Plasma cell disorders

Question 1

The ___________ encompass a spectrum of disorders characterized by a clonal proliferation of abnormal mature plasma cells, most of which produce immunoglobulin.

The cells seen here with _______ cytoplasms and an eccentric nucleus are plasma cells. A pink-ish clearing next to the nucleus can be seen in most plasma cells and is formed by the expanded __________ which is consumed with the production of immunoglobulin.

The classic plasma cell “clock face nucleus” is only seen on Hematoxylin and Eosin staining which is usually performed on solid biopsy specimens.

Answer 1

The plasma cell dyscrasias encompass a spectrum of disorders characterized by a clonal proliferation of abnormal mature plasma cells, most of which produce immunoglobulin.

The cells seen here with vivid blue cytoplasms and an eccentric nucleus are plasma cells. A pink-ish clearing next to the nucleus can be seen in most plasma cells and is formed by the expanded golgi apparatus which is consumed with the production of immunoglobulin.

The classic plasma cell “clock face nucleus” is only seen on Hematoxylin and Eosin staining which is usually performed on solid biopsy specimens.

Question 2

plasma cell disorders (6)

Answer 2

1. Monoclonal Gammopathy of undetermined significance (MGUS)
2. multiple myeloma
3. Plasma cell leukemia
4. Waldenstroms Macroglobulinemia
5. Light & Heavy chain deposition diseases
6. Cryoglobulinemia

Question 3

Recall that an immunoglobulin molecule (an antibody) is composed of two identical light chains and two identical heavy chains covalently linked together with disulfide bonds. Light chain and heavy chain are each constructed from recombination between randomly-selected, individual gene segments from v, d and j gene families. Unused gene family members are spliced out and discarded. The sites of recombination fold together form the distal, variable regions of the immunoglobulin, the region which determines _______.

Constant regions of light and heavy chains align away from the antigen recognition region and are responsible for the _________.

Answer 3

Recall that an immunoglobulin molecule (an antibody) is composed of two identical light chains and two identical heavy chains covalently linked together with disulfide bonds. Light chain and heavy chain are each constructed from recombination between randomly-selected, individual gene segments from v, d and j gene families. Unused gene family members are spliced out and discarded. The sites of recombination fold together form the distal, variable regions of the immunoglobulin, the region which determines antigen specificity.

Constant regions of light and heavy chains align away from the antigen recognition region and are responsible for the function of the antibody.

Question 4

IgG, M and A are the most common immunoglobulins, but IgE and D can rarely be seen.

Answer 4

yep

Question 5

is the most common plasma cell dyscrasia effecting 2% of the population over 50 years old and 3% over 70 years old.

Answer 5

Monoclonal gammopathy of unknown significance (MGUS

Question 6

Monoclonal gammopathy of unknown significance (MGUS:

The underlying cause is not known, but it is often associated with ________ diseases. MGUS may represent a loss of _________ where an appropriate immunologic response to infection (for example) is not completely shut off after the infection has resolved – a “leaky faucet” where the flow of antibodies continues after the main response has been turned off.

The diagnosis of MGUS is usually made incidentally on routine lab work when the total protein is found to ____the albumin.

In order to diagnose MGUS, a ________ immunoglobulin must be present, but not measure more than 3g/dl and bone marrow cannot exceed _____% plasma cells (exceeding these limits meets diagnostic criteria for ____________,?

Prognosis for most patients is _____. Based on a study from the Mayo Clinic of 1384 patient contributing a total of 11,009 patient-years of follow up, the risk of progression to any (hematologic) malignancy is < 1%/year. An Ig > 3g/dl predicted a marginally higher risk.

Answer 6

The underlying cause is not known, but it is often associated with autoimmune diseases. MGUS may represent a loss of immune regulation where an appropriate immunologic response to infection (for example) is not completely shut off after the infection has resolved – a “leaky faucet” where the flow of antibodies continues after the main response has been turned off.

The diagnosis of MGUS is usually made incidentally on routine lab work when the total protein is found to exceed the albumin by an excessive amount (the globulin fraction = total protein – albumin is predominantly composed of immunglobulins).

In order to diagnose MGUS, a monoclonal immunoglobulin must be present, but not measure more than 3g/dl and bone marrow cannot exceed 10% plasma cells (exceeding these limits meets diagnostic criteria for multiple myelmoa).

Prognosis for most patients is good. Based on a study from the Mayo Clinic of 1384 patient contributing a total of 11,009 patient-years of follow up, the risk of progression to any (hematologic) malignancy is < 1%/year. An Ig > 3g/dl predicted a marginally higher risk.

Question 7

most common emergent hematologic malignancy was _________ with a risk 25 times higher than the general population (without MGUS). Lymphomas, Waldenstrom’s Macroglobulinemia and plasmacytoma were also recorded, but at a lower rate.

Patients with MGUS can be followed expectantly with repeat SPEP every _____months.

Answer 7

most common emergent hematologic malignancy was multiple myeloma with a risk 25 times higher than the general population (without MGUS). Lymphomas, Waldenstrom’s Macroglobulinemia and plasmacytoma were also recorded, but at a lower rate.

Patients with MGUS can be followed expectantly with repeat SPEP every 6 – 12 months.

Question 8

Multiple myeloma remains a relatively unusual diagnosis, even among hematologic malignancies. The incidence appears to be slowly rising over time, while the gap between new diagnoses and deaths is widening (suggesting that patients may be living longer).

Answer 8

yep

Question 9

Multiple myeloma is a disease primarily affecting _______patients. Only 3% of diagnoses are made in patient_________. The incidence of multiple myeloma is higher in __________ and higher in males or females?. The incidence is relatively low in the Asian population.

Answer 9

Multiple myeloma is a disease primarily affecting older patients. Only 3% of diagnoses are made in patient under the age of 40. The incidence of multiple myeloma is higher in African Americans and higher in males. The incidence is relatively low in the Asian population.

Question 10

Multiple myeloma is distinguished from MGUS by several factors which mark the progression from one disease to the other.

In myeloma, the M-spike is ______ (>3g/dL) or the proportion of plasma cells in the bone marrow is _____(>10%), or there is evidence of _______ involvement.

The hallmarks of end organ involvement in multiple myeloma are an _________calcium related to the liberation from bone matrix via osteoclast activity,____________ (an elevation of creatinine), _______ possibly due to physical displacement but more likely the result of myelosuppressive cytokine interactions, and the presence of_______ by X-ray (mnemonic CRAB).

Answer 10

Multiple myeloma is distinguished from MGUS by several factors which mark the progression from one disease to the other. In myeloma, the M-spike is higher (>3g/dL) or the proportion of plasma cells in the bone marrow is higher (>10%), or there is evidence of end organ involvement. The hallmarks of end organ involvement in multiple myeloma are an elevated calcium related to the liberation from bone matrix via osteoclast activity, renal dysfunction (an elevation of creatinine), anemia possibly due to physical displacement but more likely the result of myelosuppressive cytokine interactions, and the presence of lytic bone lesions by X-ray (mnemonic CRAB).

Question 11

CRAB

Answer 11

multiple myeloma symtpms:

hyper- Calcemia
Renal dysfunction
Anemia
lytic Bone lesions

Question 12

The etiology of multiple myeloma is unknown. Only a small proportion of patients with _____ progress to MM, while most patients with MM were not known to have
_____. Attempts to identify patients with _____ who are at risk of progression as well as attempts to mark an evolution of ____ to MM have been unsuccessful.

Occupational exposure to _____ (workers in uranium mines in 1940’s & 1950’s) , chemicals used in the production of ________, and benzene are each purported to be risk factors for MM. The rate of MM is reported to be higher in ________than in other occupations.

Answer 12

The etiology of multiple myeloma is unknown. Only a small proportion of patients with MGUS progress to MM, while most patients with MM were not known to have MGUS. Attempts to identify patients with MGUS who are at risk of progression as well as attempts to mark an evolution of MGUS to MM have been unsuccessful.

Occupational exposure to radiation (workers in uranium mines in 1940’s & 1950’s) , chemicals used in the production of sheet metals, and benzene are each purported to be risk factors for MM. The rate of MM is reported to be higher in fire fighters than in other occupations.

Question 13

Multiple myeloma has been considered a malignancy of _________ differentiated, immunoglobulin-secreting plasma cells. Yet, cultures of purified MM plasma cells fail to grow colonies of plasma cells. In contrast, cultures of purified B-cells devoid of plasma cells will produce colonies of composed predominantly of ______. It is likely that the true malignant cell in MM is a ___________ who’s progeny retain the ability to mature to the plasma cell stage.

Additional evidence for this theory is the fact that MM has been seen to _____ immunoglobulin class suggesting that the true malignant cell has not yet irreversibly committed to an particular class.

Among the hematologic malignancies, MM appears to have the most intimate relationship with its __________. MM, even in advanced stages, primarily remains within the bone marrow. Adhesion molecules on MM plasma cells are the points of physical contact with bone marrow stromal elements such as osteoclasts. Contact induces / maintains antiapoptotic signals, promoting cell survival. Many cytokines also appear to play a role in MM survival including ____ which may provide autocrine and paracrine survival signals.

_________have been implicated in tumorigenesis, particularly HHV-8 which can secrete an ____-like cytokine. Mutations in oncogenes Rb, p53, Ras, bcl-2 and c-myc have also been shown to play some role.

Answer 13

Multiple myeloma has been considered a malignancy of terminally-differentiated, immunoglobulin-secreting plasma cells. Yet, cultures of purified MM plasma cells fail to grow colonies of plasma cells. In contrast, cultures of purified B-cells devoid of plasma cells will produce colonies of composed predominantly of plasma cells. It is likely that the true malignant cell in MM is a post-germinal center B-cell who’s progeny retain the ability to mature to the plasma cell stage.

Additional evidence for this theory is the fact that MM has been seen to switch immunoglobulin class (ie IgG to IgM, for example) suggesting that the true malignant cell has not yet irreversibly committed to an particular class.

Among the hematologic malignancies, MM appears to have the most intimate relationship with its micro-environment. MM, even in advanced stages, primarily remains within the bone marrow. Adhesion molecules on MM plasma cells are the points of physical contact with bone marrow stromal elements such as osteoclasts. Contact induces / maintains antiapoptotic signals, promoting cell survival. Many cytokines also appear to play a role in MM survival including IL-6 which may provide autocrine and paracrine survival signals.

Viral infections have been implicated in tumorigenesis, particularly HHV-8 which can secrete an IL-6-like cytokine. Mutations in oncogenes Rb, p53, Ras, bcl-2 and c-myc have also been shown to play some role.

Question 14

of the bone marrow microenvironment sustaining MM and leading to ____destruction. MM cells _____ to the bone marrow stromal elements, the structural network of fibroblasts, osteoblasts and osteoclasts.

This provides ______ signals which further promote adherence and MM growth as well as stimulate the stromal elements, osteoclasts in particular. The stromal elements in turn send more re-enforcing signals back to the________

Answer 14

of the bone marrow microenvironment sustaining MM and leading to bone destruction. MM cells adhere to the bone marrow stromal elements, the structural network of fibroblasts, osteoblasts and osteoclasts. This provides cytokine signals which further promote adherence and MM growth as well as stimulate the stromal elements, osteoclasts in particular. The stromal elements in turn send more re-enforcing signals back to the MM cells

Question 15

The great majority (90%) of patients with MM have a ________ immunoglobulin (M protein) in their serum, many will have M protein spilling into the _____80%.

The presence of abnormal plasma cells and/or M protein can serve as a ______feedback control on normal plasma cells causing the overall immunoglobulin levels to ______.

About 5-10% are oligo- or non-secretors with no detectable protein. These patients typically present with __________(anemia, thrombocytopenia) with or without typical lytic bone lesions and a bone marrow biopsy reveals MM. Presumably the MM plasma cells in these patients have acquired mutations in their immunoglobulin genes or synthesis pathways and are unable to produce an ________.

Answer 15

The great majority (90%) of patients with MM have a monoclonal immunoglobulin (M protein) in their serum, many will have M protein spilling into the urine. The presence of abnormal plasma cells and/or M protein can serve as a negative feedback control on normal plasma cells causing the overall immunoglobulin levels to fall.

About 5-10% are oligo- or non-secretors with no detectable protein. These patients typically present with bone marrow suppression (anemia, thrombocytopenia) with or without typical lytic bone lesions and a bone marrow biopsy reveals MM. Presumably the MM plasma cells in these patients have acquired mutations in their immunoglobulin genes or synthesis pathways and are unable to produce an M-protein.

Question 16

Bence Jones proteinuria

Answer 16

MM- free light chains are secreted into the serum b/c MM plasma cell cannot produce a heavy chain.

these small proteins then are freely filtered through the kidneys

Question 17

When an M-protein is detected, the majority are _______ – composed of covalently bound heavy and light chains – with 55% Ig__ and 25% Ig__ class. A very small fraction are IgM or IgD

IgM MM is a rare entity and should be distinguished from lymphoplasmacytic lymphoma and Waldenstrom’s macroglobulinemia _______-secreting tumors which are more closely akin to low grade lymphomas. LPL and WM do not cause ______ in the bones which sets them apart from most patients with MM. In addition these tumors are characterized by bone marrow involvement with a spectrum of cells between mature B-cells and plasma cells, whereas MM lesions are all _________

Answer 17

When an M-protein is detected, the majority are intact – composed of covalently bound heavy and light chains – with 55% IgG and 25% IgA class. A very small fraction are IgM or IgD

IgM MM is a rare entity and should be distinguished from lymphoplasmacytic lymphoma and Waldenstrom’s macroglobulinemia IgM-secreting tumors which are more closely akin to low grade lymphomas. LPL and WM do not cause lytic lesions in the bones which sets them apart from most patients with MM. In addition these tumors are characterized by bone marrow involvement with a spectrum of cells between mature B-cells and plasma cells, whereas MM lesions are all plasma cells

Question 18

“punched-out” lesions from osteoclast activation

Answer 18

MM

Bone scans which rely on incorporation of radioactive technicium into the bone matrix by osteoblasts, is the wrong test for MM and typically will show no abnormality. Because of active tumor and ostoclastic activity in / around the blastic lesions, 18FDG PET will show activity and may be particularly helpful in following the course of patients with non-secretory disease.

Question 19

Bone scan is the right test to detect lytic lesions typical of MM

Answer 19

NOPE- wrong test

Question 20

Renal injury is a frequent complication of multiple myeloma with various forms identified in the majority of patients in autopsy series. Three distinct injuries are responsible for the majority of cases

Answer 20

1. cast nephropathy
2. amyloidosis
3. monoclonal Ig deposition disease

Question 21

Cast Nephropathy
________ produced in the blood are filtered out through the glomeruli and may be directly injurious to the ascending loop of Henle leading to tubular injury, cast formation and tubular obstruction. The etiology is believed to relate to binding/recognition of the _______ mucoprotein expressed by tubular epithelial cells. Patients with cast nephropathy present with __________ (elevated creatinine) without glomerular damage (no proteinuria). Management involves treating the underlying myeloma to reduce the ________ burden; if not long standing, there may be benefit to plasma exchange / plasmapheres – a process by which blood is continuously removed by vein, spun on a centrifuge and separated plasma from cellular component by density. Plasma is siphoned off and replaced with donated plasma (fresh frozen plasma, FFP) and/or saline containing albumin before being sent back into the patient through a different vein.

Answer 21

Cast Nephropathy
Light chains produced in the blood are filtered out through the glomeruli and may be directly injurious to the ascending loop of Henle leading to tubular injury, cast formation and tubular obstruction. The etiology is believed to relate to binding/recognition of the Tamm-Horsfall mucoprotein expressed by tubular epithelial cells. Patients with cast nephropathy present with renal insufficiency (elevated creatinine) without glomerular damage (no proteinuria). Management involves treating the underlying myeloma to reduce the light chain burden; if not long standing, there may be benefit to plasma exchange / plasmapheres – a process by which blood is continuously removed by vein, spun on a centrifuge and separated plasma from cellular component by density. Plasma is siphoned off and replaced with donated plasma (fresh frozen plasma, FFP) and/or saline containing albumin before being sent back into the patient through a different vein.

Question 22

Light Chain Amyloidosis
_______ consume free light chain but do not completely digest the proteins which are secreted and subsequently precipitate and form β-pleated fibrils which accumulate in the______. These deposits stain with Congo Red. This results in injury to the glomeruli which manifests as nephrotic-range__________. Management consists of treating to reduce production of light chains, but the improvement is likely to be very slow as it requires re-uptake/clearing from the tissues; there is no benefit expected from plasma exchange and it should not be undertaken.

Answer 22

Light Chain Amyloidosis
Activated macrophages consume free light chain but do not completely digest the proteins which are secreted and subsequently precipitate and form β-pleated fibrils which accumulate in the renal insterstitium. These deposits stain with Congo Red. This results in injury to the glomeruli which manifests as nephrotic-range proteinuria. Management consists of treating to reduce production of light chains, but the improvement is likely to be very slow as it requires re-uptake/clearing from the tissues; there is no benefit expected from plasma exchange and it should not be undertaken.

Question 23

Monoclonal Immunoglobulin Deposition Disease (MIDD)
______ fragments secreted from macrophages which do not form fibrils (on the basis of size, shape and charge) but simply accumulate in tissue. These deposits cause both glomerular and tubular injury by _______ as in AL amyloidosis, but do not stain with Congo Red. These patients present with both _______. Plasma exchange will benefit/not benefit.

Answer 23

Monoclonal Immunoglobulin Deposition Disease (MIDD)
Ligh chain fragments secreted from macrophages which do not form fibrils (on the basis of size, shape and charge) but simply accumulate in tissue. These deposits cause both glomerular and tubular injury by accumulation as in AL amyloidosis, but do not stain with Congo Red. These patients present with both proteinuria and renal insufficiency. Plasma exchange will not benefit.

Question 24

Dehydration and hypercalcemia are further common, frequently linked causes of (pre-renal) kidney injury. Hydration and management of the hypercalcemia tend to reverse the injury rapidly. ______ is a common first step in the management of any patient with myeloma and kidney injury.

Answer 24

Dehydration and hypercalcemia are further common, frequently linked causes of (pre-renal) kidney injury. Hydration and management of the hypercalcemia tend to reverse the injury rapidly. Hydration is a common first step in the management of any patient with myeloma and kidney injury.

Question 25

smoldering myeloma

Answer 25

transition state between MGUS and MM

Question 26

The risk of progression from smoldering MM to symptomatic MM is significantly greater/lesser than from MGUS to symptomatic MM, yet some patients can remain in this transition state for many years and avoid treatment.

Answer 26

greater

Question 27

Diagnosis of MM (5)

Answer 27

1. serum protein electrophoresis w/ IFE
2. 24 hr. urine protein elctrophoresis
3. bone marrow aspirate and biopsy
4. quantitative immunoglobulins
5. skeletal survey

Question 28

MM where there are about 48-74 chromosomes- hyperdiploid has a better or worse prognosis

Answer 28

better prognosis

Question 29

MM chromosomal translocation:

1. t(11,14) cyclin D1- __%
2. 7(6;14) cyclin D3- __%
3. t(4;14) ______

Answer 29

1. t(11,14) cyclin D1- 20%
2. 7(6;14) cyclin D3- 5%
3. t(4;14) FGFR3

Question 30

MM is a universally _____ disease with standard therapy. Median survival without treatment is ___ year; with conventional chemotherapy, the median improves to about ____ years. For many years, the standard therapy for MM was __________combined with ____, both given orally for 5 days every 4-5 weeks. The majority of patients respond to this treatment (the M protein decreases by at least 50%), but the MM almost never __________

Answer 30

MM is a universally fatal disease with standard therapy. Median survival without treatment is less than one year; with conventional chemotherapy, the median improves to about 3 years. For many years, the standard therapy for MM was melphalan combined with prednisone, both given orally for 5 days every 4-5 weeks. The majority of patients respond to this treatment (the M protein decreases by at least 50%), but the MM almost never disappears.

Question 31

Allogeneic transplant – transplanting one person’s immune system and blood-making capacity from one patient to another – has a proven track record of cure for many hematologic malignancies. however what happens in MM?

Answer 31

Unfortunately this strategy has proven very toxic in MM when delivered with high doses of chemotherapy and radiation.

Question 32

is the current standard of care for patients less than 70 – 75 years old. in MM

Answer 32

Autologous transplant

median survival improved to > 5 years compared with < 3 years

Question 33

high doses of _______(on the order of 10 – 20 times the dose in M&P) with autologous stem cell rescue (a transplantation technique that allows escalation of drugs that we know will wipe out a patients bone marrow for good) was demonstrated to have activity in MM

Answer 33

melphalan

Question 34

The bone marrow requires blood flow to provide oxygen and nutrients to the developing blood system. Tumors occupying the bone marrow such as multiple myeloma are able to stimulate the development of new blood vessels (angiogenesis) to feed their appetite for growth. In the 1990’s new attention focused on the hypothesis that preventing the development of new blood vessels in tumors could stop their growth. Desperate for a new treatment for a chemotherapy-refractory patient with substantial vascularity within the tumor, Barlogie, et al at Arkansas tried the only FDA-approved (ie readily available) drug with purported anti-angiogenic activity, thalidomide … and it worked! Subsequent work, however, has shown that angiogenesis is probably the least of its targets.

Answer 34

yep

Question 35

MM has a symbiotic relationship with the __________ that is unique among hematologic malignancies. This became clear as people tried to figure out exactly how it worked (and why it didn’t work in a large proportion of patients).

Answer 35

bone marrow micro-environment

Question 36

immune modulating drugs and side effects

Answer 36

1. thalidomide
2. lenolidomide
3. pomalidomide

• somnolence, peripheral neuropathy, constipation and blood clots

Question 37

Subsequent studies with thalidomide in combination with steroids have shown a response rate of ____% in heavily pre-treated pts, 60-80% in treatment naïve. This has now become a standard initial therapy for newly diagnosed patients

Answer 37

20-40

Question 38

enzymatic structures tasked with destroying outdated proteins

Answer 38

proteasome

Question 39

Bortezemib is a novel boron-based agent which acts like a spoon in the proteosome disposal,_______ access by ubiquitated proteins. This in turn causes an accumulation of cells cycle sequence specific proteins ultimately preventing cell cycle ________ and leading to ______

Answer 39

Bortezemib is a novel boron-based agent which acts like a spoon in the proteosome disposal, blocking access by ubiquitated proteins. This in turn causes an accumulation of cells cycle sequence specific proteins ultimately preventing cell cycle progression and leading to apoptosis.

Question 40

Combinations of _________with traditional chemotherapy regimens is proving very potent. In a study of elderly people (not candidates for bone marrow transplant), an Italian group showed an overall and complete response rate that rivals high dose chemotherapy. Toxicity was significant on this study, particularly before the risk of blood clots was appreciated and several subjects died with pulmonary emboli. With subsequent attention to anticoagulation, this toxicity was minimized.

Similarly, combinations of a ____inhibitor with either an IMiD or chemotherapy (alkylators cyclophosphamide or melphalan) are potent and well tolerated provided side effects and risks are properly managed.

_____ therapy is currently standard initial treatment for younger patients prior to autologous transplant. Whether patients who get a good response from the tripple therapy can forgo the transplant for a period of time or altogether is currently under investigation.

Answer 40

Combinations of IMiDs with traditional chemotherapy regimens is proving very potent. In a study of elderly people (not candidates for bone marrow transplant), an Italian group showed an overall and complete response rate that rivals high dose chemotherapy. Toxicity was significant on this study, particularly before the risk of blood clots was appreciated and several subjects died with pulmonary emboli. With subsequent attention to anticoagulation, this toxicity was minimized.

Similarly, combinations of a proteosome inhibitor with either an IMiD or chemotherapy (alkylators cyclophosphamide or melphalan) are potent and well tolerated provided side effects and risks are properly managed.

Triplet therapy is currently standard initial treatment for younger patients prior to autologous transplant. Whether patients who get a good response from the tripple therapy can forgo the transplant for a period of time or altogether is currently under investigation.

Question 41

unusual sub-type of multiple myeloma. It is defined by the high number of malignant plasma cells circulating in the blood.

Answer 41

plasma cell leukemia

Question 42

Plasma cell leukemia occurs in two forms.

1. Primary PCL occurs where there is no
2. Secondary PCL is an

Answer 42

1. Primary PCL occurs where there is no preceding diagnosis of myeloma (about 5% of cases).
2. Secondary PCL is an end state of heavily treated multiple myeloma.

Question 43

In primary PCL the malignant plasma cells emerge with the ability to ________, in secondary PCL they only develop this ability much later, presumably as they acquire mutations over time.

There is a bias toward IgA in ______ PCL and these patients can present with extensive lytic bone lesions.

Survival for both primary and secondary PCL is ____. Treatment of primary disease follows that for multiple myeloma including transplant; leukemia-styled treatments ___________. Treatment of secondary disease is ______ – it is unlikely they will respond or tolerate intensive treatment at that late stage of their illness.

Answer 43

. In primary PCL the malignant plasma cells emerge with the ability to travel in the blood stream, in secondary PCL they only develop this ability much later, presumably as they acquire mutations over time. There is a bias toward IgA in primary PCL and these patients can present with extensive lytic bone lesions. Survival for both primary and secondary PCL is short. Treatment of primary disease follows that for multiple myeloma including transplant; leukemia-styled treatments do not appear effective. Treatment of secondary disease is palliative – it is unlikely they will respond or tolerate intensive treatment at that late stage of their illness.

Question 44

malignancy of plasma cell-like cells classified as a low grade lymphoma – a tumor composed of a mixture of mature B-cells, plasma cells and cells in between

Answer 44

Lymphoplasmacytic lymphoma

Question 45

is a particular subtype of LPL which produces a monoclonal IgM spike often associated with hyperviscosity

Answer 45

Waldenstrom’s Macroglobulinemia

Question 46

LPL cause bone lesion and has enlarged lymph nodes

Answer 46

false- no bone lesions

Question 47

Treatment of LPL and WM follows treatment strategies for low grade lymphoma with __________ +/- chemotherapy.

There is limited data showing effectiveness of bortezomib. Responses may take many months and symptoms from _________ may significantly worsen with treatment, therefore plasmapheresis – removal of patient serum and replacement with donated plasma or albumin – may be indicated prior to starting treatment.

Answer 47

Treatment of LPL and WM follows treatment strategies for low grade lymphoma with monoclonal anti-B cell antibodies +/- chemotherapy. There is limited data showing effectiveness of bortezomib. Responses may take many months and symptoms from hyperviscosity may significantly worsen with treatment, therefore plasmapheresis – removal of patient serum and replacement with donated plasma or albumin – may be indicated prior to starting treatment.

Question 48

1. Monoclonal light chains passively aggregate and form fibrils in tissue
2. May be associated with MM
3. Kidneys, heart and GI frequently involved
4. Onset insidious, diagnosis challenging
5. Treat as tolerated as would for MM

Answer 48

light chain amyloidosis

Question 49

a B-cell lymphoproliferative disorder that secretes a mutated monoclonal immunoglobulin that consists of only a shortened piece of the Fc region (the constant region of the heavy chain that defines the Ig class). The light chains and the variable portion of the heavy chain are missing.

Answer 49

Heavy chain disease

Question 50

heavy chain disease:

Very rare (34 cases reported) ______________disorder (1/3 CLL)

Secrete abnl. Ig lacking _____ and truncated heavy chain (____only)

In about 1/3 of cases of HCD, there is an underlying __________ responsible for the protein. 10% are associated with ____. 20% have no identifiable lymphoma. These patients typically present with fatigue, weight loss, recurrent infections. Almost all have _______, ¾ have hepatomegaly, 40% lymphadenopathy and 40% lytic bone lesions.

Treatment is aimed at controlling symptoms and relieving _______.

__________ would be a reasonable option (experience is very limited).

Answer 50

Very rare (34 cases reported) B-cell lymphoproliferative disorder (1/3 CLL)

Secrete abnl. Ig lacking light chains and truncated heavy chain (Fc only)

In about 1/3 of cases of HCD, there is an underlying chronic lymphocytic leukemia (CLL) responsible for the protein. 10% are associated with MM. 20% have no identifiable lymphoma. These patients typically present with fatigue, weight loss, recurrent infections. Almost all have splenomegaly, ¾ have hepatomegaly, 40% lymphadenopathy and 40% lytic bone lesions.

Treatment is aimed at controlling symptoms and relieving tissue infiltration. Chemotherapy would be a reasonable option (experience is very limited).

Question 51

refers to the presence of immunoglobulins in the serum which precipitate at less than body temperature (ie < 37 ºC). This may lead to a clinical picture of systemic inflammation caused by precipitating immune complexes.

Answer 51

cryoglobulinemia

Question 52

Cryoglobulins can be classified in three types:

Type I – monoclonal Ig, usually an Ig__, associated with underlying __________ (it takes an abnormal B-cell clone to turn out monoclonal Ig’s).

Type II – mixed cyroglobulinemia, consists of a monoclonal “__________” which binds the Fc portion of IgG; usually IgM, can be associated with lymphoproliferative disorders, autoimmune diseases and chronic infections (HepC, EBV, CMV, syphilis).

Type III – ______, usually represents polyclonal RF IgM’s directed against ____ portion of IgG’s

Answer 52

Cryoglobulins can be classified in three types:

Type I – monoclonal Ig, usually an IgM, associated with underlying lymphoproliferative disorder (it takes an abnormal B-cell clone to turn out monoclonal Ig’s).

Type II – mixed cyroglobulinemia, consists of a monoclonal “rheumatoid factor” which binds the Fc portion of IgG; usually IgM, can be associated with lymphoproliferative disorders, autoimmune diseases and chronic infections (HepC, EBV, CMV, syphilis).

Type III – polyclonal, usually represents polyclonal RF IgM’s directed against Fc portion of IgG’s

Question 53

The clinical manifestations of cryoglobulinemias depend on the type.

Type I cryoglobulins precipitate together leading to an increase in serum _______ which slows blood flow, reducing _______(particularly to the brain). Type I cryo’s ________complement and thus ________systemic inflamation.

Type II&III cryo’s cause activation of _____ releasing an inflammatory reaction which leads to local tissue damage. Arthragias and myalgias are common. Deposition of immune complexes in the kidneys leads to ____________.

Cutaneous __________lesions are common – erythematous macules and purpuric papules, also ulcerations, particularly in dependent areas. Interstitial pulmonary infiltrates with decreased expiratory flow can occur.

Evidence of neuropathy is common.

Answer 53

The clinical manifestations of cryoglobulinemias depend on the type.

Type I cryoglobulins precipitate together leading to an increase in serum viscosity (hyperviscosity) which slows blood flow, reducing oxygenation (particularly to the brain). Type I cryo’s do not activate complement and thus do not cause systemic inflamation.

Type II&III cryo’s cause activation of complement releasing an inflammatory reaction which leads to local tissue damage. Arthragias and myalgias are common. Deposition of immune complexes in the kidneys leads to membranoproliferative glomerulonephritis.

Cutaneous vasculitic lesions are common – erythematous macules and purpuric papules, also ulcerations, particularly in dependent areas. Interstitial pulmonary infiltrates with decreased expiratory flow can occur. Evidence of neuropathy is common.

Question 54

Treatment of cryoglobulinemia is only required once there is evidence of __________

Cold avoidance (dressing warmly or moving to warmer climate) may _____ for many patients.

__________ can be effective for severe / life threatening tissue injury or hyperviscosity. When possible, treatment should be directed against the underlying cause.

In Type I disease, the underlying lymphoproliferative disorder should be treated with ________ or _________.

In Type II disease, HCV should be looked for and treated if present with most effective treatment such as ______and ________ . Systemic anti-inflammatory therapy can be helpful – such as

Answer 54

Treatment of cryoglobulinemia is only required once there is evidence of end organ damage.

Cold avoidance (dressing warmly or moving to warmer climate) may suffice for many patients. Plasmapheresis can be effective for severe / life threatening tissue injury or hyperviscosity. When possible, treatment should be directed against the underlying cause. In Type I disease, the underlying lymphoproliferative disorder should be treated with chemotherapy or monoclonal Abs. In Type II disease, HCV should be looked for and treated if present with most effective treatment (IFN-  and ribavirin). Systemic anti-inflammatory therapy can be helpful – NSAIDS, steroids, immunosuppressants.