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CHRONIC MYELOPROLIFERATIVE DISEASES, LEUKOPENIA.
NEOPLASMS OF HEMATOPOIETIC CELLS. MYELODYSPLASTIC
SYNDROMES.
PLASMA CELL DISORDERS.
POLYCYTHEMIA
= increased concentration of RBCs- may be- relative and absolute
Relative: - due to decreased plasma volume
dehydratation, such as due to loss of water in chronic long-lasting vomiting
Absolute:
- primary= increased number of RBCs due to intrinsic abnormal proliferation
of stem cells =polycythemia vera
this disorder is closely related to myeloproliferative syndromes
- secondary= increase in RBS mass in response to an increased stimulation
caused by an increased level of erythropoetin
-may be appropriate- compensatory
- in lung diseases
- in people living for longer period in high-altitude
- in cyanotic heart diseases
or inappropritate- pathological
- for example in erythropoetin secreting tumors, such as renal cell carcinoma
Grawitz,
- in hepatocellular carcinoma
- in cerebellar hemangioma
CHRONIC MYELOPROLIFERATIVE DISEASES
= group of disorders that result from clonal neoplastic proliferations of
multipotent stem cells which may differentiate along one or more pathways
-predominant erythroid differentiation- polycythemia vera
-predominant paltelet differentiation-essential thrombocythemia
-predominant myeloid differentiation-CML
multilineage differentiation is associated with marked marrow fibrosisosteomyelofibrosis (= myeloid metaplasia with myelofibrosis)
 POLYCYTHEMIA VERA
= myeloproliferative disease characterized by excessive proliferation of
erythroid, myeloid and and megakaryocytic elements derived of the
multipotent stem cell and is associated with absolute increase in red blood
cell mass because erythroid proliferation dominates
pathogenesis:
- PV is associated with lower than normal levels of erythropoetin (in
contrast to secondary polycythemias)
- absolute increase in number of stem cells, which are extremely sensitive to
small amounts of erythropoetin- results in erytrocytosis=increased number
of RBCs in PB
morphology:
-RBCs appear normal
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- bone marrow is markedly hypercellular with hyperplasia of all three
components of active hematopoietic marrow, but predominantly of erythroid
elements
-with progression of the disease-BM becomes more fibrotic= myelofibrosis or
BM may be replaced by blasts= leukemic transformation
clinical features:
-occurs in middle-aged patients (4.-6. dec-)
-RBCs count more than 6-10 mil per mm3
-hematocrit more then 60 per cent ( high viscosity of PB)
-total leukocyte and thrombocyte counts also increased
major clinical features - result from an increased blood volume- increased
viscosity-causes vascular stasis- thrombocytic tendency and hemorrhagic
diathesis
patients are plethoric=
and slightly cyanotic ( due to stasis and low oxygenation of slowly circulating
blood)
-liver and spleen enlarged
-possible splenic and renal infarctions-pain
-headaches, GIT symptoms, hematoemesis and melena are common
-high cell turnover may cause hyperurikemia and symptoms of gout ( 5-10%
of patients)
prognosis:
about 30% of patients- die from thrombotic complications ( brain stroke or
IM)
some may have hemorrhagic complications (GIT)
in some the disease may develop to leukemia or OMF
 OSTEOMYELOFIBROSIS (=MYELOID METAPLASIA WITH
MYELOFIBROSIS)
=chronic MP disorder which is characterized by fibrotic obliteration of BM and
metaplastic extramedullary hematopoiesis principally in the spleen
morphology:
-PB variable- moderate to severe normochronic normocytic anemia
white cells may be reduced or increased with a shift to left and few immature
forms
platalet count first normal, but with the progression of the disease- very
apparent thrombocytopenia
-BM- shows diffuse fibrosis and obliteration of BM cavities, first by
hypercellular
ineffective
hematopoiesis
(composed
of
abnormal
megakaryocytes and hyperplastic myeloid elements), later by fibrosis- in this
phase the BM is hypocellular
spleen-markedly enlarged- diffuse extramedullary hematopoeiesisliver-moderately enlarged-foci of EMH
prognosis:
-most patients survive for years- sometimes transfusions are needed
-propensity to intercurrent infections
-thrombotic complications are rare, more common -bleeding disorders due to
platelet abnormalities
-about 10% of patients reveal transformation to AL
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 LEUKOPENIA
=disorder of white cells characterized by decreased numbers of any one of the
specific types of leukocytes, but most often the term implies decreased
neutrophils
=neutropenia=AGRANULOCYTOSIS
=total white cell count is reduced to about 1 thousand and less per
mm3, shortening of life-span of leukocytes ( 6-7 h)
causes:
1) inadequate or ineffective granulopoiesis
-due to suppression of stem cells ( aplastic anemias, variety of
leukemias, lymphomas)
-due to suppression of granulocytic precursors ( for example after
exposure to some drugs, toxins, etc)
-due to BM involvement for example in megaloblastic anemias
2) accelerated removal or destruction of leukocytes
-due to sequestration in the spleen - in hypersplenism-due to immunologically mediated injury to leukocytes- idiopathic or
produced by drugs
-most significant leukopenias develop due to drugs:
-dose-related ( predictable) BM suppressioncaused by alkylating agents and antimetabolites used in cancer treatment
-idiosyncratic- (unpredictable), such as caused by
aminopyrine,
chloramphenicol, chlorpromazine, thiouracil, etc
clinical course:
-fever, chills, weakness, fatique
-infections constitute the major problem (ulcerating necrotizing lesions of the
gingiva, floor of mouth, buccal mucosa,etc)
NEOPLASMS OF HEMATOPOIETIC CELLS: LEUKEMIAS,
CLASSIFICATION FAB, MYELODYSPLASTIC SYNDROMES. PLASMA
CELL DISORDERS.
 LEUKEMIAS
-malignant neoplastic proliferations of hematopoietic cells
-are characterized by diffuse replacement of the bone marrow by neoplastic
cells
-majority of leukemias arise in BM, but in some types of leukemia bone
marrow origin has not been proven as a site of origin- such as hairy cell
leukemia (spleen) and some CLL (lymph nodes)
-in most cases- neoplastic cells are also present in increased numbers in the
peripheral blood
-leukemias are clonal processes that can develop
de novo -primary leukemias
or after bone marrow injury ( after chemotherapy, radiation) or in
myelodystplastic syndromes- secondary leukemias
-hematopoietic tumors are often widespread at presentation- due to
capacity of these cells to circulate by PB
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-hematopoietic tumors do not usually form macroscopically apparent
neoplastic masses, more likely they appear in a form of diffuse enlargement
of the affected organ (liver, spleen)
-benign proliferation of hematopoietic cells are common but benign
hematopoietic tumors probably do not exist at all- in contrast to the
frequency of benign tumors of other tissues
Leukemias are classified in several ways :
1) according to onset and clinical course
1. Acute - sudden onset - rapidly progressive course leading to death
within several months if untreated, usually characterized by primitive cells called blasts
2. Chronic - insidious onset and a slow clinical course, the patients
usually survive several years even if untreated, usually characterized by
more mature neoplastic cells
2) according to the peripheral blood picture
1. leukemic - characterized by elevation of the white blood cell count in
the PB and by the presence of neoplastic cells in the PB
2. subleukemic - total white cell count is normal or lower, but
leukemic ( neoplastic) cells are present in PB
3. aleukemic - total white cell count is normal or lower and no
recognizable leukemic cells are to be found in PB
3) according to cell type
classification according to cell type is the most important of all and it
becomes more complex as new criteria evolve for cell recognition
there are two major groups of leukemias- FAB classification system
A) lymphocytic leukemias (FAB L1-L3)
B) myeloid leukemias- (FAB M1-M7)
-myeloid
-monocytic
-erythroleukemia
-megakaryocytic leukemia
-plasma cell leukemia
-eosinophilic leukemia
MORPHOLOGIC FEATURES COMMON TO ALL LEUKEMIAS
1) Changes directly caused by leukemic infiltration
leukemic cells may infiltrate any tissue or organ, but most striking changes
are seen in:
 bone marrow-red-brown or gray-white color because of complete
replacement of fatty BM by active neoplastic proliferation
-leukemic infiltrates may even erode cancellous or cortical bone
 spleen- massive splenomegaly is characteristic of CML (even more than 510kgs)- the enlarged spleen may virtually fill the abdominal cavity -in CLL
-enlargment of the spleen is less striking ( 2-3 kgs)
-acute leukemias produce only moderate splenomegaly ( 500-1000gs)
histologically:
-focal leukemic infiltrates with preserved normal structure
-in more progressive stages- diffuse massive involvement with total
efacement of underlying architecture (replaced by homogenous infiltration by
leukemic cells)
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 lymph nodes- enlargment is characteristic of some types of lymphocytic
leukemias nevertheless, some infiltration of lymph nodes may be found in
all types of leukemias
histologically:
-obliteration of underlying architecture
 liver- enlargment of the liver is somewhat more prominent in lymphocytic
than in myeloid leukemias
-leukemic infiltrates are characteristically confined to portal areas in
lymphocytic leukemias, whereas in myeloid leukemias, the infiltrates are illdefined (present within sinusoids and portal tracts)
 -infiltration of CNS- of particular importance in ALL
because of protective effect of the blood-brain barrier, the leukemic cells may
survive in the CNS even the chemotherapy and initiate a relapseprophylactic radiation or intrathecal chemotherapy is administrated
2) Secondary changes due to inhibition of normal hematopoiesis
 bleeding diathesis-caused by thrombocytopenia- is the most striking clinical feature common to
all types of leukemias
-hemorrhages may occur at any site, but the most common sites are:
-serosal linings of the bodies cavities
-serosal coverings of the viscera, particularly the lungs and the heart (
subpleural hemorrhages, subpericardial ecchymoses )
-mucosal hemorrhages- most common- into the gingiva, urinary tract
-intraparenchymatous hemorrhages- most important- the brain
 DIC- common in M3- acute promyelocytic leukemia- may lead to bleeding
disorders
infections- - prominent feature- particularly common in oral cavity, lungs,
skin, kidney
 1) ACUTE LYMPHOBLASTIC LEUKEMIA (ALL )= malignant neoplasm
composed of immature blastic elements with lymphoid differentiation
derived of bone marrow stem cell and B- or T-lymphocyte precursors
-primarily it is a disease of small children and young adults
-it constitutes about 80% of acute childhood leukemias
the age peak of about 4 years of age
treatment and prognosis:
-with chemotherapy- more than 90% of children may achieve a
complete remission and more than 60% are alive 5 years later
-adults and children with T-cell ALL or B-cell with involvement of
lymph nodes ( so called leukemic phase of Burkitt lymphoblastoma) - have
poorer prognosis
 2) CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) = malignant lymphoid
neoplasm composed of small mature lymphocytes often with extensive BM
infiltration and peripheral blood involvement
-is characterized by proliferation of small mature lymphocytes
-is the most indolent type of all leukemias
-it accounts for about 25% of all cases of leukemias
-it occurs typically in persons over 50 years of age (age peak 65), males
are affected twice as often as females
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clinical course:
-often asymptomatic in early stage of disease
- patients may present with nonspecific symptoms, such as loss of weight,
anorexia, etc
-in 60% of patients- generalized lymphadenopathy- lymph nodes are
enlarged and reveal histologically a diffuse involvement by small neoplastic
lymphocytes
-hepatosplenomegaly is common
-in all cases- there is absolute lymphocytosis-diffuse infiltration of bone marrow by the same neoplastic cellsnormal hematopoiesis remains present until advanced stage of the disease then reduction of active BM-hemopoesis
prognosis: -extremely variable-depends on clinical stage
-depends on a presence of hemolytic anemia and or
thrombocytopenia
-about 10-15% of patients develop auto-antibodies againts RBCs or platelets
 3) HAIRY CELL LEUKEMIA (HCL) -distinctive form of chronic B-cell
leukemia
-characterized by fine hair-like projections on the surface of neoplastic
cells
-occurs in older adults (50-60%)
-more common in males
morphology:
-PB shows normal white cell count in majority of patients, only about 25% of
patients with HCL show leukocytosis
- PB smears in most cases- presence of „hairy cells“- B-lymphocytederived neoplastic cells- contain tartrate-resistent acid phosphatase ( TRAP)diagnostic for HCL
typical morphologic features:
- bone marrow - infiltration-diffuse- BM shows hypercellularity and diffuse
fibrosis
-leukemic cells in bone marrow- medium-sized, with ovoid
nuclei, fine chromatin pattern and inconspicuous nucleoli, with abundant
cytoplasm, cell membrane shows hairy processes
-massive splenomegaly - diffuse infiltration
-pancytopenia - in over 50% of patients (due to BM infiltration and splenic
sequestration
prognosis: - prognosis is poor- median survival is 4 years
- splenectomy is of benefit in most patients, but results of surgical removal
of the spleen are unpredictable
-disease responds poorly to chemotherapy
 1) ACUTE MYELOID LEUKEMIA (AML)
= is BM-derived neoplasm
composed of myeloblasts and cells differentiating in granulocytic direction
-cell of origin is a granulocytic precursor cell
AML- extremely heterogenous group of leukemias
- most commonly affects persons between 15 and 40 years of age
- AML is characterized by proliferation of neoplastic myeloblasts
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- presence of so called Auer rods ( crystalline cytoplasmic inclusions seen in
PB smears)
when blasts show some degree of maturation into promyelocytes- coarse
azurophilic
granules
and
activity
of
chloracetate-esterase
and
myeloperoxidase appear
Clinical course:
- most patients present with symptoms related to BM failure
-40% have bleeding diathesis
-30% have severe infections
some reveal weight loss, fever, hepatosplenomegaly
most important clinical feature- increase in white cell count with 20-30% of
blasts
AML is classified according to its morphology according FAB classification
system into 7 categories:
M1-M4 - AML - leukemia arises from a multipotent myeloid stem cell in bone
marrow,infiltrates are composed of myeloblasts and promyelocytes
M4= acute myelomonocytic leukemia
-30% of all AMLs- myelocytic and promyelocytic differentiation is
evident
M5= acute monocytic leukemia
-arises from multipotent granulocyte-monocyte precursor,
M6= acute erythroleukemia
-less than 5% of all AMLs- rare- bizarre multinucleated blasts
M7= megakaryoblastc leukemia
-less than 5% of AMLs- pleomorphic undifferentiated blasts reactive
with anti-platelet antibodies ( platelet-glycoprotein)
prognosis:
- about 60-80% of patients achieve complete remission after intensive
chemotherapy -average duration of CR is 1 year
- but long term disease-free survival is likely in only 10-15% of patients
-overall prognosis is worse than that of ALL patients
 2) CHRONIC MYELOID LEUKEMIA (CML) = BM-derived neoplasm
composed of granulocytic cells in various stages of maturation
- cell of origin = pluripotent stem cell, that can differentiate into
myeloid, lymphoid or myelomonocytic cell lines
-this leukemia primarily affects persons between the ages of 20 and 60
-CML accounts for about 15-20% of all leukemis
morphology:
- markedly elevated leukocyte count in PB
typically: presence of Ph chromosome „Philadelphia“ (translocation t9,22)
clinical course and prognosis:
-initial symptoms- weakness, weight loss, fatigue, anorexia
-splenomegaly (hepatomegaly)- left lower chest pain- evidence of
splenic infarctions due to vascular occlusion by aggregates of granulocytes
-bleeding diathesis and anemia may be present
-remissions may be induced by chemotherapy- with busulfan, hydroxyurea
or other oral chemotherapy
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- most pateints experience clinical improvement but Ph chromosome is not
eradicated by this therapy nor is the final progression of disease altered
-most patients are likely to develop acceleration of disease or blast crisis
accelerated phase of CML:
-is characterized by increasing anemia, thrombocytopenia- followed by
blast crisis- transformation to AML
blast crisis:
-may develop abrubtly without previous accelerated phase
-is characterized by increased numbers of undifferentiated blasts in PB and
organs
median survival is 3-4 years
BM transplantation may be of value during the chronic phase of diseaseafter development of blast crisis- all forms of therapy become virtually
ineffective
 MYELODYSPLASTIC SYNDROMES (MDS)
= group of hematopoietic disorders that are characterized by ineffective
and disordered maturation of stem cells in the BM
-patients with MDS have hypercellular BMs but peripheral cytopenias
associated with morphologic abnormaliteis in one or all cell lines
-BM is partly or totally replaced by a clone of stem cells that retain the
capacity to differentiate along all three pathways of maturation, such as into
RBCs, granulocytes, platelets, but in a manner that is both ineffective and
disordered
-MDS do not meet all criteria of malignancy but the stem cell clone has
a tendency to lose an ability to differentiate, thus there is tendency to
transform to AML
Morphologic and pathologic features:
bone marrow biopsy:
- BM is hypercellular- abnormalities in all three components of
hematopoiesis
-disorder of bone marrow topography- that may appear as a
reversal of the usual location of individual components of the BM
normally: myelopoiesis is located peritrabecularly and erythropoiesis in
central areas of bone marrow cavities
-disorder in maturation-megaloblastic erythroid hyperplasia
-hypogranular myeloid precursors
-increased proportion of blasts in BM
-micromegakaryocytes
-unilobed and bilobed neutrophils
- stromal abnormalities- perivascular fibrosis and increased
reticulin
- PB shows pancytopenia
Diagnosis of MDS is based on hypercellular BM with trilineage dysplasia and
peripheral pancytopenia
Clinical features:
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-patients are usually elderly - most cases in 6th and 7th decade of life MDS is rare in individuals under the age of 60 years
in older patients- MDS is likely to occur without a prior history of
chemotherapy or radiation
-in younger people- MDS more often develops after BM injury
(chemotherapy or radiation) = secondary MDS
-more common in males
Prognosis: -the overall median survival is 1-2 years, but MDS are
prognostically diverse group of disorders-one third of patients progress to frank AML
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PLASMA CELL DISORDERS
=this group of disorders is characterized by the proliferation of a single clone
of immunoglobulin-secreting plasma cells
-followed by associated increase in serum levels of single homogenous IgG or
its fragments thus these disorders are referred to as monoclonal
gammopathies
- the monoclonal IgG can be identified in the blood and/or urine of patients
with monoclonal gammopathies - is called M component
-the M component is complete IgG or light chain-called Bence-Jones
protein- because of its small size is excreted in the urine
Variety of clinico-pathologic entities can be differentiated among monoclonal
gammapathies ( MG):
-multiple myeloma
-solitary myeloma
-Waldenstroms macroglobulinemia
 MULTIPLE MYELOMA= plasma cell myeloma= Kahler Disease
=multifocal neoplasm arising in the bone marrow, typically composed of
aggregates of neoplastic mature or immature plasma cells
-most common type of MG
Pathologic features:
bone marrow:
-15-90% of bone marrow may be even replaced by plasma cell
infiltrates -these infiltrates appear as multifocal destructive bone lesions
-diagnostic for MM is massive replacement of marrow by homogenous
sheets of mature or immature plasma cells
-neoplastic plasma cells are monoclonal- they produce the same heavy
and the same light chain of immunoglobulin-individual bone lesions appear as sharply circumscribed destructive defectsany bone may be involved- but most frequently vertebral columns, ribs, skull
kidneys:
-renal involvement- called myeloma nephrosis- in 60-80% of patients
is histologically characterized by
-interstitial infiltrates of abnormal plasma cells or chronic
inflammatory cells in the kidney
-protein casts consisting of albumin, immunoglobulins in distal
collecting tubules often surrounded by multinucleated giant cell
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-metastatic calcifications due to hypercalcemia
-pyelonephritis
systemic changes:
-systemic amyloidosis of AL type may be found in some patients
other organs:
-usually low tendency to progress to extramedullary sites-plasma cell
infiltrates may be encountered in spleen, liver, lungs, nerve trunks, lymph
nodes, etc.
Clinical features and complications:
-more common in males
-the disease is seen most commonly after the age of 50 years- the peak
age incidence of multiple myeloma is between 50 and 60 years of age
-clinical features stem from the effects of infiltration of organs,
particularly the bones and the bone marrow by the neoplastic plasma cells
and by the production of massive amounts of immunoglobulins
- bone pains- most common initial complaint
-abnormal skeletal radiographs- show lytic bone lesions and pathologic
fractures
-hypercalcemia resulting from the bone destruction may give rise to
neurologic complications- confusion, lethargy, weakness
-then weakness, fatique- due to anemia ( in 60% of patients)
-most patients present with M component in the serum and Bence-Jones
protein in the urine, minority show BJ proteinuria alone without serum M
component
-there are recurrent infections- resulting from severe suppression of
normal IgGs
-excessive production and aggregation of myeloma protein may lead to
the hyperviskosity syndrome
-renal insufficiency appears in up to 50% of patients- result s from
multiple factors- but probably the most important one is excretion of light
chains-that are believed to be toxic to epithelial tubular cells
-rarely plasma cells may be found in the peripheral blood- giving rise
to plasma cell leukemia
prognosis:
-depends on the stage of disease at diagnosis
-about 70% patients have good response to chemotherapy- return of
normal hematologic parameters = remision
-but the median survival is 2-3 years
patients with multiple bone lesions, increasing levels of M component and
increased levels of bence-Jones protein-poorer prognosis
death- most common causes include infections and renal failure
 SOLITARY MYELOMA OF BONE
= solitary bone marrow neoplasm consisitin of neoplastic plasma cells
distinctive from the MM
-constitutes about 5% of MG
-elevated levels of M protein in the blood or urine are found in
about 25% of patients
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-it is different from the MM in the absence of anemia or renal involvement
-the solitary bony lesions tend to occur in the same locations as MM and
progress to MM in most cases
 EXTRAMEDULLARY PLASMOCYTOMA
=is a solitary extraosseous lesion composed of neoplastic IgG-secreting cells
-frequently located in the lungs, in the upper respiratory tract (pharynx,
paranasal cavities), rarely seen in oral cavity, stomach
better prognosis than MM
- rarely disseminate, can be cured by local excision
 WALDENSTROM MACROGLOBULINEMIA
-constitutes about 5% of MG and shares some features with MM and
small lymphocytic malignant lymphoma - the M component is usually IgM
type- macroglobulinemia
morphologic features:
-diffuse infiltrates composed of plasma cells, plasmacytoid cells and
lymhpocytes in the marrow- no bone erosions
-tumor cells may be also found in lymph nodes, spleen, liver
clinical features:
-presents usually in older patients- most common between 6th and 7th
decades
-nonspecific complaints, such as weakness, fatigability, weight loss
-approximately 50% of patients have lymphadenopathy, and
hepatosplenomegaly
-macroglobulins greatly increase the viscosity of the blood-giving rise to so
called hyperviscosity syndrome-that is characterized by:
-neurologic problems resulting from the sluggish blood flowheadaches, dizziness, deafness
-bleeding related to hyperviscosity due to dysfunction of platelets
-cryoglobulinemia-abnormal globulins may precipitate at low
temperatures- producing for example Raynaud s syndrome
Prognosis : the average survival with chemotherapy is 2-5 years
 LANGERHANS CELL HISTIOCYTOSIS ( HISTIOCYTOSIS X)
=group of closely related clinicopathologic entities-the term includes eosinophilic granuloma, Hand-Schuller-Christian disease,
and Abt-Letterer-Siwe syndrome
-these three conditions are believed to represent different
clinicopathologic entities of the same basic disorder- they differ with respect
to the extent of organ involvement and the prognosis
-common for all of them- proliferation of neoplastic cells
resembling Langerhans cells-( these are normally present within the
epidermis and are believed to be related to mononuclear phagocytic
system)
three overlapping entities are recognized:
1/ Eosinophilic granuloma (unifocal)
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-unifocal LCH, single site is involved-most commonly bone, lymph node, lung
children and adults may be affected, the most common site- skull
-completely benign lesion
-there are no systemic manifestations, such as fever
2/ Hand-Schuller-Christian syndrome
- represents multifocal Langerhans cell histiocytosis
-onset usually before the age of five years
-fever, a diffuse skin eruptions (skin rash) and multifocal involvement of
bones, mild lymphadenopathy and hepatosplenomegaly
-more aggressive clinical course but better prognosis in contrast to the
acute disseminated form (3), in half of patients the lesions spontaneously
resolve, and in the other half chemotherapy induces recovery
3/ Abt-Letterer-Siwe syndrome
-acute disseminated form of Langerhans cell histiocytosis
-infants and young children under three years of age are affected, sometimes
the disease is present at birth
-multifocal and multiorgan involvement- lymph nodes, liver, skin, and many
other organs may be affected- anemia and thrombocytopenia may be
present
overall prognosis is poor- the course of disease is somewhat related to the
age of onset- infants under 6 months of age generally pursued a rapid course
to death, older children have better chance to survive
-five-year survival is about 50%