Sie sind auf Seite 1von 8

Critical Review

Environmental, lifestyle, and familial/ethnic factors associated with

myeloproliferative neoplasms
Lesley A. Anderson,1 Andrew S. Duncombe,2 Maria Hughes,1 Moyra E. Mills,3 Jessica C. Wilson,1 and
Mary F. McMullin4*
Myeloproliferative neoplasms (MPNs) are characterized by overproduction of mature functional blood cells
and are often associated with an acquired genetic mutation of Janus Kinase 2V617F. The etiology of MPNs
remains unknown. The aim of this article was to review and collate all known published data investigating
environmental and lifestyle factors associated with MPNs. Medline, Embase, PubMed, Cochrane, and Web
of Science were systematically searched using terms for MPNs and observational study designs to identify
studies investigating the risk factors for MPNs published before March 2010. Of 9,156 articles identied, 19
met the selection criteria. Although the studies exhibited heterogeneity, in case denitions, study design,
and risk factors investigated, several themes emerged. A strong association was found with Jewish
descent, and with a family history of MPNs. Autoimmune conditions, specically Crohns disease, were
more common in patients with MPNs. Certain occupational groups were signicantly associated with MPNs
including occupations with potential exposure to benzene and/or petroleum. Blood donation was associ-
ated with an increased risk of polycythemia vera specically. The vast heterogeneity in studies identied as
part of this review suggests that large scale systematic assessment of etiological factors associated with
MPNs is warranted. Am. J. Hematol. 87:175182, 2012. V C 2011 Wiley Periodicals, Inc.

Introduction Despite these recent advances in the identication of gene

Myeloproliferative neoplasms (MPNs) are a group of he- mutations it is likely that environmental and lifestyle factors
matopoietic malignancies resulting from a transformed he- also play a role in the development of MPNs. However, lim-
matopoietic progenitor cell. They are characterized by over- ited research has been conducted in this area. The aim of
production of mature functional blood cells. MPNs were his- this review was to systematically search the literature to iden-
torically termed myeloproliferative disorders and have tify and collate information on potential environmental, life-
undergone numerous amendments in classication. The style, and familial/ethnic risk factors associated with MPNs.
2008 World Health Organisation MPN classication groups Design and Methods
a number of related disorders including the classic MPNs Study selection. A systematic literature search was conducted
polycythemia vera (PV), essential thrombocythemia (ET), using Ovid MEDLINE (US National Library of Medicine, Bethesda,
and primary/idiopathic myelobrosis (PMF) [1] which will be MD), PUBMED (US National Library of Medicine and the National Insti-
the focus of this review. Reported incidence rates vary from tutes of Health, Bethesda, MD), EMBASE (Reed Elsevier PLC, Amster-
0.02 to 2.8 per 100,000 persons [2]. However, incidence dam, The Netherlands), and Web of Science (Thompson Reuters, Phil-
rates are not well characterized and half of all patients are adelphia, USA). The search strategy included broad terms for MPNs
(including specic terms for PV, ET, and myelobrosis) and epidemio-
asymptomatic at diagnosis [1]. PV and ET are indolent neo- logical study designs (including cohort, casecontrol, and cross-sec-
plasms with better prognosis (88% and 92% 3-year sur- tional study terms). The search did not include specic terms for
vival, respectively) compared to PMF which has a 63% 3- chronic myelogenous leukemia (CML) since this is considered a distinct
year survival in the United States [3]. clinical entity. Searches included articles published until end February
An acquired genetic mutation of Janus kinase 2 2010. No language or other restrictions were imposed.
(JAK2)V617F is present in the majority of PV patients and in Five independent researchers initially reviewed the title and abstract
approximately half of patients with ET and PMF [4]. A recent of the articles identied (LAA, MH, MM, JCW, MFMcM). Articles were
study investigating JAK2V617F mutations in 10,507 partici- considered for inclusion if they:
pants of the Copenhagen City Heart Study reported an inci-
dence rate of 171 per 100,000 persons [5]. These partici- 1. included patients with MPNs, specically PV, ET, and/or PMF.
pants had higher overall morbidity and mortality than those 2. were epidemiological studies (i.e., cohort or casecontrol study
who were JAK2V617F negative; however, 28% did not develop
3. included information on exposures/risk factors associated with
any malignancy during the 17.6-year follow-up [5]. Numerous MPNs.
other acquired mutations, for example, JAK2 exon 12 [6] and
mutations in MPL [7], CBL [8], EZH2 [9], LNK [10], TET2, 1
Centre for Public Health, Queens University Belfast, Northern Ireland;
IDH1/2, ASXL1, and IKZF1 [11] have also been identied in 2
Department of Haematology, Southampton University Hospitals Trust,
MPN patients. Inherited germ-line mutations have been United Kingdom; 3School of Nursing and Midwifery, Queens University Bel-
investigated. The 46/1 JAK2 haplotype has been identied as fast, Northern Ireland; 4Centre for Cancer Research and Cell Biology,
a polymorphism occurring in approximately 50% of the popu- Queens University Belfast, Northern Ireland
lation and is associated with a 3.7-fold increased risk of Conict of interest: Nothing to report
developing JAK2V617F associated MPNs [12]. The population *Correspondence to: Mary Frances McMullin, MD, FRCPath, Haematology,
attributable risk of 46/1 JAK2 in PV patients has been esti- Centre for Cancer Research and Cell Biology, The Queens University Bel-
fast, 97 Lisburn Road, Belfast, BT9 7BL, United Kingdom.
mated at 28%, explaining approximately 50% of the E-mail:
increased risk of PV in rst-degree relatives [12]. The GG/ Received for publication 30 September 2011; Accepted 30 September 2011
CC genotype at JAK2 rs10974944 has been associated with Am. J. Hematol. 87:175182, 2012.
an almost 2.8-fold increased risk of familial MPN [13]; how-
Published online 11 October 2011 in Wiley Online Library (
ever, other germ-line mutations remain to be identied [14]. DOI: 10.1002/ajh.22212

C 2011 Wiley Periodicals, Inc.

American Journal of Hematology 175

critical review

Observed/Expected 1.81 (95% CI 0.873.33)

Observed/Expected 2.38 (95% CI 1.144.38)

The nal articles identied were screened by two independent inves-

incidence in population of 2 per 100,000

tigators (LAA, MFMcM) to ensure all criteria were met and discrepan-

Signicant with a 5-year latency period:

cies were resolved by discussion.

120 per 100,000 compared to crude

Data extraction. Information regarding study design, study year,

[PMR 10.9 (95% CI 1.485.0)]

number of patients with MPNs, types of MPNs included, cohort/com-

Observed only in males: [SMR

Particularly non-white females:

SMR 455 (95% CI 1201,164)
parison group (number in group), exposures, and associated risk esti-

SMR 62.5 (95% CI 7.6226)

PMR 4.9 (95% CI 1.417.2)

SMR 201 (95% CI 41588)

mates were extracted from the articles.

PMR 405 (not signicant)

PMR 163 (not signicant)

105 (95% CI 13378)]

Analysis. As there was signicant heterogeneity, in the denition
of cases, study design, and risk factors investigated, a meta-analysis
was not conducted. Instead, studies were grouped according to study
design (casecontrol versus cohort) and the potential factors identied
and subjected to qualitative descriptive analysis. A table summarizing
the main risk factors identied for MPNs and the strength of evidence
associated with each factor was produced.
A total of 6,315 articles underwent initial screening after
exclusion of duplicates (n 5 2,841). Of the 51 full text
Polycythemia vera (n 5 4)

Polycythemia vera (n 5 2)
No cases of Myelobrosis
Myelobrosis (n 5 3)

Myelobrosis (n 5 3)

Myelobrosis (n 5 2)
articles screened 19 met the inclusion criteria. These stud-
Polycythemia vera

Polycythemia vera

ies were categorized into cohort (n 5 6) and casecontrol


(n 5 13) studies and are presented in Tables I and II,

Family history
Four observational studies investigated family history of
MPNs [2224,26]. Najean et al. reported an excess of PV
and ET in families compared to the reference population
[22]. Landgren et al. similarly reported increased risk of
members of the meatcutters

MPN, PV, and ET in relatives of patients with MPN, PV, or

Petroleum Renery workers

36,795 active blood donors

ET [24]. Relatives with female probands had a signicantly

Poultry workers who were
Funeral service workers

of parathyroid glands
Commercial Pressmen

Patients with adenoma

union (n 5 28,900):

higher risk of MPN than those of male probands [24]. This


was not supported in the study by Giles et al. where having

(n 5 20,169)

a son with a MPN increased the risk of MPN 50-fold [26],

(n 5 5,265)
(n  2,500)

(n 5 101)

Table II. Hemminki and Jiang reported a higher risk of PV

in patients with a parent with PV, lymphatic and myeloid
leukemia, or breast cancer [23].
No signicant associations were reported between PV
and having a parent/sibling with a cancer in any of the fol-
lowing sites: oral, stomach, colon, rectum, pancreas, lung,
Cancer incidence

cervix, endometrium, prostate, kidney, bladder, melanoma,

until 1981

until 1980

until 1986

until 1985

until 1992

until 2003






skin, nervous system, connective tissue, non-Hodgkin lym-

phoma, or Hodgkin lymphoma [23].
Jewish decent
Two studies investigated Jewish decent as a risk factor
for MPNs [21,22]. Najean et al. reported that 5.8% of PV
cases were of Jewish decent compared to 3% in the refer-






ence population in France [22]. Chaiter et al. reported that


81.2% of patients with MPNs in Northern Israel had Ashke-

nazi Jewish decent compared to 32.5% in the reference
population [21].
32 USA states and District of Columbia

PMR, proportional mortality ratio; SMR, standardized mortality ratio.

Of the six cohort studies identied, signicantly higher

states and New York City (death

mortality rates from PV and/or myelobrosis were reported

certicates); National Funeral
funeral directors), USA; Nine
(Licensing boards and state
Representative cohort of USA

in poultry workers [20], commercial pressmen [15], and pe-

New York City, Long Island,
Study location

troleum renery workers [16] compared to the reference

Directors Association
petroleum reneries

populations, Table I. Funeral service workers also appeared

New Jersey, USA

Southern Stockholm

to have a higher risk of PV but this did not reach statistical

Baltimore, USA

signicance [18].
Four casecontrol studies investigated occupational
Udine, Italy

groups associated with ET [30,31] or MPNs [26,28], Table

II. Mele et al. reported an association with working with
electrical devices only [30], Table II. ET patients were also
more likely than controls to have been cooks/waiters and
TABLE I. Cohort Studies

clerks [31], Table II. Agricultural workers have been

Johnson et al., 2010 [20]
Pizzolito et al., 1997 [19]
Kaplan et al., 1986 [16]

reported to have a higher risk of developing myeloprolifera-

Hayes et al., 1990 [18]
Zoloth et al., 1986 [15]

Merk et al., 1990 [17]

tive syndromes [28]. In an Australian casecontrol study of

myelobrosis and PV combined, rural sector jobs (process
and production workers/tradesmen, metal workers, and
farmers/farm workers) were more common in these

patients compared to controls [26], Table II. Other occupa-

tions investigated including professional, administrative,

176 American Journal of Hematology

TABLE II. CaseControl Studies

Article Study location Year Cases Controls Exposure Results

Jewish decent/Family history

Chaiter et al., 1992 [21] Hospital-based case 19751989 Agnogenic myeloid Jewish population (Northern Israel) Ashkenazi Jewish decent 81.2% in MPD patients compared to
series, Northern metaplasia, essential 32.5% in population
Israel throbocythemia. Urban residence 24 per 100,000 in MPD compared to
Polycythemia vera 11.5 per 100,000 in population.
(n 5 339)
Najean et al., 1998 [22] France 19801990 Polycythemia vera Reference population (Iie-de-France Blood donors 21% in PV patients compared to 8% in
(n 5 842) region; Aube, Eure-et-Loir, Yonne.) reference population (Blood
Data from 1990 French census, cause Transfusion data)
of death register (1990), risk of cancer Excess of PV and ET in families 11 per 100,000 observed in PV patients
in adult population and National compared to 12 per 100,000
Transfusion Center, National Jewish expected in reference population.

American Journal of Hematology

Consistory, Paris Chamber of Jewish origin 5.8% in PV patients compared to 3% in
Commerce, blood donation, religion, population
occupations in region.
Hemminki et al., 2001 [23] Sweden 19752000 PV (n 5 90170 cases Observed compared to expected rates in Parent of PV case: Breast SIR 1.61 (95%CI 1.002.38)
per year) database of all Swedes born since Lymphatic and myeloid leukemia SIR 2.52 (95%CI 1.004.73)
1932 based on age, period, PV SIR 10.9 (95%CI 3.9221.3)
residence, sex and socioeconomic
Landgren et al., 2008 Sweden 19582005 Myeloproliferative 4 population-based controls matched on First degree relatives
(MPN, PV, ET) [24] neoplasm gender, age, birth year and county of
(n5 11,039): residence.
PV (n 5 6,217) MPN patients MPN (RR 5.6 95% CI 3.88.2)
ET (n 5 2,838) PV (RR 5.7 95% CI 3.89.1)
ET (RR 7.4 95% CI 3.714.8)
MF (n 5 1,172) PV patients MPN (RR 4.9 95% CI 3.17.8)
PV (RR 6.0 95% CI 3.311.0)
ET (RR 5.4 95% CI 2.213.2)
Not otherwise specied ET patients MPN (RR 6.8 95% CI 3.413.5)
(n 5 812) PV (RR 5.4 95% CI 2.213.1)
ET (RR 8.8 95% CI 2.624.5)
Occupation/chemical exposures
Quiroga Micheo et al., Argentina 19731980 Myeloproliferative Non-neoplastic frequency matched Petroleum P 5 0.02
1981 [25] disorders: CML (age, gender) from same
n 537; PV n 5 10; hospitals. N 5 603
Agnogenic myeloid
metaplasias n54
Giles et al., 1984 [26] Tasmania, Australia 19721980 Myeloproliferative Electoral rolls (mandatory after Rural sector jobs (males) RR 2.25 (95% CI 1.21-3.8)
including Myelobrosis 6 months residence) (n 5 530) Process and production workers/ RR 2.76 (95% CI 1.54-5.72)
(n 5 28), Polycythemia tradesmen
vera (n 5 46) Metal workers (>55 years) RR 3.0 (95% CI 1.0410.6)
Farmers/farm workers (male) RR2.57 (95% CI 1.355.44)
First degree relative (males) RR5.17 (P < 0.05)
Brother with MP (males) RR 14.81 (P < 0.01)
Son with MP (males) RR 50.00 (P < 0.05)
First degree relative (females) RR 5.21 (P < 0.01
Daughter with MP (females) RR 5.21 (P < 0.05)
Lickiss et al., 1984 [27] Tasmania, Australia 19721980 Myeloproliferative Electoral rolls (mandatory after Rural residence (males: 05 years) RR 2.32 (95% CI 1.293.78)
including 6 months) (n 5 530) Rural residence (females: 05 yrs) RR 1.43(95% CI 0.523.19)
Myelobrosis (n 5 regional areas investigateda
28), Polycythemia
rubra vera (n 5 46)
Pasqualetti et al., 1991 [28] Italy - Myeloproliferative Matched controls from same geographic Agricultural work Increased risk, P < 0.05
syndromes (n 5 44) area, affected with medical diseases
except cancer/congenital diseases
(n 5 620)
critical review

TABLE II. Continued

Article Study location Year Cases Controls Exposure Results

critical review

Terreros et al., 1997 [29] Argentina 19931995 Myeloproliferative 163 age and sex matched controls from Some environmental/ occupational OR 0.95 (95%CI 0.118.00)
syndrome (n 5 9) a public hospital exposure
Benzene OR 46.6 (95% CI 2.022761)
Mele et al., 1996 [30] Italy 19861990 Essential Hospital outpatients with no Shoemaker AOR 2.7 (95% CI 0.516.0)
thrombocythemia haematologic disorders (n 5 156) Agricultural worker AOR 1.0 (95% CI 0.34.0)
(n 5 39) Electrical worker 5.1% cases, 0% controls (P 5 0.004)
Tuff house (>9 years) AOR 5.1 (95% CI 1.222.1)
Dark hair dye (>10 years) AOR 5.3 (95% CI 1.419.9)
No signicant associations were
observed with other occupational
groups, diagnostic/therapeutic X-rays,
family history of malignancy, use of
herbicides and pesticides, residence
in countryside, contact with pet and/or
farm animals, smoking or drinking.
Falcetta et al., 2003 [31] Italy 19902000 Essential Random population controls (n 5 280) Cooks/waiters OR 4.96 (95% CI 1.5916.9)
thrombocytemia Clerks OR 2.63 (95% CI 1.534.51)
(n 5 93) Hairdressers OR 5.10 (95% CI 0.8231.4)
Nurses OR 3.75 (95% CI 0.8019.4)
Farmers OR 1.74 (95% CI 0.843.56)
Electricians OR 1.42 (95% CI 0.483.78)
Photographers OR innity
Anderson et al., 2009 [32] SEER-Medicare USA 2001/2002 Polycythemia vera and Frequency matched, randomly selected Autoimmune hemolytic anemia OR 11.9 (95% CI 4.7230.2)
chronic Medicare subjects without cancer Localized scleroderma OR 2.34 (95% CI 1.025.37)
myeloproliferative (n 5 160 086) Crohns disease OR 2.18 (95% CI 1.014.71)
disease (n 5 1,017)
Kristinsson et al., 2010 [33] Sweden 19582005 Myeloproliferative 4 population-based controls matched on Myeloproliferative neoplasm
neoplasm gender, age, birth year and county of Any autoimmune disease
(n 5 11,039) residence. Idiopathic thrombocytopenic purpura
PV (n 5 6,217) Crohns OR 1.2 (95% CI 1.01.3)
ET (n 5 2,838) Polymyalgia rheumatica OR 2.9 (95% CI 1.27.2)
MF (n 5 1,172) Giant cell arteritis OR 1.8 (95% CI 1.13.0)
NOS (n 5 812) Reiters syndrome OR 1.7 (95% CI 1.22.5)
Aplastic anemia OR 5.9 (95% CI 2.414.4)
Polycythemia vera OR 15.9 (95% CI 1.8142.0)
Giant cell arteritis OR 7.8 (95% CI 3.716.7)
Aplastic anemia
Essential thrombocythemia OR 3.9 (95% CI 1.015.8)
Any autoimmune disease OR 5.9 (95% CI 1.721.0)
Polymyalgia rheumatica OR 1.2 (95% CI 1.01.6)
Giant cell arteritis OR 3.3 (95% CI 1.37.9)
Primary myelobrosis OR 2.3 (95% CI 1.34.2)
Giant cell arteritis OR 7.8 (95% CI 1.442.4)
OR 31.7 (95% CI 4.0253.6)
OR 3.3 (95% CI 1.010.8)

AOR, adjusted odds ratio; OR, odds ratio; RR, relative risk; PV, polycythemia vera; ET, essential thrombocythemia; MF, myelobrosis; MPD5myeloproliferative disorder.

American Journal of Hematology

critical review
clerical, sales, mining, transportation/communication, serv- opinion as to which occupations posed the highest risk of
ice industries, foundry workers, food and beverage workers, developing MPNs.
and hairdressers were not associated with myeloprolifera- Inherited germ-line mutations including the 46/1 JAK2
tive disorders [26]. Pasqualetti et al. reported no signicant haplotype [12] and the GG/CC genotype at JAK2
association between some environmental/occupational ex- rs10974944 [13] have been identied in patients with
posure" and myeloproliferative syndrome [28]. Najean et al. MPNs. Case studies have reported familial clustering of PV
also investigated occupation but there was no control group [3437] and ET [3841]. There have also been strong
or population statistics for comparison [22]. associations reported between Jewish decent and risk of
Chemical exposure MPNs but only to observational studies were identied
Chemical exposure was investigated by ve casecontrol [21,22]. Although further investigation of other potential
studies [25,2830]. Terreros et al. reported an almost 50- germline mutations is warranted, shared environmental and
fold increased risk of myeloproliferative syndrome in per- lifestyle factors may contribute to the excess risk observed
sons exposed to benzene [29]. Petroleum was also report- in patients with a family history of MPNs or of Jewish
edly associated with an increased risk of myeloproliferative decent.
disorders including CML [25], Table II. Conversely, Pasqua- Autoimmune conditions have been associated with the
development of myeloid neoplasms, including MPNs
letti et al. reported that exposure to a number of chemicals,
[32,33]. Interestingly, both the Swedish and USA studies
including pesticides, fertilizers, paints, and aromatic hydro-
identied reported an association between Crohns disease
carbons, e.g., benzene were not associated with myelopro- and MPNs [32,33]. A single nucleotide polymorphism in
liferative syndromes [28]. Mele et al. reported that using JAK2 (rs10758669) has been identied in both PV patients
dark hair dye for more than 10 years was signicantly asso- [42] and patients with Crohns disease [43], suggesting a
ciated with an increased risk of ET [30]. However, in a shared somatic mutation. Giant cell arteritis was associated
more recent publication no signicant associations were with PV, ET, and PMF in the Swedish study even when the
reported between ET and the use of hair dyes, pesticides, 5-year period preceding diagnosis of MPN was excluded
solvents, or dichlorodiphenyltrichloroethane [31]. [33]. Only a few case reports have been published in the lit-
Residence erature [44,45]. It has been suggested that ophthalmic cir-
In an Australian study, males living in a rural residence culation may be affected by high platelet counts and could
for 05 years had a higher risk of myeloproliferative disor- explain an increased risk of giant cell arteritis in patients
ders compared to controls [27], Table II. Interestingly, in an with MPN [45]. Based on the evidence to date, it is not
Italian casecontrol study living in a tuff house (a house possible to determine whether autoimmune conditions are
made from a volcanic porous material that emits gamma risk factors for MPNs or co-occur through similar pathways.
radionucleotides and radon) for more than 9 years was The majority of studies in this review investigating occu-
more common in ET patients than controls [30], Table II. pational exposures, including commercial pressmen [15],
Medical conditions shoe makers [30], and poultry workers [20] and MPNs sug-
A number of autoimmune conditions have been investi- gested benzene as a potential contributing factor. Addition-
gated in association with MPNs [32,33], specically PV, ET, ally, an excess risk of myelobrosis has been reported in
and PMF [33]. Only those reaching statistical signicance motor vehicle drivers (P < 0.05) and workers in car trans-
are reported in Table II. Crohns disease was associated port (P < 0.05), other road transport (P < 0.05) and railway
with myeloproliferative disorders in both the Swedish [33] sectors (P < 0.05) [46] which the authors attribute to ben-
and USA studies [32], Table II. In the Swedish study, only zene exposure from petrol. Wolff also reported a signicant
correlation between car ownership and excess risk of mye-
giant cell arteritis was associated with PV, ET, and PMF
loproliferative disease in a UK-based ecological study [47].
[33], Table II. In the cohort study by Pizzolito et al. males
However, only one small study (n 5 9) in the review speci-
with adenoma of the parathyroid gland had an increased
cally investigating benzene exposure and myeloproliferative
risk of PV [19], Table I.
syndrome demonstrated a signicant association [29]. Con-
Blood donation versely, Pasqualetti et al. reported no association between
In a cohort of active blood donors from Southern Stock- aromatic hydrocarbons, which contain one or more ben-
holm, the incidence of PV was higher than expected more zene rings, and MPNs in a study of 44 MPN patients [28].
than 5 years after blood donation [17], Table I. Blood Benzene is primarily produced from petroleum which has
donors in France were also reported to have higher rates also been associated with an increased risk of PV, ET [16]
of PV compared to the reference population (21% vs. 8%, and myeloproliferative disorders [25]. Gall rst reported a
respectively) [33], Table II. case of myeloid metaplasia (now termed PMF) in a patient
Discussion with benzene poisoning in 1938 [48]. Subsequently, ben-
This systematic review of the literature identied a zene has been reported to be associated with an increased
diverse range of studies investigating potential environmen- risk of PMF in numerous case reports [46,4953]. The
tal, lifestyle, and familial/ethnic risk factors associated with effects of benzene on risk of developing MPNs require fur-
MPNs. However, it was clear that there was signicant het- ther investigation collecting information on levels of expo-
erogeneity in the denition of cases, study design, and risk sure, time, and duration of exposure and use of protective
factors investigated. Additionally, several of the studies equipment.
were limited by small sample sizes limiting their power to Agricultural work has been associated with MPNs in
detect modest associations between potential risk factors some [26,28], but not all [30], studies. Exposure to carcino-
and MPNs. Despite this several potential etiological themes genic substances varies by type and location of farming
emerged, Table III. The strongest evidence was for an causing difcultly in the identication of key carcinogenic
increased risk of MPNs in those with a family history of compounds. The studies identied in the review were lim-
MPNs and those of Jewish decent. There was some evi- ited by small sample sizes limiting their power to detect sig-
dence to suggest an association between Crohns disease nicant associations and the ability to conduct stratied
and MPNs but the nature of this association requires fur- analyses based on type of farming or exposure.
ther investigation. Several occupational groups were investi- Radiation exposure is strongly associated with leukemia
gated across studies but there was limited consensus of [54]. Mele et al. reported an increased risk of ET in per-

American Journal of Hematology 179

critical review
TABLE III. Summary of Environmental and Lifestyle Factors Associated With Myeloproliferative Neoplasms (MPNs) Including Polycythemia Vera (PV),
Essential Thrombocythemia (ET), and Primary Myelobrosis (PMF)

Studies demonstrating no Strength of evidence

Studies showing excess risk excess risk of MPN (-5 none,* some, **5 weak,
Risk factor of MPN (MPN group) (MPN group) *** 5 moderate, **** 5 strong)

Jewish ancestry/Family history

Jewish ancestry Najean et al., 1998 (PV) [22] ****
Chaiter et al., 1992 (PV, ET) [21]
Family history Najean et al., 1998 (PV) [22] Mele et al., 1996 [30] ****
Hemminki et al., 2001 (PV) [23]
Landgren et al., 2008 (MPN, PV, ET) [24]
Giles et al., 1984 (PV/PMF) [26]
Commercial pressmen Zoloth et al., 1986 (PMF) [15] *
Petroleum renery workers/petroleum Kaplan et al., 1986 (PV, PMF) [16] *
Quiroga Micheo et al., 1980 (MPN) [25]
Funeral service workers Hayes et al., 1990 (PV, PMF) [18] -
Poultry workers Pizzolito et al., 1997 (PV) [19] *
Johnson et al., 2010 (PMF) [20]
Cooks/waitors Falcetta et al., 2003 (ET) [31] *
Clerks Falcetta et al., 2003 (ET) [31] *
Hair dressers Falcetta et al., 2003 (ET) [31] -
Mele et al., 1996 (ET) [30]
Nurses Falcetta et al., 2003 (ET) [31] -
Photographers Falcetta et al., 2003 (ET) [31] *
Child care worker Mele et al., 1996 (ET) [30] -
Shoemaker Mele et al., 1996 (ET) [30] -
Electrical worker Falcetta et al., 2003 (ET) [31] -
Mele et al., 1996 (ET) [30]
Agricultural work Pasqualetti et al., 1991 (MPN) [28] Falcetta et al., 2003 (ET) [31] *
Giles et al., 1984 (PV/PMF) [26] Mele et al., 1996 (ET) [30]
Metal workers Giles et al., 1984 (PV/PMF) [26] *
Process/production workers Giles et al., 1984 (PV/PMF) [26] *
Painter Mele et al., 1996 (ET) [30] -
Benzene/Hydrocarbons Terreros et al., 1997 (MPN) [29] Pasqualetti et al., 1991 (MPN) [28] *
Herbicides/pesticides/solvents Falcetta et al., 2003 (ET) [31] -
Mele et al., 1996 (ET) [30]
Radiation Najean et al., 1998 (PV) [22] -
Mele et al., 1996 (ET) [30]
Autoimmune conditions
Autoimmune hemolytic anemia Anderson et al., 2009 (MPN) [32] *
Localised scleroderma Anderson et al., 2009 (MPN) [32] *
Crohns disease Anderson et al., 2009 (MPN) [32] **
Idiopathic thrombocytopenic purpura Kristinsson et al., 2010 (MPN) [33] *
Polymyalgia rheumatic Kristinsson et al., 2010 (MPN, ET) [33] Anderson et al, 2009 (MPN) [32] *
Giant cell arteritis Kristinsson et al., 2010 (MPN, PV, ET, PMF) [33] Anderson et al, 2009 (MPN) [32] *
Reiters syndrome Kristinsson et al., 2010 (MPN) [33] *
Aplastic amenia Kristinsson et al., 2010 (MPN, PV, ET) [33] *
Psoriasis Kristinsson et al., 2010 (PMF) [33] Anderson et al, 2009 (MPN) [32] *
Blood donation Merk et al., 1990 (PV) [17] *
Najean et al., 1998 (PV) [22]
Patients with adenoma of parathyroid glands Pizzolito et al., 1997 [19] *
Rural residence Lickiss et al., 1984 (PV/PMF) [27] Chaiter et al., 1992 (PV/ET) [21] *
Pasqualetti et al., 1991 (MPN) [28]
Mele et al., 1996 [30]
Alcohol/tobacco Pasqualetti et al., 1991 (MPN) [28] -
Mele et al., 1996 [30]
Dark hair dye use Mele et al., 1996 (ET) [30] Falcetta et al., 2003 (ET) [31] *
Contact with animals Mele et al., 1996 (ET) [30] -

sons living in tuff houses which contain gamma-emitting ra- tions between occupational exposures and risk of MPNs.
dionuclides [30]. Additionally, PV has been reported in four In-depth investigation of occupational exposures, duration
cases (two conrmed, two suspected) exposed to radiation of exposure, usage of protective equipment, and other
during a nuclear weapons test in 1981, which exceeded the health and safety measures undertaken may help to deter-
expected number of cases [55]. However, Najean et al. mine which occupational exposures are truly associated
concluded that radiation exposure was not associated with with an increased risk of MPNs.
PV in a cohort of 842 cases [22]. Although no comparison A higher incidence of PV has been reported in blood
group was available, only four PV cases had frequent radia- donors [17,22]. There are a number of potential explana-
tion for pulmonary tuberculoisis and six had occupations tions for this apparent association. Firstly, increased blood
with potential radiaiton exposure [22]. Additionally, in Eng- screening in donors may lead to a diagnosis of an other-
land and Wales no correlation was observed between ra- wise asymptomatic MPN. Secondly, patients with high full
don levels and myeloproliferative disorders in an ecological blood counts may be more likely to be deemed suitable for
study [56]. The studies to date do not provide any conclu- blood donation. Finally, blood donation may lead to
sive evidence that radiation exposure is a strong risk factor increased erythrocyte proliferation which may be associated
for MPNs. The heterogeneity of exposure both within and with an increased risk of PV. Retrospective large scale
between occupations may mask some potential associa- investigation of blood donation in patients with PV and

180 American Journal of Hematology

critical review
other MPNs, including blood counts, frequency, and dura- 16. Kaplan SD. Update of a mortality study of workers in petroleum reneries. J
Occup Med 1986;28:514516.
tion of blood donation, may shed further light on the poten-
17. Merk K, Mattsson B, Mattsson A, et al. The incidence of cancer among blood
tial mechanisms behind this association. donors. Int J Epidemiol 1990;19:505509.
This systematic review included broad search terms for 18. Hayes RB, Blair A, Stewart PA, et al. Mortality of U.S. embalmers and funeral
MPNs and observational study designs to identify as many directors. Am J Ind Med 1990;18:641652.
published articles as possible. Foreign language articles 19. Pizzolito S, Barbone F, Rizzi C, et al. Parathyroid adenomas and malignant
neoplasms: coincidence or etiological association? Adv Clin Path
were included in the study and multiple databases were 1997;1:275280.
searched. In addition, the authors also reviewed the refer- 20. Johnson ES, Zhou Y, Lillian Yau C, et al. Mortality from malignant diseases-
ence lists of identied articles for further studies not identi- update of the Baltimore union poultry cohort. Cancer Causes Control
ed as part of the review. Unfortunately, it is not possible to 2010;21:215221.
21. Chaiter Y, Brenner B, Aghai E, Tatarsky I. High incidence of myeloproliferative
preclude the possibility that studies were not identied if disorders in Ashkenazi Jews in northern Israel. Leuk Lymphoma 1992;7:251
MPNs were one of a number of conditions investigated and 255.
not reported on in the main article. 22. Najean Y, Rain JD, Billotey C. Epidemiological data in polycythaemia vera: A
Despite recent advances in the identication of somatic study of 842 cases. Hematol Cell Ther 1998;40:159165.
23. Hemminki K, Jiang Y. Familial polycythemia vera: Results from the Swedish
and germline mutations in patients with MPNs, environmen- Family-Cancer Database [7]. Leukemia 2001;15:13131315.
tal and lifestyle risk factors are likely to play a large role in 24. Landgren O, Goldin LR, Kristinsson SY, et al. Increased risks of polycythemia
the development of these conditions. Evidence collated as vera, essential thrombocythemia, and myelobrosis among 24,577 rst-
part of this review suggests that some occupational expo- degree relatives of 11,039 patients with myeloproliferative neoplasms in Swe-
den. Blood 2008;112:21992204.
sures may be associated with MPNs. However, more in-
25. Quiroga Micheo E, Calcagno EJ, Calabria SI, et al. Retrospective epidemio-
depth investigation of levels and duration of exposure and logical study of hemopoietic system neoplasms in Argentina. Medicina
use of protective equipment are required. The relation 1981;41:187200.
between autoimmune conditions and MPNs requires further 26. Giles GG, Lickiss JN, Baikie MJ. Myeloproliferative and lymphoproliferative
investigation to determine whether shared genetic path- disorders in Tasmania, 197280: Occupational and familial aspects. J Natl
Cancer Inst 1984;72:12331240.
ways are responsible for the excess risk reported in large 27. Lickiss JN, Giles GG, Baikie MJ, et al. Myeloproliferative and lymphoprolifera-
population-based studies and specically for the associa- tive disorders in Tasmania, 197280: Patterns in space and time. J Natl Can-
tion with Crohns disease. The limited number and hetero- cer Inst 1984;72:12231231.
geneity of published studies investigating other environmen- 28. Pasqualetti P, Casale R, Colantonio D, Collacciani A. Occupational risk for
hematological malignancies. Am J Hematol 1991;38:147149.
tal and lifestyle risk factors suggest that a well-designed, 29. Terreros MC, Apezteguia M, Slavutsky IR, Guimarey LM. Exposure to occu-
large coordinated epidemiological investigation should be pational and environmental risk factors in hematologic disorders. Neoplasia
conducted. 1997;14:133136.
30. Mele A, Visani G, Pulsoni A, et al. Risk factors for essential thrombocythe-
Author Contributions
miaA casecontrol study. Cancer 1996;77:21572161.
LAA, ASD, and MFMcM designed the study. All authors 31. Falcetta R, Sacerdote C, Bazzan M, et al. Occupational and lifestyle risk fac-
were involved in the review of titles and abstracts, com- tors for essential thrombocytemia: A casecontrol study. G Ital Med Lav
mented on article drafts, and approved the nal version of Ergon 2003;25:912.
the manuscript. 32. Anderson LA, Pfeiffer RM, Landgren O, et al. Risks of myeloid malignancies
in patients with autoimmune conditions. Br J Cancer 2009;100:822828.
References 33. Kristinsson SY, Landgren O, Samuelsson J, et al. Autoimmunity and the risk
1. Tefferi A, Vardiman JW. Classication and diagnosis of myeloproliferative neo- of myeloproliferative neoplasms. Haematologica 2010;95:12161220
plasms: The 2008 World Health Organization criteria and point-of-care diag- 34. Manoharan A, Garson OM. Familial polycythaemia vera: A study of 3 sisters.
nostic algorithms. Leukemia 2008;22:1422. Scand J Haematol 1976;17:1016.
2. Kutti J, Ridell B. Epidemiology of the myeloproliferative disorders: Essential 35. Ratnoff WD, Gress RE. The familial occurrence of polycythemia vera: Report
thrombocythaemia, polycythaemia vera and idiopathic myelobrosis. Pathol of a father and son, with consideration of the possible etiologic role of expo-
Biol 2001;49:164166. sure to organic solvents, including tetrachloroethylene. Blood 1980;56:233
3. Kutti J. Platelet production rate in polycythemia vera after myelosuppressive 236.
therapy. Acta Med Scand 1972;192:161164. 36. Nielsen H, Nordin H. Polycythemia vera in a Danish family. Ugeskr Laeger
4. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine 1991;153:20722073.
kinase JAK2 in human myeloproliferative disorders. Lancet 2005;365:1054 37. Inaba T, Shimazaki C, Hirai H, et al. Familial polycythemia vera in father and
1061. daughter. Am J Hematol 1996;51:172.
5. Bojesen SE, Nielson C, Birgens H, et al. JAK2 V617F mutation positives in 38. Schlemper RJ, Vandermaas APC, Eikenboom JCJ. Familial essential throm-
the general population. J Clin Oncol 2010;28:6599. bocythemiaClinical characteristics of 11 cases in one family. Ann Hematol
6. Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia 1994;68:153158.
vera and idiopathic erythrocytosis. N Engl J Med 2007;356:459468. 39. Eyster ME, Saletan SL, Rabellino EM, et al. Familial essential thrombocythe-
7. Pardanani AD, Levine RL, Lasho T, et al. MPL515 mutations in myeloprolifer- mia. Am J Med 1986;80:497502.
ative and other myeloid disorders: A study of 1182 patients. Blood 40. Wiestner A, Padosch SA, Ghilardi N, et al. Hereditary thrombocythaemia is a
2006;108:34723476. genetically heterogeneous disorder: Exclusion of TPO and MPL in two fami-
8. Grand FH, Hidalgo-Curtis CE, Ernst T, et al. Frequent CBL mutations associ- lies with hereditary thrombocythaemia. Br J Haematol 2000;110:104109.
ated with 11q acquired uniparental disomy in myeloproliferative neoplasms. 41. Yagisawa M, Kamizaki K, Nagase T, et al. Familial essential thrombocythemia
Blood 2009;113:61826192. in a daughter and mother. Nippon Naika Gakkai Zasshi 1990;79:531532.
9. Ernst T, Chase AJ, Score J, et al. Inactivating mutations of the histone meth- 42. Pardanani A, Fridley BL, Lasho TL, et al. Host genetic variation contributes to
yltransferase gene EZH2 in myeloid disorders. Nat Genet 2010;42:722726. phenotypic diversity in myeloproliferative disorders. Blood 2008;111:2785
10. Pardanani A, Lasho T, Finke C, et al. LNK mutation studies in blast-phase 2789.
myeloproliferative neoplasms, and in chronic-phase disease with TET2, IDH, 43. Ferguson LR, Han DY, Fraser AG, et al. Genetic factors in chronic inamma-
JAK2 or MPL mutations. Leukemia 2010;24:17131718. tion: Single nucleotide polymorphisms in the STAT-JAK pathway, susceptibility
11. Tefferi A. Novel mutations and their functional and clinical relevance in myelo- to DNA damage and Crohns disease in a New Zealand population. Mutat
proliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Res 2010;690:108115.
Leukemia 2010;24:11281138. 44. Espinosa G, Font J, Munoz-Rodriguez FJ, et al. Myelodysplastic and myelo-
12. Jones AV, Chase A, Silver RT, et al. JAK2 haplotype is a major risk factor for proliferative syndromes associated with giant cell arteritis and polymyalgia
the development of myeloproliferative neoplasms. Nat Genet 2009;41:446 rheumatica: A coincidental coexistence or a causal relationship? Clin Rheu-
449. matol 2002;21:309313.
13. Kilpivaara O, Mukherjee S, Schram AM, et al. A germline JAK2 SNP is asso- 45. Montalto M, Biolato M, Gallo A, et al. Severe giant cell arteritis associated
ciated with predisposition to the development of JAK2(V617F)-positive myelo- with essential thrombocythaemia. Int J Immunopathol Pharmacol
proliferative neoplasms. Nat Genet 2009;41:455459. 2010;23:12711274.
14. Rumi E, Passamonti F, Della Porta MG, et al. Familial chronic myeloprolifera- 46. Tondel M, Persson B, Carstensen J. Myelobrosis and benzene exposure.
tive disorders: Clinical phenotype and evidence of disease anticipation. J Clin Occup Med (Lond) 1995;45:5152.
Oncol 2007;25:56305635. 47. Wolff SP. Correlation between car ownership and leukemia: is non-occupa-
15. Zoloth SR, Michaels DM, Villalbi JR, Lacher M. Patterns of mortality among tional exposure to benzene from petrol and motor vehicle exhaust a causative
commercial pressmen. J Natl Cancer Inst 1986;76:10471051. factor in leukemia and lymphoma? Experientia 1992;48:301304.

American Journal of Hematology 181

critical review
48. Gall EA. Benzene poisoning with bizarre extramedullary hematopoiesis. Arch 53. Bernardini P, Giannandrea F, Voso MT, Sica S. Myeloproliferative disorders
Pathol 1938;25:315. due to the use of gasoline as a solvent: Report of three cases. Med Lav
49. Rawson R, Parker F Jr, Jackson H Jr. Industrial solvents as possible etiologic 2005;96:119125.
agents in myeloid metaplasia. Science 1941;93:541. 54. Wakeford R. Radiation in the workplaceA review of studies of the risks of
50. Aksoy M. Malignancies due to occupational exposure to benzene. Haemato- occupational exposure to ionising radiation. J Radiol Prot 2009;29:A61A79.
logica 1980;65:370373. 55. Caldwell GG, Kelley DB, Heath CW Jr, Zack M. Polycythemia vera among
51. Port M, Hyman JB. Myeloid metaplasia as a result of chronic benzene intoxi- participants of a nuclear weapons test. JAMA 1984;252:662664.
cation. N Y State J Med 1965;65:22602262. 56. Wolff SP, Stern G. Geographic associations between radon and cancer: Is
52. Uppenkamp M, Meusers P, Donhuijsen K, Brittinger G. Benzene-associated domestic radon level a marker of socioeconomic status? J Radiol Prot
myelobrosis at an early stage. Internist (Berl) 1990;31:769772. 1991;11:225.

182 American Journal of Hematology