Page 480 - Clinical Hematology_ Theory _ Procedures ( PDFDrive )

464 PART 6 ■ Neoplastic Disorders

Secon ry yelof brosis is c use by inf ltr tive isor ers, Another tur tion l bnor lity is the issoci tion o

inclu ing lign ncies n in ections, or exposure to che - nucle r- cytopl s ic tur tion, inclu ing the ount o

ic l toxins or irr i tion. ense gr nules, n the evelop ent o the e rc tion

e br ne syste s well s the occurrence o e peripolesis

Epidemiology (i.e., intern liz tion o he topoietic cells) lre y in i -

ture or eg k ryobl stic ele ents.
P tients with yelof brosis y un ergo te por ry or per - A striking v riety in the ppe r nce o ense gr nules o

nent tr nsition to PRV or y convert to CML. Approxi tely the lph type lso requently exists. T ro bocytes show

one f h o p tients with PRV evelop yelof brosis. gi nt or s with either hypertrophy o the open c n licul r

PMF is unco on, with the nu ber o new c ses esti- syste or n bun nce o ense gr nules n bet glyco-

te t 1,000 to 2,000 per ye r in the Unite St tes or n gen ccu ul tion. Other re rk ble e tures inclu e oc l

over ll r te o 2 per 100,000 worl wi e. T e inci ence o sponge-like proli er tion o the open c n licul r syste

yelof brosis, however, is known to be incre se er expo- in ny o the l rge pl telets n gi nt n use gr nules

sure to irr i tion n che ic ls such s benzene. o the lph n os iophilic type. T ese bnor lities in

Although there h ve been ew reports o p tients in the eg k ryocytes n thro bocytes y h ve cert in unc-

pe i tric popul tion, the jority o p tients with PMF re tion l i plic tions (e.g., he orrh ge n thro bosis) th t

in their l te 50s, 60s, n 70s. It is lso ore co on in the re o en encountere out o proportion to the pl telet counts

white popul tion, n en n wo en re equ lly ecte .
in this isor er.

In ition, those no lies in ic te isorg niz tion
Pathophysiology
o eg k ryopoiesis, which y contribute to the bnor l

PMF is clon l isor er o the ultipotenti l progenitor cell rele se o ctors (pl telet- erive growth ctor n PF4)

co p rt ent. T e bloo - rrow b rrier is isrupte e rly pre o in ntly involve in the process o yelof brosis. It

in the course o yelof brosis, so th t bl st cells n co - h s been postul te th t pl telet- erive growth ctor n

itte ste cells such s colony- or ing unit, gr nulocyte- PF4 re involve in the i b l nce o the ech nis o e -

croph ge (CFU-GM), BFU-E, n colony- or ing unit, ull ry stro inten nce, which triggers the bone rrow

eg k ryocyte (CFU-Meg) cells esc pe into the circul ting yelof brotic process. A rel tionship between the presence

bloo in l rge nu bers. o yelof brosis n bnor l levels o bet thro boglobu-

Sclerosis o the bone evelops in bout h l o p tients. lin, PF4, n itogenic ctivity in pl telet-poor pl s n

However, yelof brosis, the pre o in nt clinic l ni es- pl telet extr cts h s been observe in p tients with PMF.

t tion, occurs secon rily n is not co ponent o the

bnor l clon l proli er tion. T e process o f brosis ensues Karyotype

ro proli er tion o f brobl sts n incre se coll gen pro- Approxi tely 40% o p tients cquire recurrent cytogenetic

uction in re ction to the bnor l clone o he topoietic bnor lities n ne rly 80% cquire nonspecif c berr tions.

cells. Fibrosis is prob bly the result o pro uct secrete by Sever l chro oso l bnor lities re overrepresente

eg k ryocytes. in p tients with yelof brosis. T ese lter tions involve the

I the constituents o the he topoietic icroenviron ent

( yeloi stro ) re ex ine icroscopic lly, n over ll long r o chro oso e 1; onoso y n p rti l eletion
o chro oso es 5, 7, 9, 11, n 13; loss o Y chro oso e;
incre se, p rticul rly in so-c lle un i erenti te (pri itive n triso y o 8, 9, n 21. P rti l triso y 1q is k ryotypic

pluripotent) n lso in tr nsition l (f brobl stic) reticul r ch nge etect ble in unsti ul te peripher l bloo cell cul-

cells n yof brobl sts, c n be observe . Un i erenti te tures or bone rrow cultures, which suggests th t p rti l

n tr nsition l reticul r cells s well s yof brobl sts see triso y 1q is pri ry chro oso e berr tion in yelof -

to or n integr l p rt o the he topoietic icroenvi- brosis n is relev nt to the p thogenesis o this isor er.

ron ent n re ssu e to pl y n i port nt role in the K ryotypic ch nges occur s secon ry events uring the

evolution o ise se-specif c yelof brosis. In ition, the ultistep process o leuke ogenesis. T ere ore, ch nges such

evolution o e ull ry f brosis is thought to be ssoci te s t(5;17) y represent ther py-in uce bnor lity non-

with the striking pre o in nce o l rge, typic l, possibly r n o ly rel te to the ter in l ph se o yeloi isor ers.

over ge n hyperpolyploi eg k ryocytes, but not with Myelof brosis is riven in ost c ses by t le st three genetic

n incre se in precursor cells. lter tions: JAK2V617F, CALR, n MPL. It is urther iversi-

Dysmegakaryocytopoiesis le ing to n overpro uction o

e ective pl telets is the ost const nt e ture o yelof - fe by the cquisition o other geno ic n epigeno ic ber-
r tions: ASXL1, E 2, EZH2, IDH1/2, n SRSF2.
brosis. Rese rch f n ings i ply th t the signif c nt incre se

in circul ting progenitor cells o the eg k ryocyte lin- Clinical Signs and Symptoms

e ge y be gener te by extr e ull ry, prob bly splenic

he topoiesis. One bnor lity o the eg k ryopoiesis P tients with yelof brosis usu lly exhibit progressive ne-

in bone rrow tissue, however, is pronounce pleo or- i , spleno eg ly, n rrow f brosis. Spleno eg ly

phis o the eg k ryocytic cell line consisting o gi nt n so e hep to eg ly re c use by extr e ull ry

or s, icro eg k ryocytes, n n ke (pyknotic) nuclei. he topoiesis. P tients y note e sy bruising or blee ing