Lymphoproliferative disorder Flashcards
1
Q
What is a lymphoproliferative disorder?
A
A clonal neoplastic proliferation of lymphocytes
2
Q
What are the lymphoprolif- erative disorders?
A
- CLL
- hairy cell leukemia
- LGL leukemia
- lymphoma (e.g., Hodgkin disease and NHL)
- plasma cell dyscrasias (e.g., MM and WM)
3
Q
What is the most common form of leukemia in Western countries?
A
CLL comprises 30% of all cases of adult leukemia, with an annual incidence of 4 in 100,000 persons.
4
Q
What is CLL?
A
- CLL = Chronic lymphocytic leukemia
- A neoplastic proliferation with accumulation of immune-incompetent lymphocytes within the bone marrow, peripheral blood, and lymphoid organs
5
Q
What are the morphologic characteristics of CLL?
A
Small, mature lymphocytes with clumped chromatin and scant cytoplasm
6
Q
What is the median age of onset of CLL?
A
65 years
7
Q
What are the symptoms of CLL?
A
Up to 70% of persons with CLL are asymptomatic at diagnosis.
- Generalized lymphadenopathy, fever, night sweats, weight loss, easy fatigability, weakness, and increased bleeding are common complaints.
- Frequent infections and exaggerated responses to insect bites are occasionally noted.
8
Q
How is the diagnosis of CLL made?
A
An increase in the absolute number (>5,000) of lymphocytes in the peripheral blood, which, on the peripheral smear, appear as small, mature lymphocytes.
Flow cytometry shows a monoclonal population that coexpresses CD19 and CD5.
Frequently, there is lymphadenopathy, splenomegaly, and bone marrow infiltration, making it difficult to distinguish CLL from its lymphomatous counterpart, SLL.
9
Q
What is the staging system for CLL?
A
The Rai system is the one most commonly used:
- Stage 0—lymphocytosis alone
- Stage I—lymphocytosis with lymphadenopathy
- Stage II—lymphocytosis with splenomegaly or hepatomegaly
- Stage III—lymphocytosis with anemia
- Stage IV—lymphocytosis with anemia and thrombocytopenia
10
Q
What are the median survival times for Stage 0?
A
15 years
11
Q
What are the median survival times for Stage I?
A
9 years
12
Q
What are the median survival times for Stage II?
A
5 years
13
Q
What are the median survival times for Stage III?
A
2 years
14
Q
What are the median survival times for Stage IV?
A
2 years
15
Q
What specific hematologic complication can be associated with CLL?
A
AIHA (autoimmune hemolytic anemia)
16
Q
What is the treatment for CLL?
A
- Observation if the patient is asymptomatic.
- Oral alkylating agents or fludarabine are commonly used in symptomatic patients.
17
Q
What are the indications for the treatment for CLL?
A
Some indications include the presence of autoimmune hemolytic anemia, autoimmune thrombocytopenia, bulky lymphadenopathy, progressive hyperlym- phocytosis, and frequent bacterial infec- tions, but the exact time to initiate treatment is an area of much debate.
18
Q
Chronic myleogenous leukemia
A
(Please see Chapter 6, “Myeloproliferative Diseases” section.)
19
Q
What is hairy cell leukemia?
A
A fairly uncommon chronic lymphoprolif- erative disorder with a clonal neoplastic proliferation of a lymphocyte that is related to memory B cells, activated B cells, and preplasma cells
20
Q
What is the morphologic appearance of hairy cell leukemia?
A
- A large lymphocyte with an eccentric nucleus (looks like a fried egg), with delicate, lacy chromatin and small nucleoli as well as abundant grayish-blue cytoplasm with fine irregular filamentous projections.
- These projections can be very hard to see on a peripheral smear.
21
Q
What is the median age of onset of hairy cell leukemia?
A
50–55 years of age.
Not reported in children or teens
22
Q
For hairy cell, what is the male to female ratio?
A
There is a male to female ratio of 4:1.
23
Q
What ethnic group has a higher preponderance of hairy cell?
A
More common in Ashkenazi Jewish males
24
Q
What are the presenting symptoms of hairy cell leukemia?
A
Weakness, weight loss, recent pyogenic infection, or symptoms attributable to splenomegaly
25
What are the physical findings of hairy cell leukemia?
Splenomegaly occurs in 80% of cases.
| Rarely, patients have lymphadenopathy or hepatomegaly.
26
Do patients with hairy cell leukemia have an elevated WBC count?
Not usually; 80% of patients have leukopenia.
| Pancytopenia is a common presentation.
27
What is unusual about the bone marrow aspirate?
Hairy cell leukemia
The bone marrow is often difficult to aspirate, resulting in a “dry tap.”
28
How is the diagnosis of hairy cell leukemia made?
- By the appropriate clinical scenario and by “hairy cells” seen on peripheral smear or bone marrow examination.
- A special stain called “TRAP” (tartrate-resistant acid phosphatase) is confirmatory, as is flow cytometric data.
29
What is the treatment for hairy cell leukemia?
- The nucleoside analogs cladribine and pentostatin are used with good response rates, which are durable for most patients.
- Because the hairy cells express CD20, the anti-CD20 antibody, rituximab, is also gaining some popularity.
30
What is an LGL?
On peripheral smear, an LGL appears as a large lymphocyte with abundant pale cytoplasm with prominent azurophilic granules.
31
What are the 2 types of LGL syndromes?
T cell and NK cell
32
How is the diagnosis of LGL syndrome made?
Increase in LGLs on peripheral smear, which, by flow cytometry, shows clonality with the appropriate phenotype (CD3, CD56)
33
What is the presentation of T-cell LGL?
Chronic, sometimes severe, neutropenia with frequent bacterial infections. Infil- tration of the spleen, bone marrow, and liver is not uncommon. Interestingly, 25% of cases are associated with rheumatoid arthritis, making it difficult to distinguish from Felty syndrome.
34
What is the presentation of NK-cell LGL?
- Usually, an acute clinical course involving fever and B symptoms (see the following text).
- Anemia and thrombocytopenia are more common than with T-cell LGL.
- Massive hepatosplenomegaly, lymph node involvement, and GI symptoms are common.
35
What is lymphoma?
A heterogeneous group of malignancies of lymphocytes that usually arise in lymph nodes but may originate in any organ
36
What are the 2 broad categories of lymphomas?
- Hodgkin disease
| - NHL
37
How do NHL and Hodgkin disease differ in their natural history?
lymphoma
- NHL commonly presents with diffuse disease.
| - Hodgkin disease presents more commonly with localized disease.
38
What are the typical presenting symptoms of lymphoma?
- Persistent painless adenopathy and B symptoms.
- Generalized pruritus with unexplained lymphadenopathy and pain in lymph nodes after alcohol ingestion are highly suggestive of Hodgkin disease.
- Lymphomas can present with symptoms attributable to enlarged lymph nodes anywhere in the body.
39
What are B symptoms?
lymphoma
Fever (>38°C x 3 consecutive days), drenching night sweats, and weight loss (>10% of body weight over 6 months)
40
What are the typical physical findings in lymphoma?
Lymphadenopathy and hepatosplenomegaly are the most predominant findings.
41
What are the typical presenting symptoms for CNS lymphoma?
- Headache
- altered mental status
- focal neurologic findings
42
What is Waldeyer’s ring?
lymphoma
The ring of lymphoid tonsillar tissue in the oropharynx.
43
What are the typical presenting symptoms for lymphoma involving Waldeyer’s ring?
- Sinusitis
| - earaches
44
What are the typical presenting symptoms of mediastinal lymphomas?
- Cough
- shortness of breath
- chest pain
- hemoptysis
45
What are the typical presenting symptoms of abdominal lymphomas?
- Abdominal pain
- nausea
- vomiting
- back pain
46
What are the WHO histologic subtypes of Hodgkin disease?
- Nodular lymphocyte predominant
| - Classic Hodgkin lymphoma
47
What is classic Hodgkin lymphoma divided into?
- nodular sclerosing
- mixed cellularity
- lymphocyte rich
- lymphocyte depleted
48
What is the name of the pathologic cell in Hodgkin disease?
Reed-Sternberg cell
49
What is the age distribution of Hodgkin disease?
There is a bimodal age distribution:
- with a young adult form peaking from age 16 to 34 years
- and an older adult form peaking from age 55 to 74 years.
50
What is the staging system for Hodgkin disease?
The Modified Ann Arbor staging system is used.
51
For Hodgkin disease, describe the criteria for Stage I?
Involvement of a single lymph node region or single extralymphatic site (IE)
52
For Hodgkin disease, describe the criteria for Stage II?
Involvement of 2 or more lymph node regions on the same side of the diaphragm, or localized extranodal extension plus 1 or more nodal regions (IIE)
53
For Hodgkin disease, describe the criteria for Stage III?
Involvement of lymph node regions on both sides of the diaphragm, may be accompanied by localized extralymphatic extension (IIIE) or splenic involvement (IIIS)
54
For Hodgkin disease, describe the criteria for Stage IV?
Diffuse or disseminated involvement of 1 or more extralymphatic organs or tissues with or without associated lymph node involvement
55
What are the common sites of extranodal Hodgkin disease?
Liver, lung, bone marrow, bone, and skin
56
What are the standard tests used to work up Hodgkin disease?
- H&P
- CBC
- chemistry panel; liver function tests
- ESR
- CT scan of the chest, abdomen, and pelvis and sometimes neck
- and bilateral bone marrow biopsies (only for advanced disease, cytopenias or B symptoms).
- PET scans are gaining wider use.
57
What is the treatment for Hodgkin disease?
Combination chemotherapy with or without radiation therapy
58
What are some of the long- term complications of Hodgkin disease?
See the following text.
59
What risk factors are associated with the development of NHL?
- Exposure to herbicides/pesticides by agricultural workers
- autoimmune diseases
- congenital immunodeficiency states
- Helicobacter pylori
- AIDS
- EBV
- HTLV-1
60
What are the broad clinical subgroups of NHL?
- The histologic classification of NHL is complex and controversial, a more useful subgrouping is by either indolent or aggressive clinical behavior.
- The most common indolent lymphoma is follicular and the most common aggressive lymphoma is diffuse large B cell.
61
What is the clinical behavior of indolent NHL?
- Typically indolent.
- Not curable.
- Median survival is 7 years, with some patients having extremely prolonged survival with observation alone.
62
What is the typical clinical behavior of aggressive NHL?
- Rapid progression and death, if not treated.
| - Cure is achieved in 40%–50% of patients treated with standard combination chemotherapy regimens.
63
What is the staging system for NHL?
The Modified Ann Arbor staging system
| -> see under section “Hodgkin Disease”
64
What factors are crucial for choosing therapy for NHL?
- Histologic subtype and stage.
| - The International Prognostic Index (IPI) is also commonly used.
65
What risk factors are assessed in the IPI?
NHL
Think “APLES”:
- Age > 60 years
- Performance status ECOG 2–4 (see the preceding text)
- LDH > normal level
- Extranodal sites of disease (>1)
- Stage II–IV disease
66
What is the treatment for indolent NHL?
- Observation if the patient is asymptomatic.
- Oral chemotherapy can be effective as initial treatment for symptomatic disease.
- Localized symptomatic NHL can be effectively palliated with radiation therapy.
- Combination chemotherapy and single-agent nucleoside analogs are effective but not proven to be better than oral regimens as initial treatment.
67
What monoclonal antibody therapy is used in the treat- ment of NHL?
- Rituximab.
- Rituximab targets the CD20 receptor.
- It is used with chemotherapy in the initial treatment and as single agent in the maintenance therapy.
68
What is the treatment for aggressive NHL?
Combination chemotherapy with rituximab (if CD20 +) carries a 60%–70% complete response rate, but recurrence occurs in approximately half of patients within 1–2 years.
69
What is a plasma cell dyscrasia?
An abnormal proliferation of plasma cells that usually secrete a monoclonal immunoglobulin
70
What is the monoclonal protein associated with plasma cell dyscrasias?
An immunoglobulin.
- The most common is IgG, with IgA being a close second. - All of the following may be present:
* IgM, kappa light chains
* lambda light chains
* IgD
* IgE monoclonal proteins.
71
What are the major plasma cell dyscrasias?
- MGUS
- MM
- WM
- amyloidosis
72
What are the diagnostic criteria for an MGUS?
plasma cell dyscrasias
An MGUS must have:
- Serum M protein <3.5 g/dL (IgG) or <2 g/dL (IgA) <10% plasma cells in the bone marrow
- Urine light chains <1 g/24 h
- No lytic bone lesions
73
What is the incidence of MGUS?
plasma cell dyscrasias
Increases with age with 1% at age 25 and 10% at age 80
74
What is the rate of progression of MGUS to MM?
plasma cell dyscrasias
1%–3% per year
75
What is MM?
- Multiple Myeloma
| - A malignant proliferation of terminally differentiated B lymphocytes (plasma cells) resulting in end-organ damage
76
What is the incidence of MM?
1% of all cancers and 10% of all hematologic malignancies
77
What is the median age for the development of MM?
The median age is 65 years.
78
What are the risk factors for the development of MM?
- The disease is much more common in African Americans.
| - Exposures to radiation, alkylating agents, asbestos, pesticides, HHV-8, and SV40 have been implicated as risk factors.
79
Do all patients with MM have an M protein in the serum?
No.
- Only 80% of patients have an M protein in the serum; 20% have only light chains, which can be measured in a 24-hour urine collection or with a serum light-chain assay.
- These light chains will NOT be picked up on a regular urinalysis.
- Approximately 1% of patients with MM are termed “nonsecretors” and have no identifiable M protein.
80
In nonsecretors, where is the immunoglobulin?
On staining of the plasma cells, the protein is shown to be within the cytoplasm, but the plasma cells cannot excrete the immunoglobulin molecule.
81
What are the clinical manifestations of MM?
- Osteolytic bone lesions with an associated risk of pathologic fractures of the long bones, vertebrae, pelvis, and ribs
- Anemia and pancytopenia
- Hypercalcemia
- Renal insufficiency
- Recurrent bacterial and viral infections (due to hypogammaglobulinemia)
- Hyperviscosity
- Peripheral neuropathies
- Spinal cord compression (not common)
- Myelomatous meningitis (not common)
82
What are the causes of renal insufficiency or failure in patients with MM?
Amyloidosis, light-chain deposition disease, hypercalcemia, hyperuricemia with uric acid crystallization within the collecting ducts and tubules, and plasma cell infiltration
83
What are the major criteria for the diagnosis of MM?
- M protein >3.5 g/dL (IgG) or >2 g/dL (IgA)
- Marrow plasmacytosis >30%
- Plasmacytoma
84
What are the minor criteria for the diagnosis of MM?
- Lytic bone lesions
- Marrow plasmacytosis 10%–30%
- M protein less than defined previously
- Decreased levels of normal immunoglobulins
85
How is the diagnosis of MM made?
Need 1 major criterion plus 1 minor criterion, or 3 minor criteria
86
What tests should be done in the workup of a patient suspected to have MM?
CBC, chemistry panel to include uric acid, quantitative immunoglobulins, serum protein electrophoresis, 24-hour urine collection for protein electrophoresis, and Beta2-microglobulin, total body skeletal survey, and bone marrow aspirate and biopsy
87
What is the treatment for MM?
- Alkylating agent chemotherapy with corticosteroids was the traditional mainstay.
- Now, thalidomide and its derivatives are used in the initial treatment of MM.
88
How is solitary plasmacytoma treated?
MM
Can generally be treated with localized radiation therapy for cure; however, 80% of patients recur with MM.
89
WM = ?
waldenström macroglobulinemia
90
What is the characteristic cell type in WM?
A mature lymphocyte with plasma cell features that produces IgM. The disease is commonly referred to as a “lymphoplasmacytic disorder.”
91
What are the common presenting symptoms of WM?
Weakness, fatigue, oral and nasal mucocutaneous bleeding, symptoms attributable to splenomegaly, and symptoms attributable to hyperviscosity
92
What are the symptoms attributable to hyperviscosity?
- Headache
- blurred vision
- paresthesias
- focal or diffuse weakness
- deafness
- symptoms secondary to congestive heart failure
93
What are the important physical findings of WM?
Hepatosplenomegaly and lymphadenopathy
94
What is the treatment for WM?
- Oral alkylating agents can be used.
- Newer therapies include nucleoside analogs (fludarabine, cladribine), monoclonal antibodies (anti-CD20), and thalidomide and high-dose chemotherapy followed by stem cell transplantation for younger patients.
