*It is also characteristically positive for cyclin D1 protein*.

Front 135

135. Mantle cell lymphoma is associated with which translocation?

Back 135

Mantle cell lymphoma is associated with an (11:14) translocation involving the IgH locus on chromosome 14 and the cyclin D1 locus on chromosome 11.

The t(11;14) leads to increased expression of cyclin D1, which promotes G1 to S phase progression during the cell cycle.

Front 136

136. What are the clinical features of mantle zone lymphomas?

Back 136

While the most common presentation is painless lymphadenopathy, symptoms related to splenomegaly or involvement of the GI tract are not unusual.

The prognosis is generally poor, as the median survival is only 3-4 years. Most pts succumb eventually to organ dysfunction caused by tumor infiltration.

Front 137

137. What are marginal zone lymphomas?

Back 137

These lymphomas are a group of B-cell tumors that variously arise w/in the lymph nodes, spleen, or extranodal tissues.

Those occurring at extranodal sites deserve special attention b/c of their unusual pathogenesis.

Front 138

138. Why do marginal zone lymphomas occurring at extranodal sites deserve special attention?

(3 reasons)

Back 138

1. They often arise w/in tissues involved by chronic inflammatory disorders of autoimmune or infectious etiology (ex: salivary gland in Sjogren's, stomach with H. pylori)
2. They remain localized for polonged periods, spreading systemically only late in their course
3. They may regress if the inciting agent (e.g. H. pylori) is eradicated

Front 139

139. So how would you describe marginal zone lymphomas?

Back 139

This neoplasm lies on a continuum btwn reactive lymphoid hyperplasia and full-blown B-cell lymphoma.

The process begins as a reactive, polyclonal immune reaction. W/the acquisition of mutations and chromosomal aberrations over time, a monoclonal B-cell neoplasm emerges that is still dependent on reactive T-helper cells for growth and survival.

Front 140

140. What is hairy cell leukemia?

What is its immunophenotype?

Back 140

This is a rare B-cell neoplasm that predominantly affects middle-aged Caucasian males (M:F is 4:1)

Hairy cells usually express CD19 and CD20, surface IgH, and either κ or λ light chain, CD11c, CD25, and CD103.

Front 141

141. What is the morphology of hairy cell leukemia (HCL)?

Back 141

HCL derives its name from the appearance of the leukemic cells, which have fine hairlike projections.

On routine peripheral blood smears, hairy cells have round, oblong, or reniform nuclei and modest amts of pale blue cytoplasm, often w/thread-like or bleb-like extensions.

Front 142

142. What is an interesting feature about HCL?

Back 142

B/c these cells are enmeshed in an ECM composed of reticulin fibrils, they usually cannot be aspirated form the bone marrow (dry tap).

Front 143

143. What are the clinical features of HCL?

Back 143

Clinical manifestions result largely from infiltration of bone marrow, liver, and spleen. *Splenomegaly, often massive, is the most common and sometimes the only abnormal physical findings.

Pancytopenia, resutling from marrow failure and splenic sequestration is seen in more than half of cases.

There is an increased incidence of atypical mycobacterial infections.

HCL tends to follow an indolent course. For unclear reasons, the tumor cells are exceptionally sensitive to particular chemo regimens, which produce long lasting remissions in a majority of pts.

Front 144

144. What is peripheral T-cell lymphoma, unspecified?

Back 144

This is a wastebasket Dx category. Certain findings are characteristic of tumors in this category. The tumors diffusely efface the architecture of involved lymph nodes and are typically composed of a pleomorphic mixture of small, intermediate, and large sized malignant T cells.

They can have a prominent infiltrate of reactive cells such as eosinophils and macrophages, probably attracted by T cell derived cytokines. Prominent angiongenesis is also seen sometimes.

Front 145

145. How is the Dx of peripheral T-cell lymphoma, unspecified made?

Back 145

The Dx can be coonfirmed only by immunophenotyping.

*By definition, all peripheral T-cell lymphomas have a mature T-cell phenotype, lacking TdT and usually expressing CD2, CD5, surface CD3, and either αβ or γδ TCR's.

Front 146

146. What are the symptoms of peripheral T-cell lymphoma, unspecified?

Back 146

Most pts present w/generalized lymphadenopathy, sometimes accompanied by eosinophilia, pruritus, fever, and weight loss.

*These tumors have a significantly worse prognosis than comparably aggressive mature B-cell neoplasms (e.g., DLBCL).

Front 147

147. Anaplastic large cell lymphoma has a strong association with rearrangements involving _______?

Back 147

Anaplastic large cell lymphoma has a strong association with rearrangements involving the ALK gene on chromosome 2p23.

Such rearrangements break the ALK locus and lead to the formation of chimeric genes encoding ALK fusion proteins, which behave as constitutively active tyrosine kinases.

*ALK rearrangements are specific for this entity.

Front 148

148. What is anaplastic large cell lymphoma?

Back 148

As its name implies, this tumor often comprises large anaplastic cells, some of which typically contain horseshoe shaped nuclei and voluminous cytoplasm (so called hallmark cells).

The tumor cells sometimes cluster about venules and infiltrate lymphoid sinuses, mimicking the appearance of metastatic CA.

Front 149

149. What are the clinical features of anaplastic large cell lymphomas with and w/o ALK rearrangements?

Back 149

Those w/ALK rearrangements tend to occur in children or young adults, freq involve soft tissues, and carry a very good prognosis with a 75-80% cure rate w/chemo.

Those lacking ALK rearrangements occur in older adults and have a poor prognosis, similar to that of peripheral T-cell lymphoma, not otherwise specified.

Front 150

150. What is adult T-cell leukemia/lymphoma?

Back 150

This neoplasm of CD4+ T cells is observed in adults infected w/human T-cell leukemia virus type 1 (HTLV-1).

It is most freq in regions where HTLV-1 is endemic (southern Japan, West Africa, and the Caribbean basin) and is characterized by skin lesions, generalized lymphadenopathy, hepatoslenomegaly, peripheral blood lymphocytosis, and hypercalcemia.

Front 151

151. What is the morphology of adult T-cell leukemia/lymphoma?

Back 151

The appearance of the tumor cells varies widely, but cells w/multilobulated nuclei, described as "cloverleaf" or "flower" cells, are freq found in involved tissues and peripheral blood.

Reed-Sternberg cells may be present, but these are rare.

The tumor cells contain clonal HTLV-1 provirus, compatible with direct pathogenic involvement of the virus in this neoplasm.

Front 152

152. What are the clinical features of adult T-cell leukemia/lymphoma?

Back 152

Most pts present w/rapidly progressive disease that is fatal w/in months to 1 year despite aggressive chemo.

In addition to causing lymphoid malignancies, HTLV-1 infection can give rise to a progressive demyelinating disease affecting the CNS and the spinal cord.

Front 153

153. What are mycosis fungoides and Sezary syndrome?

Back 153

Mycosis fungoides and Sezary syndrome of different manifestations of a tumor of CD4+ helper T cells characterized by a marked predilection to involve the skin.

Front 154

154. What are the 3 stages of mycosis fungoides?

Back 154

THe cutaneous lesions show 3 distinct stages.

1. It presents with an inflammatory premycotic phase
2. Progresses through a plaque phase
3. Goes to a tumor phase

Front 155

155. What is the morphology of mycosis fungoides?

Back 155

Histologically, there is infiltration of the epidermis and upper dermis by neoplastic T cells,k which usually have nuclei w/a cerebriform appearance due to marked infolding of the nuclear membrane.

Disease progression is characterized by extracutaneous spread, most commonly to lymph nodes and bone marrow.

Front 156

156. What is Sezary syndrome?

Back 156

Sezary syndrome is a variant in which skin involvement is manifested as a *generalized exfoliative erythroderma*.

In contrast to mycosis fungoides, the skin lesions rarely proceed to tumefaction. In addition, there is an associated leukemia of Sezary cells w/characteristic cerebriform nuclei.

Front 157

157. What are the clinical features of mycosis fungoides and Sezary syndrome?

Back 157

Although cutaneous disease dominates the clinical picture in these disorders, sensitive molecular analyses have shown that tumor cells are found early int he disease course in blood, bone marrow, and lymph nodes.

These are indolent tumors w/a median survival rate of 8-9 years. Transformation into a large cell lymphoma of T-cell type occasionally occurs as a terminal event.

Front 158

158. What is large granular lymphocytic leukemia?

Back 158

There are 2 variants: T-cell and NK cell, both of which mainly occur in adults.

Pts w/T cell disease usually present with mild to moderate lymphocytosis and splenomegaly; lymphadenopathy and hepatomegaly are usually absent.

NK-cell disease often presents in an even more subtle fashion, w/little or no lymphocytosis or splenomegaly.

Front 159

159. What is the cytologic hallmark of large granular lymphocytic leukemia?

Back 159

The cytologic hallmark is the presence of lymphocytes in the peripheral blood and bone marrow *with abundant blue cytoplasm containing scattered coarse azurophilic granules*.

Marrow involvement is usually focal, w/o physical displacement of normal hematopoietic elements.

Front 160

160. What are the clinical features of large granular lymphocytic leukemia?

Back 160

Depsite the relative paucity of marrow infiltration, neutropenia and anemia dominate the clinical picture. Neutropenia is often accompanied by a striking decrease in late myeloid forms in the bone marrow. Less commonly, LGL is associated with pure red cell aplasia.

***An increased incidence of rheumatologic disorders has also been observed in LGL.

Front 161

161. What is Felty syndrome?

Back 161

Some pts with LGL have the triad of rheumatoid arthritis, splenomegaly, and neutropenia.

Front 162

162. What is extranodal NK/T-cell lymphoma?

Back 162

This neoplasms is rare in the US and Europe but makes up 3% of NHLs in Asia. Most commonly presenting as a destructive midline mass involving the nasopharynx or, less commonly, the skin or other extranodal sites, such as the testis.

***The tumor cell infiltrate typically surrounds and invades small vessels, leading to extensive ischemic necrosis.*** The cytoplasm of the large tumor cells contains large azurophilic granules resembling those observed in normal NK cells.

Most are aggressive and poorly responsive to therapy.

Front 163

163. What is the main difference between NHL and HL?

Back 163

While NHLs freq occur at extranodal sites and spread in an unpredictable fashion, HL arises in a single node or chain of nodes and spreads first to the anatomically contiguous nodes.

Front 164

164. What is Hodgkin lymphoma?

Back 164

HL is one of the most common forms of malignancy in young adults, w/an average age at Dx of 32 years. HL is characterized morphologically by the presence of distinctive neoplastic giant cells called Reed-Sternberg cells that induce the accumulation of reactive lymphocytes, histiocytes (macrophages) and granulocytes).

Most HLs are unusual tumors of B-cell origin.

Front 165

165. What are the 5 subtypes of HL?

Back 165

1. Nodular sclerosis*
2. Mixed cellularity*
3. Lymphocyte rich*
4. Lymphocyte depletion*
5. Lymphocyte predominance

*Classical forms

Front 166

166. What are Reed-Sternberg cells?

Back 166

Diagnostic Reed-Sternberg cells are large (15-45um in diameter) and have either multiple nuclei or a single nucleus with multiple nuclear lobes, each w/a large inclusion like nucleolus about the size of a small lymphocyte (5-7 um in diameter).

Front 167

167. What is the difference btwn the classical forms and the lymphocyte predominance form of HLs?

Back 167

The first 4 subtypes have a similar immunophenotype.

In lymphocyte predominance HL, the Reed-Sternberg cells have a characteristic B-cell immunophenotype distinct from that of the classical HL subtypes.

Front 168

168. What are the 4 variants of Reed-sternberg cells?

Back 168

1. Mononuclear variants (oblong or round nucleus)
2. Lacunar cells (seen in the nodular sclerosis subtype)
3. Mummification (classical forms)
4. Lymphohistocytic cells (popcorn kernels; specific to lymphocyte predominance subtype)

Front 169

169. Is the finding of Reed-Sternberg cells sufficient for a HL Dx?

Back 169

Although Reed-Sternberg cells are requisite for the Dx, they must be present in an appropriate background of non-neoplastic inflammatory cells (lymphocytes, plasma cell, eosinophils).

Front 170

170. What is the predictable spread of HL?

Back 170

Nodal disease first, then splenic disease, hepatic disease, and finally marrow involvement and extranodal disease.

B/c of this uniform pattern of spread, pts with limited disease may be cured w/local radiotherapy.

Front 171

181. What is HL, nodular sclerosis type?

Back 171

This is the most common form of HL, constituting 65-70% of cases.

It is characterized morphologically by the presence of (1) a particular variant of the Reed-Sternberg cell, the lacunar cell, and (2) collagen bands that divide the lymphoid tissue into circumscribed nodules.

The tumor cells have a characteristic immunophenotype: CD15+, CD30+, and negative for CD45 and B-cell and T-cell markers.

Front 172

182. What are the clinical features of HL, nodular sclerosis?

Back 172

As in other forms of HL, involvement of the spleen, liver, bone marrow, and other organs and tissues can appear in due course and take the form of irregular tumor nodules resembling those present in the nodes.

The nodular sclerosis type occurs with equal freq in males and females. It has a propensity to involve the lower cervical, supraclavicular, and mediastinal lymph nodes of adolescents or young adults and is only rarely associated with EBV. The prognosis is excellent.

Front 173

183. What is HL, mixed cellularity type?

Back 173

This form of HL consitutes about 20-25% of cases.

Lymph nodes involvement by the mixed cellularity type takes the form of diffuse effacement by a heterogeneous cellular infiltrate, which includes small lymphocytes, eosinophils, plasma cells, and benign macrophages, admixed with the neoplastic cells.

***Diagnostic Reed-Sternberg cells and mononuclear variants are usually plentiful.

Front 174

184. What are the clinical features of mixed cellularity HL?

Back 174

Mixed cellularity HL is more common in males and strongly associated w/EBV, as the Reed-Sternberg cells contain EBV genomes in at least 70% of cases.

Compared to nodular sclerosis subtypes, it is more likely to be associated with older age, systemic symptoms such as night sweats and weight loss, and advanced tumor stage.

Nonetheless, the prognosis is very good.

Front 175

185. What is HL, lymphocyte-rich type?

Back 175

HL, lymphocyte-rich type is an uncommon form of classical HL in which reactive lymphocytes make up the vast majority of the cellular infiltrate.

In most cases, lymph nodes are diffusely effaced, but vague nodularity due to the presence of residual B-cell follicles can sometimes be seen.

It is associated with EBV in about 40% of cases an also has a very good to excellent prognosis.

Front 176

186. How is HL, lymphocyte rich distinguished from the lymphocyte predominant subtype?

Back 176

This entity is distinguished by the presence of frequent mononuclear and diagnostic Reed-Sternberg cells with the characteristic CD45-, CD20-, CD15+, CD30+ immunophenotype.

Front 177

187. What is HL, lymphocyte depletion type?

Back 177

This least common form of HL is characterized by a paucity of lymphocytes and a relative abundance of Reed-Sternberg cells or their pleomorphic variants.

The phenotype of the tumor cells is identical to that observed in the nodular sclerosis and mixed cellularity types.

Front 178

188. What are the clinical features of HL, lymphocyte depletion type?

Back 178

Lymphocyte depletion HL is observed predominantly in older pts, HIV-positive individuals, or pts in nonindustrialized countries and is often EBV-associated.

Advanced stage and systemic symptoms are freq, and the overall outcome is somewhat less favorable than with other subtypes.

Front 179

189. What is HL, lymphocyte predominance type?

Back 179

This uncommon variant is characterized by nodal effacement by a nodular infiltrate of small lymphocytes admixed with variable numbers of benign histiocytes.

Typical Reed-Sternberg cells are difficult to find. ***More common are so-called L&H variants that have a delicate, multilobed nucleus resembling a popcorn kernel ("popcorn cell").

Front 180

190. What is the immunophenotype of HL, lymphocyte predominance type?

Back 180

In contrast to other forms of HL, L&H variants express B-cell markers (e.g. CD20) and the germinal center-specific transcription factor BCL6.

Furthermore, L&H variants w/in individual tumors have identical IgH gene rearrangements and have Vh segments that show evidence of ongoing somatic hypermutation, something that only occurs in germinal center B cells.

Front 181

181. How does EBV DNA affect the Reed-Sternberg cells in HL?

Back 181

The configuration of EBV DNA is the same in all tumor cells w/in a given case, indicating that infection occurs before cellular transformation. EBV-positive tumor cells express latent membrane protein-1 (LMP-1), a protein encoded by the EBV genome that has transforming activity.

Front 182

182. What does LMP-1 do?

Back 182

LMP-1 transmits signals that upregulate NF-κB, a transcription factor of broad importance in lymphocyte activation.

Hence, inappropriate activation of NF-κB appears to be a common event in classical HL.

Front 183

183. A characteristic accumulation of reactive cells occurs in response to ___________ secreted by the Reed-Sternberg cells?

Back 183

IL-5, IL-6, IL13, TNF, and GM-CSF.

Once attracted by the cytokines, the reactive infiltrate in turn supports the growth and survival of tumor cells.

Front 184

184. What genetic alterations are present in Reed-Sternberg cells?

Back 184

Reed-Sternberg cells are aneuploid and often possess diverse clonal chromosomal aberrations. Gains of chromosome 2p, the site of the c-REL proto-oncogene, are particularly common and may also act to upregulate NF-κB activity.

Front 185

185. What are the clinical features of HL?

Back 185

HL, like NHL, usually presents with a painless enlargement of lymph nodes.

Younger pts with the more favorable histologic types tend to present with stage 1 or 2 disease and are usually free from systemic mainfestations.

Pts w/disseminated disease (stages 3 and 4) or the mixed cellularity or lymphocyte depletion subtype are more likely to have systemic symptoms such as night sweats and weight loss.

Front 186

186. What is an interesting feature of HL?

Back 186

One rare paraneoplastic symptom specific to HL is pain in involved lympho nodes on consumption of EtOH.

Front 187

186. What is the most important prognostic variable in HL?

Back 187

Tumor stage rather than type is the most important prognostic variable.

The cure rates of pts with stages 1 and 2A is close to 90%. Even with advanced disease, (stages 4A and 4B), 60-70% 5 year disease free survival is obtained.

Front 188

187. What is a potential long term problem of HL treatment?

Back 188

Long term survivors of chemo and radiation therapy have an increased risk of developing second CAs.

Myelodysplastic syndromes, AML, and lung CA lead the list of second malignancies, but also included are NHL, breast CA, gastric CA, sarcoma, and malignant melanoma.

Front 189

188. What is a common feature of myeloid neoplasms?

Back 189

The common feature that unites this group of neoplasms is an origin from hematopoietic progenitor cells capable of giving rise to terminally differentiated cells of the myeloid series (erythrocytes, granulocytes, monocytes, and platelets.

These disease primarily involve the bone marrow and to a lesser degree the secondary hematopoietic organs (the spleen, liver, and lymph nodes) and present with altered hematopoiesis.

Front 190

189. What are the 3 categories of myeloid neoplasia?

Back 190

1. Acute myelogenous leukemias, characterized by the accumulation of immature myeloid forms in the bone marrow and the suppression of normal hematopoiesis
2. Myelodysplastic syndromes, associated with ineffective hematopoiesis and associated cytopenias
3. Chronic myeloproliferative disorders, usually associated w/an increased production of terminally differentiated myeloid cells

Front 191

190. What is the hierarchy of hematopoietic progenitor cells?

Back 191

At the top sits the pluripotent stem cells, which give rise to multipotent progenitor cells committed to lymphoid or myeloid differentiation.

The latter in turn produce more committed progenitors, which eventually give rise to terminally differentiated cells of a single type (e.g., erythrocyte, monocyte).

In addition to giving rise to committed daughter cells, hematopoietic progenitor cells must also replicate themselves w/o differentiating (or else they would eventually disappear), a process known as self-renewal.

Front 192

191. How is hematopoiesis regulated in myeloid neoplasms?

Back 192

Nomral hematopoiesis is regulated by homeostatic feedback mechanisms involving cytokines and growth factors.

*These mechanisms are deranged in marrows involved by myeloid neoplasms, which escape from normal homeostatic controls on growth and survival, and suppress the function of residual normal stem cells.

Front 193

192. What are the 2 things that further influence the specific manifestations of myeloid neoplasms?

Back 193

1. The position of the transformed cell w/in the hierarchy of progenitors

2. The effect of the transforming events on differentiation programs, which may be blocked or preferentially shunted toward one lineage at the expense of others

Front 194

193. What ages does AML affect?

Back 194

Acute myelogenous leukemias affect primarily adults, peaking in incidence btwn the ages of 15-39, but are also observed in older adults and children.

Front 195

194. What is the pathogenesis of AML?

Back 195

Most AMLs are associated w/acquired genetic alterations that inhibit terminal myeloid differentiation.

As a result, normal marrow elements are replaced by relatively undifferentiated blasts exhibiting one or more types of early myeloid differentiation.

Front 196

195. What are the most common chromosomal abnormalities in AML?

Back 196

The most common chromosomal rearrangements, t(8;21), and inv(16), involve genes that encode two subunits, CBF1α and CBF1β.

Both the t(8;21) and the inv(16) result in the formation of chimeric genes encoding fusion proteins with so-called dominant negative activity, meaning they interfere w/the function of the normal CBF1α/CBF1β heterodimer.

Front 197

196. What is the problem with an interference on the CBF1α/CBF1β heterodimer?

Back 197

Myeloid progenitors harboring such alterations thus give rise to daughter cells exhibiting a partial or complete block in terminal differentiation.

**A deficit of CBF1α/CBF1β activity is not sufficient to cause leukemia, indicating that other aberrations must collaborate w/defects in critical transcription factors to produce AML.

Front 198

197. What is a one example of this pathogenic collaboration in AML?

Back 198

An example of this collaboration underlies a form of AML, acute promyelocytic leukemia, associated w/a t(15;17) translocation.

This translocation produces a fusion gene encoding a portion of a transcription factor, retinoic acid receptor-α (RARα), fused to a portion of another protein, PML.

Front 199

198. So what happens when a fused RARα-PML occurs?

Back 199

RARα normally activates transcription, but when fused to PML, it is converted to a repressor that turns off genes required for full and complete myeloid differentiation.

Front 200

199. What is another example of a pathogenic collaboration in acute promyelocytic leukemia?

Back 200

In addition to the t(15;17), acute promyelocytic leukemia cells also freq acquire point mutations in FLT3, that result in its constitutive activation.

Tyrosine kinases produce signals that promote cellular proliferation and survival, activities that synergize w/the block in differentiation produced by the RARα-PML fusion protein.

Front 201

200. What are the main features of AMLs?

Back 201

In all AMLs, the accumulation of proliferating neoplastic myeloid precursor cells in the marrow suppresses remaining normal hematopoietic progenitor cells by physical replacement as well as by other unknown mechanisms. The failure of normal hematopoiesis results in anemia, neutropenia, and thrombocytopenia, which cause most of the major clinical complications of AML.

Therapeutically, the aim is to clear the bone marrow of the leukemic clone, thus permitting resumption of normal hematopoiesis.

Front 202

201. The Dx of AML is based on....?

Back 202

Based on the finding that myeloid blasts make up more than 20% of the cells in the marrow.

Several types of myeloid blasts are recognized, but more than one type of blast can be seen.

Front 203

202. What are myeloblasts? What are Auer rods?

Back 203

Myeloblasts have delicate nuclear chromatin, 2-4 nucleoli, and more voluminous cytoplasm than lymphoblasts. The cytoplasm often contains fine, azurophilic, peroxidase positive granules.

Distinctive red-staining peroxidase-positive structures called Auer rods, which represent abnormal azurophilic granules, are present in many cases are are particularly numerous in AML associated with the t(15;17) (acute promyelocytic leukemia).

Front 204

203. What are monoblasts?

Back 204

Monoblasts often have folded or lobulated nuclei, lack Auer rods, and are preoxidase negative and nonspecific esterase positive.

In some AMLs, blasts exhibit megakaryocytic differentiation, which is often accompanied by marrow fibrosis caused by the release of fibrogenic cytokines.

Front 205

205. What is the peripheral blood like in AML?

Back 205

The number of leukemic cells in the peripheral blood is highly variable. Blast counts can be more than 100,000 cells per microliter, but are under 10,000 in about 50% of pts.

*Occasionally, the peripheral smear might not contain any blasts (aleukemic leukemia). For this reason, bone marrow examination is essential to exclude acute leukemia in pancytopenic pts.

Front 206

206. AML arising de novo in pts w/no risk factors are often associated with what genetic abnormalities?

Back 206

AML arising de novo in pts w/no risk factors are often associated with balanced translocations, particularly t(8;21), inv(16), and t(15;17).

Front 207

207. AML following myelodysplastic syndromes or exposure to DNA damaging agents are often associated with...?

Back 207

AML following myelodysplastic syndromes or exposure to DNA damaging agents are often associated with deletions or monosomies involving chromosomes 5 and 7 and usually lack chromosomal translocations.

***The exception to this rule is AML occurring after treatment with topoisomerase II inhibitors, which is often associated w/translocations involving the MLL gene on chromosome 11 at band q23.

Front 208

208. What are the clinical features of AML?

1/3

Back 208

Similar to ALL. Most pts present w/in weeks or a few months of the onset of symptoms related to anemia, neutropenia, and thrombocytopenia, most notably fatigue, fever, and spontaneous mucosal and cutaneous bleeding. Often, the bleeding diathesis caused by thrombocytopenia is the most striking clinical feature.

Front 209

209. What are the clinical features of AML?

2/3

Back 209

Cutaneous petchiae and ecchymoses, serosal hemorrhages into the linings of the body cavities and viscera, and mucosal hemorrhages into the gingivae and urinary tract are common.

Procoagulants and fibrinolytic factors released by leukemic cells, especially in acute promyelocytic leukemia (M3), exacerbate the bleeding diathesis.

Infections are frequent, particularly in the oral cavity, skin, lungs, kidneys, urinary bladder, and colon, and are often caused by opportunists such as fungi, Pseudomonas, and commensals.

Front 210

210. What are the clinical features of AML?

3/3

Back 210

Mild lymphadenopathy and organomegaly can occur. In tumors w/monocytic differentiation (M4 and M5), infiltration of the skin (leukemia cutis) and the gingiva can be observed.

CNS spread is less common than in ALL but still seen.

Front 211

211. What are myeloblastomas, granulocytic sarcomas, or chloromas?

Back 211

Quite uncommonly, pts present with localized masses composed of myeloblasts in the absence of marrow or peripheral blood involvement.

These tumors, known as myeloblastomas, granulocytic sarcomas, or chloromas, inevitably progress to systemic AML over a period of up to several years.

Front 212

212. What are the FAB classifications of AMLs?

Back 212

MO: Minimally differentiated AML
M1: AML w/o differentiation
M2: *AML w/maturation
M3: Acute promyelocytic leukemia
M4: Acute myelomonocytic leukemia
M5: Acute monocytic leukemia
M6: Acute erythroleukemia
M7: Acute megakaryocytic leukemia

*Most common (30-40%)

Front 213

213. What is the prognosis for AML?

Back 213

AML is a difficult disease to treat. Approx 60% of the pts achieve complete remission w/chemo, but only 15-30% remain free from disease for 5 years.

*AMLs associated w/t(8;21) or inv(16) have a relatively good prognosis w/conventional chemo.

*In contrast, the prognosis is dismal for pts w/AML w/prior myelodysplastic syndrome or following genotoxic therapy.

Front 214

214. What can overcome the block in differentiation induced by the RARα-PML fusion protein?

Back 214

It can be overcome by pharmacologic doses of the vitamin A derivative all-trans-retinoic acid, causing neoplastic promyelocytes to differentiate into neutrophils.

Like their normal counterparts, neutrophils derived from the neoplastic clones are short lived and rapidly die, thus clearing the marrow and allowing resumption of normal hematopoiesis.

Front 215

215. Can pts with AML be treated with retinoic acid alone?

Back 215

Unfortunately, all pts ultimately relapse if treated w/retinoic acid alone, probably b/c retinoic acid fails to prevent continued self renewal of the neoplastic progenitor cell.

Front 216

216. What does myelodysplastic syndrome mean?

Back 216

The term myelodysplastic syndrome (MDS) refers to a group of clonal stem cell disorders characterized by maturation defects associated w/ineffective hematopoiesis and an increased risk of transformation to AML.

Front 217

217. Summarize the main problem in MDS for me. Please.

Back 217

In pts w/MDS, the bone marrow is partly or wholly replaced by the clonal progeny of a mutant multipotent stem cell that retains the capacity to differentiated into red cells, granulocytes, and platelets but in an ineffective and disordered fashion. These disturbances usually manifest as peripheral blood cytopenias.

Front 218

218. MDS arises in what 2 distinct settings?

Back 218

1. Idiopathic or primary MDS occurs mainly at ages over 50 and often develops insidiously.

2. Therapy-related MDS (t-MDS) is a complication of previous genotoxic drug or radiation therapy that appears 2-8 years after treatment.

*All forms of MDS can transform to AML, but this occurs most rapidly and w/highest freq in t-MDS.

Front 219

219. What is the pathogenesis of MDS?

Back 219

Unknown. Myelodysplastic bone marrow progenitors undergo apoptotic cell death at an increased rare, the hallmark of ineffective hematopoiesis.

Both primary MDS and t-MDS occurring after exposure to genotoxic therapy are associated with similar clonal chromosomal abnormalities, including monosomy 5 and monosomy 7, deletions of 5q and 7q, trisomy 8, and deletions of 20q.

Front 220

220. What is the most characteristic finding in the morphology of MDS?

Back 220

The most characteristic finding is disordered (dysplastic) differentiation affecting all non-lymphoid lineages (erythroid, granulocytic, monocytic, and megakaryocytic).

Front 221

221. What is the morphology of the erythroid series in MDS?

3 specific features...

Back 221

W/in the erythroid series, common abnormalities include:

1. *Ringed sideroblasts*, erythroblasts with iron laden mitochondria visible as perinuclear granules in Prussian blue-stained aspirates or biopsies
2. *Megaloblastoid maturation*
3. *Nuclear budding abnormalities*, recognized as nuclei w/misshapen, often polypoid outlines

Front 222

222. What about the morphology of neutrophils in MDS?

Back 222

Neutrophils often contain decreased numbers of secondary granules, toxic granulations, and/or Dohle bodies.

***Pseudo-Pelger-Huet cells, neutrophils w/only 2 nuclear lobes, are freq observed, and neutrophils may even be seen tat completely lack nuclear segmentation.

Front 223

223. What about megakaryocytes in MDS?

Back 223

Megakaryocytes w/single nuclear lobes or multiple separate nuclei ("pawn ball megakaryocytes") are also characteristic.

Front 224

224. What does the peripheral blood contain in MDS?

Back 224

The peripheral blood often contains pseudo-Pelger-Huet cells, giant platelets, macrocytes, poikilocytes, and a relative or absolute monocytosis.

Myeloblasts may be increased and usually make up less than 10% of the peripheral leukocytes.

Front 225

225. What are the clinical features of MDS?

Back 225

Primary MDS affects mainly individuals older than 60. When symptomatic, it presents w/weakness, infections, and hemorrhages, all due to pancytopenia. In up to half of the cases, MDS is discovered incidentally on routine blood testing.

The median survival in primary MDS varies from 9-29 months, but some can live for 5 years or more.

Overall, progression to AML occurs in 10-40% of individuals and is often accompanied by thrombocytopenia and neutropenia.

The outlook is worse in t-MDS, which has a median survival of only 4-8 months.

Front 226

226. What are chronic myeloproliferative disorders?

Back 226

The neoplastic cell is a multipotnent progenitor cell that is capable of giving rise to mature erythrocytes, platelets, granulocytes, monocytes, and lymphocytes.

The singular exception is chronic myelogenous leukemia, in which the pluripotent stem cell that gives rise to lymphoid and myeloid cells is affected.

As in AML, the neoplastic cells and their offspring flood the bone marrow and suppress residual normal progenitor cells; however, in the chronic myeloproliferaive disorders, terminal differentiation is relatively unaffected. This combo leads to marrow hypercellularity and increased hematopoiesis, often accompanied by elevated peripheral blood counts.

Front 227

227. What are the 4 most common chronic myeloproliferative disorders?

Back 227

1. CML
2. Polycythemia vera
3. Essential thrombytosis
4. Primary myelofibrosis

Front 228

228. What are the similar features in these 4 chronic myeloproliferative disorders?

Back 228

The neoplastic stem cells have the capacity to circulate and home to secondary hematopoietic organs, particularly the spleen, where they give rise to extramedullarly hematopoiesis.

As a result, all chronic myeloproliferative disorders cause varying degrees of splenomegaly. They also share the propensity to terminate in a spent phase characterized by marrow fibrosis and peripheral blood cytopenias. Further, all can progress over time to acute leukemia, but only CML does so invariably.

Front 229

229. What is CML?

Back 229

CML is a disease primarily of adults btwn the ages of 25-60 years, with the peak incidence in the 4th and 5th decades of life.

**CML is distinguished from other chronic myeloproliferative disorders by the presence of a distinctive molecular abnormality, namely, a translocation involving the BCR gene or chromosome 22 and the ABL gene on chromosome 9.**

In more than 90% of CML cases, there is the Philadelphia chromosome (Ph), which is created by a reciprocal (9;22)(q34;q11) translocation.

Front 230

230. What is the importance of the BCR-ABL fusion gene?

Back 230

The resultant BCR-ABL fusion gene directs the synthesis of a fusion protein with tyrosine kinase activity, resulting in autophosphorylation and activation of downstream pathways.

The net effect of these events is cell division and inhibition of apoptosis, independent to ligand binding. This contributes to unregulated myeloproliferation.

*The target of transformation is a pluripotent stem cell.*

Front 231

231. What is the morphology of CML?

Back 231

In contrast to normal bone marrow, CML marrows are usually 100% cellular, w/maturing granulocytic precursors comprising most of the increased cellularity.

*A characteristic finding is the presence of scattered storage histiocytes w/wrinkled, green blue cytoplasm (sea-blue histiocytes). Increased deposition of reticular fibers is typical, but overt marrow fibrosis is rare.

Neoplastic extramedullary hematopeoiesis w/in the splenic red pulp produces marked splenomegaly w/possible infarction.

Front 232

232. What is the morphology of the peripheral blood in CML?

Back 232

Peripheral blood exam reveals a marked leukocytosis, often exceeding 100,000 cells per mm^3. The circulating cells are predominantly neutrophils, metamyelocytes, and myelocytes, with less than 10% myeloblasts.

Peripheral blood eosinophilia and basophilia are also common, and up to 50% of pts have thrombocytosis early in the course of the disease.

Front 233

233. What are the clinical features of CML?

Back 233

The onset of CML is insidious. Mild-to-moderate anemia and hypermetabolism due to increased cell turnover lead to easy fatigability, weakness, weight loss, and anorexia.

Sometimes the first symptom is a dragging sensation in the abdomen caused by the extreme splenomegaly or acute onset of left upper quadrant pain due to splenic infarction.

Front 234

234. What is the prognosis of CML?

Back 234

CML has a slow progression, and even w/o treatment, a median survival of 3 years can be expected. After a variable period averaging 3 years, approx 50% of pts enter an accelerated phase. W/in 6-12 months after, the accelerated phase terminates into a blast crisis.

In the remaining 50% of pts, blast crises occur abruptly w/o an intermediate accelerated phase.

Front 235

235. What occurs in the accelerated phase and blast crisis?

Back 235

The accelerated phase is marked by increasing anemia and thrombocytopenia and sometimes striking peripheral blood basophilia. Additional clonal cytogenetic abnormalities can also appear.

The blast crisis resembles acute leukemia. In 70% of bast crises, the blasts have the morphologic and cytochemical features of myeloblasts, whereas in most of the remainder, the blasts contain the enzyme TdT and express early B-lineage markers such as CD10 and CD19.

Front 236

236. Can CML be treated?

Back 236

Drugs that inhibit the BCR-ABL kinase induce complete hematologic remissions in more than 90% of pts.

However, BCR-ABL inhibitors suppress but do not extinguish the CML clone and, as a result, may not prevent progression to blast crises.

Moreover, while pts in blast crisis initially respond to BCR-ABL kinase inhibitors, they recur rapidly with refractory disease.

Front 237

237. What is polycythemia vera?

Back 237

Polycythemia vera is a neoplasms arising in a multipotent myeloid stem cell that is characterized by increased marrow production of erythroid, granulocytic, and megakaryocytic elements.

This leads to erythrocytosis (polycythemia), granulocytosis, and thrombocytosis in the peripheral, the polycythemia being responsible for most of the clinical symptoms.

Front 238

238. What is the pathogenesis of polycythemia vera?

Back 238

Polycythemia vera progenitor cells have markedly decreased requirements for erythropoietin and other hematopoietic growth factors. Accordingly, serum erythropoietin levels in polycythemia vera are very low, weheras almost all other forms of absolute polycythemia are caused by elevated erythropoietin levels.

B/c it is characterized by panmyelosis (an increase in all 3 lineages), it seems likely that mutations in a factor or factors common to multiple hematopoietic growth factor signaling pathways are involved.

Front 239

239. What is the morphology of polycythemia vera?

Back 239

The bone marrow is hypercellular, but some residual fat is often observed. The increase in erythroid progenitors can be subtle and is usually accompanied by increased numbers of maturing granulocytic precursors and megakaryocytes. At the time of Dx, a moderate to marked increase in marrow reticular fibers is seen in approx 10% of pts. Mild organomegaly is common in the early stages.

***The peripheral blood smear often shows increased basophils and abnormally large platelets***

Front 240

240. What happens in the later stages of polycythemia vera?

Back 240

Late in the course, polycythemia vera can progress to a spent phase characterized by extensive marrow fibrosis that displaces hematopoietic cells.

This is accompanied by increased extramedullarly hematopoiesis in the spleen and liver, which often leads to prominent organomegaly.

Front 241

241. What is the clinical course of polycythemia vera?

Back 241

Appears insidiously, usually in late middle age (median: 60). Most symptoms are related to the increased red cell mass and HCT. The elevation of HCT is usually accompanied by increased total blood volumes.

Pts are plethoric and somewhat cyanotic owing to stagnation and deoxygenation of blood in peripheral vessels. Headache, dizziness, hypertension, and GI symptoms are common. There is often intense pruritus and an increased likelihood of peptic ulcers, both possibly resulting from release of histamine from basophils.

High cell turnover gives rise to hyperuricemia and symptomatic gout is seen in 5-10% of cases.

Front 242

242. The abnormal blood flow and abnormal platelet function in polycythemia vera leads to...?

Back 242

Increased risk of both major bleeding and thrombotic episodes.

About 25% of pts first come to clinical attention w/thrombotic episodes, often manifesting as DVT, MI, and stroke.

Other common sites for thromboses include hepatic veins, portal and mesenteric veins, and the venous sinuses of the brain.

Front 243

243. What are the CBC ranges in polycythemia vera?

Back 243

The Hb concentration ranges from 14-28 gm/dL w/HCT levels of 60% or more. Sometimes, chronci beleding leads to iron deficiency, which can suppress erythropoiesis sufficienctly to lower the HCT into the normal range.

The WBC is elevated, ranging btwn 12,000-50,000 cells per mm^3, and the platelets are greater than 500,000 cells per mm^3.

Front 244

244. What is the prognosis of pts with polycythemia vera?

Back 244

Without treatment, death from bleeding or thrombosis occurs w/in months of Dx. However, simply maintaining the red cell mass nearly normal levels by phlebotomies extends the survival to about 10 years.

In the later stages, the spent phase is marked by features of primary myelofibrosis.***

Front 245

245. What is essential thrombocytosis?

Back 245

In this hematopoietic stem cell disorder, increased proliferation and production are largely confined to the megakaryocytic elements, most pts having platelet counts exceeding 600,000 per mm^3.

*Since all chronic myeloproliferative disorders can be associated w/thrombocytosis, essential thrombocytosis is a Dx of exclusion.

Front 246

246. What is the pathogenesis of essential thrombocytosis?

Back 246

Unknown. Dysfunctions of platelets derived from the neoplastic clone contribute to the major clinical features of bleeding and thrombosis.

Front 247

247. What are the features of the bone marrow and peripheral blood in essential thrombocytosis?

Back 247

Cellularity is usually increased mildly to moderately.

Megakaryocytes are often markedly increased in number and include abnormally large forms.

***Peripheral smears usually reveal abnormally large platelets,*** often accompanied by mild leukocytosis. Neoplastic extramedullary hematopoiesis can occur w/in the spleen and liver, producting mild organomegaly in about 50% of pts.

Front 248

248. What are the clinical features of essential thrombocytosis?

Back 248

Essential thrombocytosis usually occurs past the age of 60, but it may also be seen in young adults. The major clinical manifestations are thrombosis and hemorrhage, rpobably reflecting both qualitative and quantitative abnormalities in platelets.

The types of thrombotic events resemble those of polycythemia vera; they include DVT, portal and hepatic vein thrombosis, and MI.

Front 249

249. What is a characteristic symptom of essential thrombocytosis?

Back 249

Erythromelalgia, the throbbing and burning of hands and feet caused by occlusion of small arterioles by platelet aggregates.

Erythromelalgia can also be seen in polycythemia vera pts w/high platelet counts.

Front 250

250. What is the prognosis like in essential thrombocytosis?

Back 250

Essential thrombocytosis is an indolent disorder w/long asymptomatic periods punctuated by occasional thrombotic or hemorrhagic crises. Median survival times are 12-15 years.

For unclear reasons, both thrombosis and bleeding occur in those pts with very high platelet counts. Myelosuppressive alkylating drugs or other agents are used to lower platelet counts.

Front 251

251. What is primary myelofibrosis?

Back 251

The hallmark of primary myelofibrosis is rapid development of obliterative marrow fibrosis. histologically, the appearance is identical to the spent phase that occurs occasionally late in the course of other chronic myeloproliferative disorders.

Myelofibrosis suppresses bone marrow hematopoiesis, leading to peripheral blood cytopenias and extensive neoplastic extramedullarly hematopoiesis in the spleen, liver, and lymph nodes.

Front 252

252. What is the pathogenesis of primary myelofibrosis?

Back 252

The pathologic features of primary myelofibrosis stem from extensive collagen deposition by non-neoplastic fibroblasts in the marrow. Fibrosis inexorably displaces hematopoietic elements, including stem cells , from the marrow, leading to extensive extramedullary hematopoiesis in the spleen, the liver, and sometimes the lymph nodes.

The marrow fibrosis is likely caused by the inappropriate release of fibrogenic factors from neoplastic megakaryocytes.

Front 253

253. What 2 fibrogenic factors are implicated in primary myelofibrosis?

Back 253

PDGF and TGF-β

Front 254

254. What happens as marrow fibrosis progresses?

Back 254

Circulating hematopoietic stem cells take up residence in secondary hematopoietic organs, such as the spleen, the liver, and the lymph nodes, which become the main sites of hematopoiesis.

Front 255

255. What is the morphology of primary myelofibrosis?

Back 255

Early in the course, the marrow if often hypercellular owing to increases in maturing cells of all lineages. Morphologically, the erythroid and granulocytic precursors appear normal, but megakaryocytes are large, dysplastic, and abnormally clustered. During this cellular phase, fibrosis is minimal.

W/progression, the marrow becomes hypocellular and diffusely fibrotic.

Very late in the disease course, the fibrotic marrow space can be largely converted to bone, a development that is termed "osteosclerosis".

Front 256

256. Myelofibrotic obstruction of the marrow space leads to...?

Back 256

Leads to extensive extramedullary hematopoiesis, principally the spleen, which is usually marked enlarged.

histologically, there is trilineage hematopoiesis, usually associated w/a predominance of large, clustered megakaryocytes.

Front 257

257. What are the characteristics of the peripheral blood in primary myelofibrosis?

Back 257

The peripheral blood reveals a number of characteristic findings in full-blown myelofibrosis. Fibrotic distortion of the marrow microenvironment leads to inappropriate release of nucleated erythroid progenitors and early granulocytes, and immature cells also enter the circulation from sites of extramedullary hematopoiesis.

**The presence of erythroid and granulocytic precursors in the peripheral blood is termed leukoerythroblastosis*.

Front 258

258. What are dacrocytes?

Back 258

The fibrotic marrow distorts and damages the membranes of erythroid progenitors in the marrow, leading to the appearance of teardrop-shaped erythrocytes (dacrocytes).

Although characteristic of primary myelofibrosis, dacrocytes can be observed in many infiltrative disorders of the bone marrow.

Front 259

259. What is the clinical course of primary myelofibrosis?

Back 259

Primary myelofibrosis is uncommon in individuals younger than 60. Except when preceded by polycythemia vera or CML, it usually comes to clinical attention b/c of either progressive anemia or marked splenic enlargement, producing a sensation of fullness in the left upper quadrant.

Nonspecific symptoms such as fatigue, weight loss, and night sweats result form increased metabolism associated w/the expanded mass of hematopoietic cells. Owing to a high rate of cell turnover, hyperuricemia and secondary gout can complicate the picture.

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260. What are the laboratory findings in primary myelofibrosis?

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The laboratory findings include a moderate-to-severe normochromic normocytic anemia accompanied by leukoerythroblastosis. The WBC is usually normal or reduced but can be markedly elevated during the early cellular phase.

The platelet count is usually normal or elevated at the time of Dx, but thrombocytopenia supervenes as the disease progresses.

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261. What is Langerhans cell histiocytosis?

Back 261

These disorders are referred to as Letterer-Siwe syndrome, Hand-Schuller-Christian disease, and eosinophilic granuloma. These 3 conditions are now considered different expressions of the same basic disorder.

The tumor cells in each are derived from dendritic cells and express HLA-DR, S-100, and CD1a. They have abundant, often vacuolated cytoplasm and vesicular nuclei containing linear grooves or folds.

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262. What is a characteristic feature of Langerhans cell histiocytosis?

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*The presence of Birbeck granules in the cytoplasm is characteristic*. Birbeck granules have a pentalaminar, rodlike, tubular appearance and sometimes a dilated terminal end (tennis-racket appearance).

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263. What is the pathogenesis of Langerhans cell histiocytosis?

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The distribution of neoplastic dendritic cells in lymphoid tissues and viscera, characteristic of these disorders, is likely attributable to aberrant expression of chemokine receptors.

Whereas normal, skin resident dendritic cells express CCR5, their neoplastic counterparts co-express CCR6 and CCR7, and this allows the abnormal dendritic cells to migrate into tissues that express the relevant chemokines - CCL20 in skin and bone (ligand for CCR6), and CCL19 and 21 in lymphoid organs (ligands for CCR7).

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264. What is multifocal multisystem Langerhans cell histiocytosis (Letterer-Siwe disease)?

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Letterer-Siwe disease occurs most freq before 2 years of age but occasionally affects adults. ***A dominant clinical feature is the development of cutaneous lesions resembling a seborrheic eruption, which is caused by infiltrates of Langerhans cells over the front and back of the trunk and on the scalp.*** Most of those affected have concurrent hepatoslenomegaly, lymphadenopathy, pulmonary lesions, and eventually, destructive osteolytic bone lesions.

Extensive infiltration of the marrow often leads to anemia, thrombocytopenia, and predisposition to recurrent infections such as otitis media and mastoiditis. The course of untreated disease is rapidly fatal.

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265. What are unifocal and multifocal unisystemic Langerhans cell histiocytoses (eosinophilic granuloma)?

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Eosinophilic granulomas are characterized by ***expanding, erosive accumulations of Langerhans cells, usually w/in the medullary cavities of bones.*** Histiocytes are variably admixed w/eosinophils, lymphocytes, plasma cells, and neutrophils.

The eosinophilic infiltrate is usually prominent but is sparse in a subset of cases. Virtually any bone in the skeletal system can be involved, most commonly the calvarium, ribs, and femur.

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266. What are unifocal lesions?

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Unifocal lesions usually affect the skeletal system in older children or adults. They can be asymptomatic, or they can cause pain, tenderness, and in some instances, pathologic fractures.

This is an indolent disorder that can heal spontaneously or be cured by local excision or irradiation.

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267. What is multifocal *unisystem Langerhans cell histiocytosis?

Back 267

Multifocal unisystem Langerhans cell histiocytosis usually affects young children, who present w/multiple erosive bony masses that sometimes expand into adjacent soft tissue.

In about 50% of pts, involvement of the posterior pituitary stalk of the hypothalamus leads to diabetes insipidus.

Many pts experience spontaneous regression; other can be treated successfully w/chemo.

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268. What is the Hand-Schuller-Christian triad?

Back 268

The combo of calvarial bone defects, diabetes insipidus, and exophthalmos is referred to as the Hand-Schuller-Christian triad

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269. What about pulmonary Langerhans cell histiocytosis?

Back 269

Pulmonary Langerhans cell histiocytosis represents a special category of disease most often seen in adult smokers. It can regress spontaneously on cessation of smoking and usually comprises a polyclonal population of Langerhans cells, suggesting it is a reactive hyperplasia rather than a true neoplasm.