Pulmonary Hypertension in the Field of Hematological and Oncological Diseases

Pulmonary hypertension (PH) is defined by hemodynamic criteria, including a mean pulmonary artery pressure of >20 mm Hg measured by right heart catheterization (RHC) [1]. Patients with PH commonly experience symptoms, which also significantly impair their quality of life such as fatigue, weakness, dyspnea, chest pain, or even syncope, particularly during physical exertion. The disease’s severity is highlighted by its progressive nature, potentially leading to right heart failure and death if left untreated [2]. If PH is suspected, an echocardiogram is performed and might be followed by further imaging and/or RHC to establish the diagnosis of PH [1].

PH is classified into five major groups based on underlying pathological mechanisms: group 1: pulmonary arterial hypertension (PAH), group 2: PH associated with left heart disease, group 3: PH associated with lung diseases, group 4: PH associated with pulmonary artery obstructions, and group 5: PH with unclear and/or multifactorial mechanisms [3]. Emerging evidence indicates a link between PH and hematological disorders and both current and past neoplasms [4]. PH due to hematological disorders and malignant or benign neoplasms can be categorized into groups based on unique pathophysiological characteristics, treatment-related mechanisms, or other indirect causes. However, the correlation between hematological disorders, especially neoplasms, and PH remains not fully understood. This review aimed to delineate the current knowledge on PH associated with hematological disorders and neoplasms.

Solid tumors in cancer patients induce a range of pathophysiological mechanisms, leading to pulmonary artery obstruction and PH. These obstructions can arise from direct tumor invasion, vascular compression, or tumor macro- or microembolism and their subsequent effects. This chapter aims to examine the predominant causes of PH in the context of solid tumors, including sarcomas, tumor macroembolism, or pulmonary tumor embolism (PTE), which represent a substantial part of group 4 PH and pulmonary tumor thrombotic microangiopathy categorized in group 5 PH.

Sarcomas are a heterogeneous group of tumors originating from mesenchymal tissues. Primary pulmonary artery sarcoma, a particularly rare and aggressive subtype, arises from endothelial cells of the pulmonary arteries [5]. Occlusion of the pulmonary arteries by pulmonary artery sarcoma can lead to PH, which may mimic pulmonary thromboembolic disease in terms of symptoms or diagnostic findings and complicate the diagnostic process [6, 7]. Pulmonary artery sarcoma tends to cause nonspecific subacute symptoms, including dyspnea, cough, hemoptysis, fatigue, and chest pain. Patients often present at an advanced stage, with manifestations of right heart failure secondary to PH [7]. Gadolinium-enhanced magnetic resonance imaging or ¹⁸F-2-fluoro-2-deoxy-d-glucose-positron emission tomography scans are effective methods to differentiate between thrombotic mass and tumor [8]. In contrast, other commonly used diagnostic tools, such as ventilation-perfusion (V/Q) scans and computer tomography pulmonary angiography (CTPA, e.g., Fig. 1), are not fully capable to distinguish between these two entities [7]. An early diagnosis is crucial to enable prompt surgical radical resection combined with adjuvant therapy, which has been shown to achieve the best survival outcome [9, 10].

Pulmonary tumor macroembolism and PTE are forms of pulmonary vascular involvement in cancer, resulting from metastases of primary tumors located elsewhere in the body. Tumor macroembolism occurs when metastases obstruct the pulmonary arteries with tumor clots, mimicking proximal pulmonary embolism [11]. It typically occurs through one of four pathways: The vena cava, arterial blood circulation, direct extension from adjacent viscera or retrograde spread through the lymphatic system [12]. Metastatic spread to the heart is frequently associated with malignancies such as breast, lung, or esophagus cancer as well as leukemia, malignant melanoma, or lymphoma [13]. Cases of tumor macroembolism are described for choriocarcinoma [13, 14], breast cancer [15], cervical carcinoma [12, 13], and lung carcinoma [16]. Clinically, tumor macroembolism may present acutely with a rapid onset of symptoms, including progressive dyspnea and subacute cor pulmonale, right heart failure, and death [17]. The rapid disease progression and similarity to thromboembolism make antemortem diagnosis particularly challenging [16]. While CTPA may reveal pulmonary artery narrowing, differentiating between tumor embolism, thromboembolism, and pulmonary artery sarcoma remains difficult [8, 16]. Additional diagnostic modalities, such as ¹⁸F-2-fluoro-2-deoxy-d-glucose-positron emission tomography imaging alongside the evaluation of biomarkers, can help find the correct diagnosis [13].

Pulmonary tumor embolism, first described in 1937 [18], involves the occlusion of small pulmonary arteries by emboli composed of tumor cells [18]. It causes PH due to incomplete clearance of emboli, triggering local coagulation and persistent vascular obstruction without remodeling [19]. Surrounding interstitial invasion is typically not observed in tumor embolism, highlighting the distinction from metastases [20]. Due to its often clinically silent onset, it is frequently underdiagnosed, with postmortem studies (e.g., Fig. 1) reporting microscopic tumor emboli in up to 26% of pulmonary arteries among patients with solid tumors [11]. Affected patients typically become symptomatic at a late stage, presenting a rapid clinical course characterized by progressive dyspnea, which may be accompanied by cough, hypoxia, and chest pain, ultimately leading to right ventricular dysfunction and right heart failure [11, 21]. Pulmonary tumor embolism is most commonly associated with various types of adenocarcinomas such as liver [22], gastric [23], or choriocarcinoma [24], according to case reports. As previously mentioned, diagnosing tumor embolism antemortem is particularly challenging due to the often undiagnosed, underlying cancer. When identified antemortem, aggressive treatment of the underlying cancer is indicated, according to case reports [11]. However, clear guidelines are still lacking.

Pulmonary tumor thrombotic microangiopathy was first described in 1990, significantly later than PTE [25]. It is a condition that occurs after tumor embolism and is caused by nonocclusive clusters of tumor cells lodging within the pulmonary vessels, leading to fibrointimal remodeling of both pre- and postcapillary vessels within the pulmonary vasculature and lymphatic system [19]. Due to the secretion of growth factors by the tumor cells, the proliferation of endothelial and non-endothelial cells is induced. Additionally, activation of the coagulation cascade leads to thrombus formation, subsequent luminal stenosis, and vascular inflammation [11].

The development of PH in PTTM shares a similar origin with PH in PTE, with the added contribution of fibrocellular intimal proliferation and vascular remodeling through PAH-like mechanisms [11]. In PTTM, PH arises as the number of stenotic vessels increases [19, 25].

Patients with PTTM typically exhibit rapid disease progression, leading to right heart failure and death [26]. Additionally, symptoms such as chest pain and hemoptysis have been described [26]. Diagnosis is often not established until after the patient’s demise [27]. Postmortem studies have frequently revealed an association between PTTM and certain types of cancer, including gastric [19, 28], breast [29], lung [30], hepatocellular [31], and ovarian cell [32, 33] adenocarcinomas as well as gallbladder carcinoma [34]. While chest radiography is often normal, patients desaturate during the 6-min walk test and potentially show vascular limitations in pulmonary function tests and elevated D-dimers and hypoxemia in blood testing [11]. By using radionuclide V/Q scans, the detection of multiple peripheral perfusion defects is possible, even when CTPA appears normal [11, 27].

Treatment options and supportive care strategies are limited due to the scarcity of large case studies and the reliance on a limited number of case reports, which makes comprehensive management challenging. Rapid diagnosis and treatment of the underlying neoplastic disease is critical, alongside PH-targeted therapy and antiproliferative drugs [35, 36]. Particularly, the tyrosine kinase inhibitor imatinib is a promising drug potentially leading to the recanalization of affected vessels and has been used in treating PTTM [37, 38]. However, patient survival outcomes remain poor [39]. PTTM should be considered in patients with PH who present with rapid deterioration, particularly in the context of a cancer diagnosis.

In patients with chronic myeloproliferative neoplasms (MPNs), various etiologies contributing to precapillary PH have been identified. These include JAK2 mutation-positive myeloid neoplasms such as essential thrombocythemia, polycythemia vera, and myelofibrosis, as well as the Philadelphia chromosome-positive chronic myeloid leukemia (CML) [1, 40]. There appears to be an association between myelofibrosis and the development of PH, while essential thrombocythemia and polycythemia vera are more frequently linked to chronic thromboembolic pulmonary hypertension (CTEPH) [1, 41]. The precise prevalence and impact of PH in MPN remain unclear, as evidenced by the varying prevalence rates reported in the meta-analysis of Ferrari et al. [40] ranging from 3.8% to 58%. However, it is evident that the occurrence of PH in MPN is associated with an increased risk of mortality, attributable to hematologic progression, cardiovascular disease, and overall mortality [42]. Additionally, guidelines for screening and therapeutic interventions are lacking.

Polycythemia vera and essential thrombocythemia are primarily driven by mutations in the JAK2 gene, with mutations in the CALR or MPL genes also common, particularly in essential thrombocythemia. Polycythemia vera is characterized by an overproduction of red blood cells, resulting in elevated hematocrit levels and increased blood viscosity. In contrast, essential thrombocythemia typically involves excessive platelet production, leading to elevated platelet counts [43]. Both conditions are associated with an increased risk of thrombotic events due to the hypercoagulable state they induce. Patients may present with symptoms of thrombosis or bleeding and are at risk of developing CTEPH due to hypercoagulability and subsequent thromboembolic events that damage the pulmonary vasculature [43]. Additionally, splenomegaly, a common clinical finding in myeloproliferative disorders, can lead to portal hypertension and contribute to the development of portopulmonary hypertension, a specific subtype of PH. Diagnosing PH in polycythemia vera and essential thrombocythemia involves a thorough clinical assessment, echocardiography to assess pulmonary artery pressure and right heart function, and RHC for a definitive diagnosis. Recent meta-analyses suggest that the development of PH in patients with polycythemia vera appears to be less common compared to other MPN [40]. However, when PH does occur in polycythemia vera, it is associated with an inferior prognosis [40]. Management of polycythemia vera and essential thrombocythemia requires guidance by a hematologist or medical oncologist and aims to prevent thromboembolic complications. Treatment guidelines are based on risk stratification, considering patient age, prior thromboembolic events, and, in the case of essential thrombocythemia, cardiovascular risk factors, and a JAK2 Val617Phe mutation. Patients without contraindications receive aspirin. For polycythemia vera, hematocrit levels are managed through phlebotomy (low-risk) or cytoreductive agents (high-risk). Essential thrombocythemia patients are monitored under watchful waiting in low-risk cases, with cytoreductive therapy reserved for high-risk situations [43]. When CTEPH occurs, management should align with ESC/ERS guidelines [1] including the use of anticoagulants, assessment for pulmonary endarterectomy, and PH-specific drugs [43, 44]. Early detection of PH in affected patients is crucial to improve outcomes and reduce the risk of right heart failure.

Myelofibrosis (MF) is a myeloproliferative hematopoietic condition, characterized by progressive bone marrow fibrosis, leading to extramedullary hematopoiesis and splenomegaly [45]. Common clinical manifestations include severe anemia, constitutional symptoms (e.g., fever, fatigue, night sweats) cachexia, bone pain, thrombosis, or bleeding. MF can also arise secondary to essential thrombocythemia or polycythemia vera [45]. Diagnosis requires all three major and at least one minor criteria. The major criteria are pathognomonic histologic bone marrow picture with (atypic) megakaryocytic proliferation and fibrosis grade 2–3, exclusion of other myeloid neoplasia, and a JAK2, CALR, or MPL mutation, or an alternative clonal marker or the exclusion of reactive fibrosis. Minor criteria are anemia, leukocytosis, splenomegaly, elevated LDH, or leukoerythroblasts in the peripheral blood [45, 46]. Causes of mortality in patients with MF typically include progression to leukemia, cardiovascular events, and complications arising from cytopenia such as infections or bleeding [45]. Extramedullary hematopoiesis can furthermore lead to PH, especially in advanced disease, which has been reported as an exceptionally high-risk complication in MF and adversely affects overall patient prognosis compared with other MPN [40, 45, 47]. Diagnosing PH in MF is challenging because symptoms often overlap with MF itself, and routine screening programs are lacking [40]. However, there is still considerable debate regarding which patients should be screened for PH using echocardiography to enable early detection without increasing costs or the risk of overdiagnosis [48, 49]. N-terminal prohormone of brain natriuretic peptide levels have been reported as a potential predictor of PH in MF and could serve as an indicator for initiating echocardiography [49]. Management of PH in the context of myelofibrosis involves addressing the underlying disease along with the potential use of PH-specific drugs [1]. In the case of myelofibrosis, targeted therapies include JAK2 inhibitors for symptomatic management, while allogenic hematopoietic stem cell transplantation is considered a potential curative treatment or a means to prolong survival [45]. However, further studies are needed in patients with MPN to establish clear screening criteria for PH and clarify treatment guidelines.

CML is a myeloproliferative disorder caused by a translocation involving the Philadelphia chromosome, which results in the BCR-ABL1 translocation, leading to constitutive tyrosine kinase activity [50]. Tyrosine kinase inhibitors (TKIs) are recommended, with imatinib being a prominent example for the first generation. Currently, there are second- (dasatinib, bosutinib, and nilotinib) as well as third-generation TKI (ponatinib) and asciminib representing a new class of TKI, each offering distinct therapeutic advantages [51]. The use of TKI in patients with CML has significantly improved outcomes, allowing many patients to achieve a near-normal life expectancy [52]. However, several studies have shown that TKI can induce PH as a side effect [53, 54]. Specifically, PH occurred in 10.7% of patients treated with TKI, with the highest incidence (21.6%) in those receiving dasatinib [54]. Recent guidelines [55] recommend screening for underlying cardiopulmonary disease before starting dasatinib and continuing to monitor for symptoms during treatment. Additionally, some studies suggest that PH may already be present in certain CML patients before initiating TKI treatment. In a prospective study by Venton et al. [56], 3 among 28 CML patients studied, showed signs of PH prior to treatment initiation using TKI. Multivariate analysis by Song et al. [54] concluded that while drug effects may contribute to the risk of PH, they are not the sole cause. However, no studies have investigated the causes and prevalence of PH in CML patients, aside from those related to TKI treatment.

Other hematological disorders, mainly hereditary hemoglobinopathies characterized by genetically caused defects in globin chain synthesis, significantly contribute to the development of PH. PH associated with hematological diseases is classified under group 5 PH, with unclear and/or multifactorial mechanisms. The most prominent hemoglobin disorders typically leading to chronic hemolytic anemias and causing PH include sickle cell disease (SCD) and thalassemia. Even when classified within group 5 PH due to the multifactorial mechanisms, vascular remodeling (group 1 PH), artery occlusion by embolic material (group 4 PH), or left heart diseases (group 2 PH) can occur [1, 57].

SCD is an autosomal recessive disorder characterized by a Glu6Val mutation in the beta-globin gene, resulting in the production of hemoglobin S and the formation of sickle-shaped red blood cells under deoxygenated conditions [58]. These abnormal cells can trigger endothelial activation, potentially leading to hemolysis, vaso-occlusive crisis, and arterial vasculopathy [58]. Registry data analysis indicates that half of the patients with SCD exhibit pulmonary complications over time, with 6–10% of all SCD patients developing PH [39, 59].

PH associated with SCD can result from a complex interplay of mechanisms and may present as either pre- or postcapillary PH, with both types occurring at comparable rates [59]. Contributing factors for precapillary PH include hemolysis-induced reduction of nitric oxide levels, elevated pro-inflammatory markers as well as microvascular occlusion and the development of thromboembolic disease, potentially leading to CTEPH. Additionally, chronic hypoxia can lead to hypoxic pulmonary vasoconstriction. In contrast, postcapillary PH is primarily driven by anemia-induced hypercirculation, leading to left ventricular diastolic dysfunction [59, 60].

Several studies have reported a significant increase in mortality among patients with SCD and PH [60‒63]. Upon confirmation of PH in patients with SCD, the treatment of choice is SCD-specific therapy with hydroxyurea and blood cell transfusion. Currently, there are no specific guidelines for treating PH in SCD. However, treatment should be tailored to the underlying cause of PH. It is crucial to refer affected patients to PH centers for optimal management and to follow a multidisciplinary approach by PH and SCD teams [1].

Thalassemia is a genetic disorder caused by defects in the production of the α- or β-globin chains of hemoglobin, leading to various thalassemia syndromes that are broadly classified as either alpha or beta thalassemia. It is most prevalent in sub-Saharan Africa, the Mediterranean, and the Middle East [64, 65]. According to clinical presentation and severity, they can be further divided into three groups: (1) transfusion-dependent thalassemia, (2) non-transfusion-dependent thalassemia, and (3) thalassemia minor [64, 66]. Transfusion-dependent thalassemia is characterized by severe anemia manifesting in early childhood and requiring lifelong blood transfusion and chelation therapy. Non-transfusion-dependent thalassemia, on the other hand, is a very diverse group with varying degrees of anemia and presentation in late childhood, where blood transfusions are occasionally required [64]. In contrast, patients with thalassemia minor are typically asymptomatic.

Thalassemia-related complications, which contribute to increased morbidity and mortality, are a significant concern in aging patients with thalassemia [66]. PH potentially leading to right heart failure is a particular issue, especially in patients with non-transfusion-dependent β-thalassemia [67]. Pathomechanisms are similar to those of PH in SCD and are attributed to factors such as ineffective erythropoiesis and peripheral hemolysis, resulting in chronic anemia, depletion of NO, iron overload, and a hypercoagulable state due to increased prothrombotic markers [65]. With a reported prevalence rate of 2.1% detected via RHC [68], the prevalence of PH in patients with β-thalassemia is notably higher than in the general population. Comprehensive management of β-thalassemia patients should include regular screening for PH. Further research is essential to improve prognosis and enhance the quality of life for affected individuals [1, 69].

PH during or following specific cancer therapies represents a significant potential complication attributable to various mechanisms associated with different PH groups [4]. Some drugs used in cancer treatment have the potential to induce drug-associated PAH, classified under PH group 1. Additionally, other drug-related mechanisms may lead to group 2 or 3 PH through the development of left heart or parenchymal lung disease [4]. Furthermore, cancer-related treatments such as radiation therapy or the use of totally implantable central venous access systems can also contribute to the development of PH [1, 4, 70].

Alkylating agents, such as mitomycin C or cyclophosphamide, are integral to treatment regimens for various cancers, including solid tumors and hematological malignancies. In two observational studies of the French PH registry [71, 72], cyclophosphamide was the most frequent risk factor for inducing pulmonary veno-occlusive disease in patients who had undergone chemotherapy. Mitomycin C was also associated with the occurrence of pulmonary veno-occlusive disease. These findings are consistent with observations in various animal models [71, 72].

Bleomycin, a compound produced by Streptomyces verticillus, is commonly used in cancer chemotherapy [73]. Its potential to induce pulmonary toxicity, particularly pulmonary fibrosis, is well documented and may lead to group 3 PH associated with lung diseases, especially with long-term use or high cumulative doses [4].

Anthracyclines, including doxorubicin, daunorubicin, idarubicin, and epirubicin, are commonly used topoisomerase inhibitors in cancer chemotherapy. These agents are effective against many cancers, including solid tumors and hematological malignancies [74]. However, they are also well known for their cardiotoxicity, which can lead to left heart disease and subsequently the development of postcapillary PH [4]. The risk of developing PH with anthracycline treatment underscores the need for regular cardiovascular monitoring during and after therapy.

The introduction of TKI has revolutionized the treatment of CML [51]. However, their use is associated with the potential development of drug-associated PAH. In particular, the second-generation drug dasatinib has been identified as a definite inducer of PH [75], while bosutinib and the third-generation drug ponatinib are considered possible inducers of PH [1, 76]. Dasatinib is notable for its potential to induce regression of PAH upon withdrawal of the drug [77]. Nevertheless, a long-term study by Weatherald et al. [78] found that dasatinib-induced PAH persisted in 37% of all patients even after discontinuation. When PAH persists, discontinuation of TKI or switching to an alternative TKI is recommended, along with the potential use of PAH-specific drugs, accompanied by close monitoring [4, 78].

Proteasome inhibitors, including carfilzomib and bortezomib, are utilized in treating plasma cell diseases and lymphoma [79]. Notably, carfilzomib is associated with adverse respiratory events, including acute respiratory failure, acute respiratory distress syndrome, interstitial lung disease, and the development of drug-associated PAH [80]. In contrast, the association of bortezomib, which is indicated as first-line therapy after diagnosis, with respiratory complications is less well established [80].

The use of totally implantable central venous access systems is common in cancer patients for administering chemotherapy and other therapies, including parenteral nutrition and immunosuppressive treatments. However, recent research indicates that totally implantable central venous access systems may contribute to the development of CTEPH even years after their removal [70]. This association could be mediated through mechanisms such as catheter-related thrombosis, inflammation, or infection, which may facilitate the occurrence of CTEPH. Affected patients also seem to show more compromised hemodynamics at diagnosis and exhibit reduced perioperative survival rates during pulmonary endarterectomy [70].

Radiation-induced heart disease can lead to PH group 2 through left heart dysfunction, while radiation-induced lung disease can contribute to PH group 3 through parenchymal lung damage [4]. The long-term risk of PH following radiation therapy highlights the importance of long-term follow-up and cardiovascular monitoring in cancer survivors.

PH in hematologic and oncologic diseases can result from multiple causes (Fig. 2). Despite various underlying pathologies, accurate identification of PH and its potential contributing conditions is essential. Following a systematic workup, a multidisciplinary approach to management is crucial to ensure optimal treatment and improve survival.

All authors declare no conflicts of interest in relation to this manuscript.

This review did not receive any funding from external sources.

L.R. and M.L. conceived the project and contributed to analyzing and interpreting the data, writing and revising the article critically for important intellectual content, and providing final approval of the version to be published. F.L., B.L., J.M.E., S.P., H.P., L.G., C.W., and S.U. contributed to data collection, analysis, and critical revision of the article for important intellectual content. All authors took responsibility for freedom from bias of the discussed interpretation.