Page 1312 - Hematology_ Basic Principles and Practice ( PDFDrive )

1158 Part VII Hematologic Malignancies

longer time period. For example, patients with an underlying allergic TABLE End-Organ Damage Typically Observed in Patients
disease, an inherited disorder accompanied by HE, or those with 71.7 With Hypereosinophilic Syndrome
organ-specific HE syndromes, such as eosinophilic pneumonia,
usually fail to develop the cardiac damage seen in patients with Cardiac
typical HES. When neither an underlying disease nor HE-related Intramural thrombi
organ damage is found, the diagnosis HE of undetermined signifi- Valve regurgitation
3
cance (HE US ) is established. In general, the risk of HES is lower in
reactive forms of HE, especially when the underlying disease can Constrictive pericarditis
be treated successfully. Correspondingly, IL-5 transgenic mice with Endomyocardial fibrosis
massive HE do not develop significant end-organ damage, suggest- Myocarditis
ing that other factors (in addition to IL-5) are likely necessary for Cardiomyopathy
the occurrence of a HE-related organ damage. In patients with an
underlying MPN or other underlying myeloid neoplasm, the risk Neurologic
of HE-related organ damage (HES) is relatively high. The highest Fatigue
risk is found in patients with mutations in PDGFR genes. Likewise, Thromboembolism and stroke
most untreated patients with F/P+ MPN-eo or CEL may develop Peripheral neuropathy
HES with cardiac involvement over time. Additional risk factors
may also contribute in these patients: these factors include, among Central nervous system dysfunction and dementia
others, an additional prothrombophilic state, late detection of the Paresthesias and/or sensory deficits
disease, and late initiation of specific (anti-CEL) therapy. There may Epilepsy
also be a certain genetic predisposition for early occurrence of tissue Dermatologic
HE in patients with F/P+ CEL (F/P+ MPN-eo). In particular, the Angioedema
severity (extent) of tissue HE seems to correlate with a polymorphic
16
variant (SNP in the 5′-UTR) in the IL-5RA gene. However, it Urticaria
remains unclear whether this SNP predisposes to HES development Papular and/or nodular lesions
or progression, and thus is relevant clinically. Today, the general Mucosal ulcers
recommendation is to initiate therapy with imatinib early in all F/P+
patients, regardless of genetic, molecular or other factors, in order to Vesicobullous lesions
prevent any HES occurrence as well as disease progression (to acute Microthrombi
leukemia). Pulmonary
A number of different organ systems are affected in patients Pulmonary infiltrates
with HES. The most common manifestations are summarized in Pulmonary thromboembolism
Table 71.7. Although multiple organ systems are involved and the
manifestation patterns are quite complex with varying courses and Pneumonitis
outcomes, some common pathogenetic factors have been described. Fibrosis
One common feature is the mobilization of the tissue microenviron- Pleural effusion
ment by eosinophil-derived mediators and cytokines, which leads Ocular
to tissue remodeling, fibrosis, and increased angiogenesis. Another
common factor is tissue inflammation, which is typically triggered Microthrombi
by eosinophil-derived cytokines and chemokines. Finally, HE-related Vasculitis
organopathies may often result from direct cytotoxic damage that is Retinal arteritis
induced by the various toxic mediators produced and released by Connective Tissue
(reactive and neoplastic) eosinophils. With regard to thrombosis, Arthralgias
several different eosinophil-derived mediators have been implicated,
including TNF-α, plasminogen activator inhibitors (PAIs), and Effusions
17
eosinophil-derived DNA traps (see Table 71.1). In addition, ECPs Polyarthritis
have the capacity to alter thrombomodulin activity. A number of Raynaud phenomenon
different compounds produced by eosinophils, including cationic
proteins and various cytokines, may induce fibrosis. Among these Digital necrosis
cytokines, OSM may play a particular role as a HES-related profi- Gastrointestinal
11
brogenic cytokine. HE-related neoangiogenesis may be triggered Ascites
by IL-8, OSM, and vascular endothelial growth factor (VEGF). All Diarrhea
these cytokines are produced and secreted by normal/reactive and also Gastritis
by neoplastic eosinophils. However, neoplastic eosinophils produce
some of these cytokines in excess over their normal counterparts. Colitis
For example, F/P+ eosinophils express and release huge amounts of Cholangitis
OSM, IL-8, and VEGF. The F/P mutant induces the production and
secretion of these mediators in neoplastic cells in a STAT5-dependent
manner. Concerning the mobilization of the microenvironment
in various organs in patients with HES, a most critical F/P target
gene may be OSM. Notably, OSM initiates not only fibrosis and such as the JAK2-mutated variants. One explanation may be that
angiogenesis by triggering fibroblast proliferation and tube forma- eosinophils invade heart and lung tissues via “physiologic” routes,
tion in endothelial cells, but also by inducing the production of which may not be the case in other MPNs where HE usually does
multiple cytokines and chemokines in stromal cells. Among these not occur. An additional explanation may be that eosinophil-derived
mediators are IL-8, SDF-1, and other chemotactic factors that can mediators are toxic to certain (tissue-specific) cell types such as car-
recruit additional CXCR4+ precursor cells and eosinophils to local diomyocytes. Indeed, as noted earlier, eosinophils express a number
tissue sites. 11 of different cationic proteins capable of inducing endothelial and
An unresolved question is why HE-related fibrosis and thrombosis endocardial damage and neurotoxicity. In addition, the eosinophil
affect certain tissues and organs, including the heart, whereas the has the capacity to generate reactive oxidative species that can
same organs are spared by other thrombophilia-inducing MPN types, augment tissue damage.