8/8/2019 12-09-13 Learning Issues - William Damonte

http://slidepdf.com/reader/full/12-09-13-learning-issues-william-damonte 1/7

Mr. Demonte Learning Objectives

1. Delirium vs dementia, reasons for both.

Dementia vs Delirium

In order to make a diagnosis of dementia, delirium must be ruled out. However,

patients with dementia are at increased risk of delirium and may have both. Delirium

is an acute disorder of attention and global cognition (memory and perception) and is

treatable. The diagnosis is missed in more than !" of cases. The risk factors for

delirium include age, pre#e$isting brain disease, and medications. There are many

causes, the most common are%

  D  Dementia

  E &lectrolyte disorders

  L 'ung, liver, heart, kidney, brain

  I Infection

  R  $ Drugs  I  Inury, *ain, +tress

  U  nfamiliar enviroment

  M  -etobolic

. !E"1 and !"# signi$cance%. Multi&le m'eloma( &atholog', s'm&toms, treatment

#ELL O! ORI)I*  -ultiple myeloma (--) appears to arise from the malignant

transformation of post#germinal center plasma cells (e/ector 0 cells # white blood cells

that secrete large volumes of antibodies).

 The malignant plasma cells of -- have a low proliferative rate and have generally been

unable to sustain tumor growth in vivo,

 This suggests that precursor cells are responsible for proliferation of the malignant cell

population. It has been proposed that these abnormal precursor 0#cells originate in the

lymph nodes and migrate to the bone marrow, which provides a microenvironment

conducive to terminal plasma cell di/erentiation 123. This could e$plain the observation

that the malignant plasma cells appear to be restricted to the microenvironment of the

bone marrow, even though the disease is widely disseminated throughout the a$ial

skeleton.

OVERVIEW OF PATHOGENESIS — The pathobiology of multiple myeloma (MM) is a complex

process leading to the replication of a malignant clone of plasma cell origin. While some steps in this

pathway have been elucidated, many remain unnown. !irtually all MM cases are preceded by a

premalignant plasma cell proliferative disorder nown as monoclonal gammopathy of undetermined

significance (M"#$) %&'. M"#$ is the premalignant stage. "ammopathy means a disturbance in the

8/8/2019 12-09-13 Learning Issues - William Damonte

http://slidepdf.com/reader/full/12-09-13-learning-issues-william-damonte 2/7

synthesis of immunoglobulins. M"#$ is present in over percent of the population above the age of

*, and progresses to myeloma or a related malignancy at a rate of + percent per year.

or now, the theory is that insults to the plasma cell clone, either through additional genetic

abnormalities or changes in the bone marrow microenvironment, result in the progression of M"#$ to

MM.

- lymphocytes start in the bone marrow and move to the lymph nodes. s they progress, they mature and

display different proteins on their cell surface. When they are activated to secrete antibodies, they are nown

as plasma cells.

Multiple myeloma develops in - lymphocytes after they have left the part of the lymph node nown as

the germinal center . The normal cell line most closely associated with MM cells is generally taen to be either

an activated memory - cell or the precursor to plasma cells, the plasmablast.%+*'

The immune system eeps the proliferation of - cells and the secretion of antibodies under tight control. When

chromosomes and genes are damaged, often through rearrangement, this control is lost. /ften, a promotergene moves (or translocates) to a chromosome where it stimulates an antibody gene to overproduction.

  chromosomal translocation between the immunoglobulin heavy chain gene (on chromosome +0, locus 12)

and an oncogene (often ++1+, 0p+3., 3p2+, +312 and 2*1++%++') is fre1uently observed in patients with

multiple myeloma. This mutation results in dysregulation of the oncogene which is thought to be an important

initiating event in the pathogenesis of myeloma. The result is proliferation of a plasma cell clone and genomic

instability that leads to further mutations and translocations. The chromosome +0 abnormality is observed in

about *4 of all cases of myeloma. 5eletion of (parts of) chromosome + is also observed in about *4 of

cases.

6roduction of cytoines %+2' (especially 7893) by the plasma cells causes much of their localised damage, such

as osteoporosis, and creates a microenvironment in which the malignant cells thrive. ngiogenesis (the

attraction of new blood vessels) is increased.

The produced antibodies are deposited in various organs, leading to renal failure, polyneuropathy and various

other myeloma9associated symptoms.

 The diagnosis of -- is often suspected because of one (or more) of the following clinical

presentations%

40one pain with lytic lesions discovered on routine skeletal 5lms

46n increased total serum protein concentration and7or the presence of a monoclonal

protein in the urine or serum

8/8/2019 12-09-13 Learning Issues - William Damonte

http://slidepdf.com/reader/full/12-09-13-learning-issues-william-damonte 3/7

4+ystemic signs or symptoms suggestive of malignancy, such as une$plained anemia

4Hypercalcemia, which is either symptomatic or discovered incidentally

46cute renal failure with a bland urinalysis or rarely the nephrotic syndrome due to

concurrent primary amyloidosis.

+nemia  6 normocytic, normochromic anemia (hemoglobin 89: g7d') is present in ;<

percent at diagnosis and in =; percent at some time during the course of the disease 1>3.

 This anemia can be related to bone marrow replacement, kidney damage, and7or can be due

to dilution in the case of a large -#protein. 6nemia commonly results in complaints of

fatigue and pallor seen on physical e$amination.

-acrocytosis (mean corpuscular volume ?9!! f') was present in = percent of 9!:; patients

studied 1>3. In this study, < patients (99 percent) with a -@A ?9!! f' had a vitamin 09:

level B:!! ng7'. This 5nding is similar to a prevalence of vitamin 09: de5ciency of 9C

percent seen in a separate study of 22C consecutive patients with plasma cell dyscrasias

1:23. hile the mechanism for low vitamin 09: levels in these patients is not known,

investigations must be done to rule out pernicious anemia.

one &ain  0one pain, particularly in the back or chest, and less often in the e$tremities,

is present at the time of diagnosis in appro$imately 2! percent of patients 1>3. The pain is

usually induced by movement and does not occur at night e$cept with change of position.

 The patientEs height may be reduced by several inches because of vertebral collapse.

*lasmacytomas of the ribs occur and can present either as e$panding costal lesions or soft

tissue masses.

Renal disease  The serum creatinine concentration is increased in almost one#half of

patients at diagnosis (and is ?: mg7d' (9;; micromol7') in appro$imately :! percent)F renal

failure may be the presenting manifestation of -- 1>,:;3. Two maor causes of renal

insuGciency in patients with -- are light chain cast nephropathy (also called myeloma

kidney) and hypercalcemia. *atients who do not secrete light chains are not at risk for

myeloma kidney. ther causes of renal failure in a patient with myeloma include concurrent

light chain (6') amyloidosis, light chain deposition disease, and drug#induced renal damage.

enal disease in -- is discussed in more detail separately. (+ee Types of renal disease in

multiple myeloma.)

-'&ercalcemia  Hypercalcemia is found in :> percent of one series of patients with --at the time of diagnosisF serum calcium was J99 mg7d' (:.; mmol7liter) in 9< percent and

can reKuire emergent treatment 1>3. The ioniLed calcium should be measured if the patient

has a high serum calcium level but no symptoms of hypercalcemia. &levation of the serum

calcium may be due to binding of the monoclonal protein with calcium 1<93. (+ee Treatment

of the complications of multiple myeloma, section on EHypercalcemiaE andTreatment of

hypercalcemia and Hypercalcemia of malignancy, section on Esteolytic metastasesE.)

8/8/2019 12-09-13 Learning Issues - William Damonte

http://slidepdf.com/reader/full/12-09-13-learning-issues-william-damonte 4/7

f note, severe hypercalcemia can act as an unmeasured cation and thereby result in a low

anion gap. 6 decreased anion gap may also be due to the presence of a cationic IgM

molecule.

PATHOLOGIC FEATURES

Monoclonal proteins — The presence of a monoclonal (M) protein in the serum or urine is a ma:or

criterion for the diagnosis of multiple myeloma (MM). The vast ma:ority (;& percent) of patients with MM

will have an M9protein produced and secreted by the malignant plasma cells, which can be detected by

protein electrophoresis of the serum ($6<6) and=or of an ali1uot of urine (#6<6)

Risk actors — <pidemiologic data suggest a genetic predisposition as well as other potential ris factors

including older age, immunosuppression, and environmental exposures %>9+2'. ?ormonal factors may

play a role, since women have significantly lower age9specific prevalence rates when compared with men.

  genetic predisposition is predominantly supported by the findings that the incidence of M"#$ varies by

ethnicity and that a small, but unnown, fraction of cases are familial. $uch cases may be due to either

shared genes or environmental factors.

!one "arro# e$a"ination — bone marrow aspirate and biopsy are a ey component to the

diagnosis of MM (picture  and picture 3). The bone marrow of the vast ma:ority of patients

contains +* percent or more clonal plasma cells. ?owever, due to patchy bone marrow

involvement, bone marrow aspirate and biopsy may show less than +* percent plasma cells in

approximately 0 percent of patients. s an example, in the Mayo @linic series, plasma cells

constituted more than +* percent of all nucleated cells in ;3 percent of patients, but this value

ranged from less than percent to almost +** percent, with a median value of * percent %>'.

  diagnosis of MM can be made in patients with less than +* percent clonal plasma cells on

biopsy if other diagnostic criteria are fulfilled an% after histopathologic confirmation of a soft tissue

or bony plasmacytoma %+*'. $ince bone marrow involvement may be more focal than diffuse,

some patients may re1uire bone marrow aspirate=biopsy from several different sites or a guided

biopsy of a focal lesion diagnosed by either MA7 or 6<T=@T (integrated positron emission

tomography and computed tomography) scan in order to establish the diagnosis.

Morp&olo'( — The morphological features of plasma cells can differ depending upon their

maturity and, at times, they may be morphologically indistinguishable from myeloblasts. Mature

plasma cells are oval with abundant basophilic cytoplasm. The nucleus is round and eccentrically

located with a mared perinuclear hof, or cytoplasmic clearing (picture 0). The nucleus containsBcloc9faceB or Bspoe wheelB chromatin without nucleoli. 7mmature plasma cells have dispersed

nuclear chromatin, prominent nucleoli and a high nuclear to cytoplasmic ratio.

The cytoplasm of myeloma cells may contain condensed or crystalliCed cytoplasmic

immunoglobulin resulting in the following unusual findings, which are not limited to MM %+'D

EMultiple pale bluish9white, grape9lie accumulations (eg, Mott cells, Morula cells)

8/8/2019 12-09-13 Learning Issues - William Damonte

http://slidepdf.com/reader/full/12-09-13-learning-issues-william-damonte 5/7

E@herry9red refractive round bodies (eg, Aussell bodies)

E!ermilion staining glycogen9rich 7g (eg, lame cells)

E/verstuffed fibrils (eg, "aucher9lie cells, thesaurocytes)

E@rystalline rods

)IAGNOSIS

E*al+ation — 6atients suspected of having multiple myeloma (MM) should initially undergo a complete

history and physical examination. The history should pay specific attention to complaints of bone pain,

constitutional symptoms, neurological symptoms, and infections. The physical examination should include

a detailed neurologic exam.

7n addition, we perform the following laboratory studies as an initial screen to loo for MM %&;9>2'D

E complete blood count and differential with examination of the peripheral blood smear.

E chemistry screen that includes measurements of serum calcium, creatinine, albumin, lactate

dehydrogenase, beta92 microglobulin, and @9reactive protein. ($ee B$taging and prognostic studies

in multiple myelomaB.)

E$erum free monoclonal light chain (8@) analysis.

E serum protein electrophoresis ($6<6) with immunofixation and 1uantitation of immunoglobulins.

($ee BAecognition of monoclonal proteinsB.)

E routine urinalysis and a 209hour urine collection for electrophoresis (#6<6) and immunofixation.

$erum free 8@ analysis may be used in place of a 209hour urine collection in con:unction with

$6<6 and immunofixation for screening purposes only %>'. ?owever, if a plasma cell proliferative

disorder is identified, the #6<6 and immunofixation are necessary. ($ee BAecognition of monoclonal

proteinsB.)

E$erum viscosity should be measured if the M9protein concentration is high (ie, F g=d8) or there

are symptoms suggestive of hyperviscosity. ($ee B<pidemiology, pathogenesis, clinical

manifestations and diagnosis of WaldenstrGm macroglobulinemiaB, section on H?yperviscosity

syndromeH.)

E-one marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and

fluorescence in situ hybridiCation (7$?). lthough a bone marrow evaluation is indicated for all

patients with MM at diagnosis, it may be deferred for persons that are clinically suspected of having

M"#$ with a small monoclonal protein (less than +. g=+** m8), minimal or no abnormalities in

serum free light chains, and no end organ damage.

8/8/2019 12-09-13 Learning Issues - William Damonte

http://slidepdf.com/reader/full/12-09-13-learning-issues-william-damonte 6/7

E metastatic bone survey with plain radiographs including the humeri and femoral bones should be

performed in all patients. 7f patients have a normal bone survey in the setting of bone pain, or have

neurological deficits that may be due to spinal cord compression, additional imaging such as MA7,

@T, or 6<T=@T should be performed to rule out myeloma bone disease. MA7 and 6<T=@T are useful

in patients in whom there is uncertainty about the extent of bone disease, and the role of these

imaging modalities is evolving.

/reatment

Treatment for multiple myeloma is focused on therapies that decrease the clonal plasma cell population and

conse1uently decrease the signs and symptoms of disease. 7f the disease is completely asymptomatic

7n addition to direct treatment of the plasma cell proliferation, bisphosphonates (e.g. pamidronate or Coledronic

acid) are routinely administered to prevent fracturesI they have also been observed to have direct anti9tumor

effect even in patients without nown seletal disease. 7f needed, red blood cell transfusionsor erythropoietin can be used for management of anemia.

 7n recent years, high9dose chemotherapy with autologous hematopoietic stem9cell transplantation has become

the preferred treatment for patients under the age of 3. 6rior to stem9cell transplantation, these patients

receive an initial course of induction chemotherapy. The most common induction regimens used today

are thalidomide Jdexamethasone, borteComib based regimens, and lenalidomide Jdexamethasone.%+0'

%+'  utologous stem cell transplantation ($@T), the transplantation of a patientKs own stem cells after

chemotherapy, is the most common type of stem cell transplantation for multiple myeloma. 7t is not curative, but

does prolong overall survival and complete remission. llogeneic stem cell transplantation, the transplantation

of a healthy personKs stem cells into the affected patient, has the potential for a cure, but is only available to a

small percentage of patients.%++' urthermore, there is a J+*4 treatment9associated mortality rate

6atients over age 3 and patients with significant concurrent illness often cannot tolerate stem cell

transplantation. or these patients, the standard of care has been chemotherapy with prednisone

and melphalan (chemotherapy drug 5rst investigated as a possible treatment for

melanoma but was shown to be ine/ective. However itEs been found to be e/ective

against myeloma. Aecent studies among this population%+3' suggest improved outcomes with new

chemotherapy regimens, e.g. with borteComib.%+&' Treatment with borteComib, melphalan, and prednisone had

an estimated overall survival of >4 at * months, lenalidomide plus low9dose dexamethasone an >24

survival at 2 years and melphalan, prednisone and lenalidomide had a ;*4 survival at 2 years. ?ead9to9head

studies comparing these regimens have not been performed

0. Dierent t'&es of anemiasa. ' si2e( macroc'tic, normoc'tic, macroc'ticb. ' color( h'&erchromic, h'&ochromic

3. 4idne's and red blood cell &roduction

8/8/2019 12-09-13 Learning Issues - William Damonte

http://slidepdf.com/reader/full/12-09-13-learning-issues-william-damonte 7/7

5. one scan vs s6eletal surve' Nuclear medicine bone scans are one of a number of methods of bone imaging, all of

which are used to visually detect bone abnormalities. +uch imaging studies

include magnetic resonance imaging (-I), O#ray computed tomography (@T) and in

the case of Ebone scansE nuclear medicine. However, a nuclear bone scan is afunctional test% it measures an aspect of bonemetabolism or bone remodeling, which

most other imaging techniKues cannot. The nuclear bone scan competes with

the PDM#*&T scan in seeing abnormal metabolism in bones, but it is considerably less

e$pensive.

;. -o7 are l'tic lesions formed8