Intrathoracic manifestations of hematologic malignancies: a narrative review

Introduction

Hematologic malignancies arise from aberrant proliferation of lymphoid, myeloid or monocytic cells. Globally, the age-standardized incidence rate for all hematologic malignancies has been increasing (1,343,850 new cases reported in 2019), but fortunately, the age-standardized death rate has declined (1). Pulmonary sequelae of hematologic malignancies are often recognized as a major health concern (2). Hematologic malignant disease impacting the respiratory system and treatment-related sequelae may mimic infection, so prompt recognition of non-infectious pulmonary manifestations is paramount. Further as therapeutics evolve, the development of synchronous hematologic malignancies and/or therapy-related entities may emerge. In this review, we aim to discuss the various non-infectious pulmonary manifestations of hematologic malignant disease (Figure 1), as well as highlight potential treatment-related sequalae. We present this article in accordance with the Narrative Review reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-25-139/rc).

Figure 1 Overview of intrathoracic manifestations of hematologic malignancies.

Methods

A literature review was done in PubMed Central and Google Scholar for articles published in English from January 1^st, 2014, to January 1^st, 2024. Methodology is summarized in Table 1.

Hematologic malignant disease

Hematologic malignancies can be broadly classified into three major categories: leukemias, lymphoma and plasma cell neoplasms (primarily multiple myeloma). For this review, we will focus on the first two categories.

Definitions

Leukemias and lymphomas differ in their origin, presentations and sites of involvement. Leukemias primarily involve the bone marrow and peripheral blood and often present with leukocytosis and/or cytopenia. Lymphomas impact the lymphatic system with infiltration of malignant lymphocytes that present as mass-like lesions or lymphadenopathy in lymphoid tissues including lymph nodes, the spleen, or extra-nodal sites.

Classification for both is based on cell lineage (B-cell, T-cell, or myeloid), morphology, immunophenotype and genetic features. However, some features of leukemias and lymphomas may overlap, and the World Health Organization (WHO) classification uses a threshold of >25% bone marrow involvement to distinguish between leukemia and lymphoma in some cases [lymphoblastic neoplasms, and chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia] (3).

Leukemias are subdivided into myeloid and lymphoid origins, and these include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), CLL, and chronic myeloid leukemia (CML). Lymphomas are divided into Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL).

Epidemiology

In the United States, hematologic malignancies account for 9.6% of new cancer diagnoses annually (4). Evolving risk factors for hematologic malignancies include increasing lifespan, genetic predisposition, high body mass index (BMI), environmental or chemical exposure, certain infections and treatment of prior malignancies leading to chemotherapy or radiation exposure (5). The proportion of attributable mortality risk for different risk factors varies based on the socio-demographic index (SDI), an indirect measure of economic development. Obesity has contributed to a higher proportion of deaths in countries with higher SDIs, whereas deaths attributable to occupational chemical exposures were more common in countries with lower SDIs (1).

NHL comprises 90% of all lymphomas in the United States, and immunosuppression is an important risk factor for lymphoma. NHL is mostly seen in adults aged 65–74 years. Diffuse large B-cell lymphoma (DLBCL) is highly aggressive and the most prevalent subtype of NHL. HL is seen in a bimodal distribution affecting adolescents and young adults, and less commonly adults aged 75–79 years (5).

The incidence of leukemia and HL has decreased since 1990, however leukemia had the highest incidence and mortality rate of all hematologic malignancies in 2019. The incidence of CML, AML and CLL all increase with age (5).

CLL is the most common leukemia in the United States and is an independent risk factor for synchronous solid organ tumors and hematologic malignancies. The incidence of AML increases exponentially with age. However, treatment-related AML can also occur in younger patients with a history of pediatric leukemias who were treated with alkylating agents or topoisomerase inhibitors (5).

Acute lymphocytic leukemia (ALL) has a marked bimodal distribution with peak incidences in childhood and again among elderly adults aged 80–84 years. Notably, 5-year survival rates for ALL are inversely correlated with the initial age of diagnosis (5). CML is most frequently diagnosed between 65–74 years of age and is caused by the reciprocal translocation t(9:22)(q32:q11). Due to the introduction of targeted tyrosine kinase inhibitors (TKIs), 5-year survival rates have improved from less than 50% prior to 2001 to 68.7%.

Mediastinal disease

The mediastinum is a common site for both primary and secondary involvement by hematologic malignancies (Table 2). Both NHL (40–45%) and HL (85%) will have intrathoracic mediastinal lymphadenopathy (6). Many primary mediastinal malignancies in both adults and children include lymphoproliferative disorders such as HL, primary mediastinal (thymic) large B-cell lymphoma (PMBCL), T-lymphoblastic lymphoma (T-LBL) and anaplastic large cell lymphoma (Figure 2).

Figure 2 Malignant processes affecting the lung. (A) Young woman with primary mediastinal large B-cell lymphoma presented with cough, dyspnea with exertion, night sweats, fever, and weight loss. Imaging revealed consolidation in right upper lobe (white arrow) with infiltrates (white arrowhead) and right pleural effusion (asterisk). Pleural effusion was exudative with predominant neutrophils and negative cultures. Flow cytometry of pleural effusion confirmed B-cell lymphoma. Consolidation and pleural effusion improved after chemotherapy was initiated. (B) Middle aged woman with relapsed anaplastic lymphoma presented with respiratory insufficiency. Imaging displayed extensive consolidative opacities (white arrows) in the middle and lower lobes with ground glass changes (white arrowhead). Infiltrates improved after restarting chemotherapy. (C) Middle aged man presented with dyspnea, facial edema, and new diagnosis of B-cell lymphoma with mediastinal lymphadenopathy (arrow) resulting in superior vena cava syndrome. (D) Elderly woman presented with history of follicular lymphoma (mesenteric mass) presented with recurrent disease noted with subcarinal FDG-avid lymph node (arrow) found to have recurrent follicular lymphoma after EBUS-TBNA. Written informed consent from the patients for the publication of this article and accompanying images was waived as the images are retrospectively collected. EBUS-TBNA, endobronchial ultrasound-guided transbronchial needle aspiration; FDG, fludeoxyglucose.

HL, especially the nodular sclerosis subtype, affects axial lymph nodes in a contiguous manner and the progression is more predictable, but it is difficult to distinguish HL from NHL based on distribution of involved lymph nodes alone (7).

PMBCL is a subtype of diffuse large B cell lymphoma which arises from thymic B-cells (7,8). This may present in young women as an anterior or superior mediastinal mass and is strongly correlated with human immune deficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS) (7).

T-LBL also commonly presents as an anterior mediastinal mass due to massive infiltration of T-cell precursors from the thymus into the mediastinum. This is frequently seen in children but may affect adolescents and young adults (6). T-LBL can cause rapid disease progression into nodal and extranodal structures in the mediastinum. Mediastinal involvement may lead to superior vena cava (SVC) syndrome and extrinsic compression of the tracheobronchial tree (8,9).

Additionally, lymphoid leukemias such as CLL and ALL may present with mediastinal lymphadenopathy. Aggressive mediastinal infiltration is seen more commonly in lymphoblastic leukemias. For example, T-cell ALL arises from the same precursor cells as T-LBL and can manifest as an anterior mediastinal mass in adolescents and young adults. However, T-cell ALL is differentiated from T-LBL by the presence of greater than 20% circulating blasts. Patients with CLL are also at risk of Richter transformation, or the progression of CLL to DLBCL (9,10). Rarely, CLL may also transform into classical HL (9). Patients with CLL and new mediastinal findings should undergo tissue sampling to rule out de novo malignancies or Richter transformation (6,9).

Mediastinal involvement is rare in patients with leukemia, but it can represent extramedullary hematopoiesis in chronic hematologic diseases such as myeloproliferative neoplasm (MPN) or rarely myeloid sarcoma (2). Myeloid sarcoma occurs when extramedullary tissue comprised of myeloid precursor cells aggregates in one or more solid masses due to AML involvement (10).

Positron emission tomography and computed tomography (PET-CT) are crucial in diagnostic evaluation, for it helps to identify extent of disease and confirm appropriate biopsy targets. In cases of leukemia, PET-CT is most useful in identifying Richter transformation (9), as well as in early detection of extramedullary lesions and myeloid sarcoma (10). However, because PET-CT is not always specific for a diagnosis of cancer, histologic confirmation may be necessary. Excisional or core needle biopsy are the preferred methods of histological diagnosis of lymphoma (6). Bronchoscopy with endobronchial ultrasound-guided (EBUS) transbronchial needle aspiration (TBNA) is a reliable, less invasive form of tissue sampling, and it may be considered as a non-invasive option prior to mediastinoscopy (8). Diagnostic yield for lymphoma with EBUS-TBNA can vary based on lymphoma subtype, disease status and adequacy of the sample, but sensitivities range from 57% to 91% for diagnosis (11,12). Sensitivity is higher in relapsed or recurrent disease, with rapid onsite evaluation and ancillary techniques such as flow cytometry.

Disease of the serosal membranes

Hematologic malignancies can cause both pericardial and pleural effusions. Mechanisms can include direct infiltrations of pericardium or pleura by malignant cells, obstruction of lymphatic drainage by mediastinal lymphadenopathy, and sequelae of therapies including chemotherapy- or radiation-induced serositis (13-15).

Pericardial disease

Pericardial diseases include acute pericarditis, constrictive pericarditis, and pericardial effusion (16). Clinical presentation may vary depending on the size of the effusion and symptoms can include dyspnea, chest pain or pleurisy, fever, arrhythmia, and in severe cases, hypotension and/or shock. Some patients may be asymptomatic, and effusions may be incidentally detected on imaging, while others may present with features consistent with pericardial tamponade. In a nationwide Danish retrospective cohort study of patients with acute pericarditis (n=13,759), overall standardized incidence ratio for acute pericarditis (along with pericardial effusion) was 3.1 for myeloid leukemia, 2.8 for HL and 2.3 for NHL (17).

Pericardial disease may also be a sequela of treatment, particularly with radiation and alkylating agents such as busulfan and cyclophosphamide in lymphoma (15). Imatinib, used in CML treatment, and arsenic trioxide, which is used to treat refractory or relapsed acute promyelocytic leukemia, can cause pericardial effusions (18,19). In a retrospective study reviewing 2,592 patients with AML, ALL and myelodysplastic syndrome (MDS), pericardial effusions were present in 20% of patients, and although they were predominantly small, their presence did not impact survival (15).

Clinically significant pericardial effusions may be treated with pericardiocentesis followed by placement of a pericardial drain. In addition to treatment of the underlying disease, recurrent malignant pericardial effusions can be managed with repeated pericardiocentesis or surgical pericardial windows, but optimal management is unclear (20). Albeit more rare, constrictive pericarditis can present with fluid overload, concomitant pleural effusions, or with decreased cardiac output on exertion. Diagnosis can be confirmed with cardiac imaging including cardiovascular magnetic resonance (16). Definitive treatment for constrictive pericarditis is pericardiectomy preferably in experienced centers (20).

Pleural disease

Lymphomatous effusions are the most frequent malignant pleural effusions (MPEs) among hematologic malignancies, particularly when there is mediastinal involvement (14). MPEs are seen in 30% of cases of HL and 20% of cases of NHL (2). They are also seen more frequently in lymphoid leukemias. Pleural involvement has been found in 21% of patients with leukemia and is most common in ALL. Effusions have been noted in 3 to 16% of CLL patients (2). In a retrospective series of pleural effusions in acute leukemia and MDS, the most frequent etiology of pleural effusions was infection (47%) followed by malignancy (36%). In leukemia, pleural involvement includes effusions, pleural masses or thickening (10). Myeloid disease involving the pleura is rare, with myeloid sarcoma and extramedullary hematopoiesis being the most common types associated with lung and pleural involvement (21).

Pleural fluid analysis, including cytology and flow cytometry, can aid in the diagnosis. Lymphocyte-predominant exudates are common, but infection and other etiologies should be excluded due to inherent immunosuppression (2). MPEs are typically exudative but can also be transudative. Chylothorax may occur in 19% of NHL and 3% of HL (2,22). Diagnostic sensitivity for pleural fluid cytology can vary from 17.4% to 66.7% for hematologic malignancies (23). Efficacy may improve with the addition of flow cytometry (2). For exudative effusions of unclear etiology, tissue biopsy of pleura should be considered, and bone marrow biopsy may also be helpful particularly if there is transformation (MDS to AML, low grade to high grade lymphoma) (13).

Management for MPEs primarily involves treating the underlying malignancy. Symptom management may also necessitate serial thoracentesis, chemical pleurodesis and/or indwelling pleural catheters (IPCs). Recent studies demonstrate that IPCs in patients with hematologic malignancies have similar rates of bleeding complications and infection compared to solid organ tumors, despite the presence of neutropenia or thrombocytopenia (20,24). Spontaneous pleurodesis after IPC placement has been reported in anywhere from 30% to 68% of patients, and the frequency of patients requiring repeat pleural procedures is less in those with IPCs than those who undergo chemical pleurodesis (24,25). A single center study that reviewed 172 patients with hematologic malignancies with IPC placement showed a rate of IPC related complications of 9.5%, and the incidence of empyema was 2.9% and major bleeding was 1.7%. The median time to removal of IPCs was 81 days after placement (24). Guidelines and algorithms for evaluation, placement, and removal of IPCs reduce complications, while providing effective palliation of symptoms (24).

Primary lymphoma affecting the pleura

Primary effusion lymphoma is a rare extra-nodal lymphoma that originates in the pleura with no evidence of systemic disease at the time of diagnosis. It is a rare, aggressive B-cell lymphoma that localizes to serous body cavities with effusions (peritoneum, pleural space, pericardium) in the absence of a discrete mass (26). It is associated with human herpesvirus 8 (HHV-8) and often co-infected with Epstein-Barr virus (EBV). This entity has a predilection for those who are immunocompromised like patients with HIV or post-solid organ transplantation. Fluid overload-associated lymphoma is a newly recognized rare entity which presents as an effusion-based lymphoma in patients with underlying medical conditions, but it is negative for HHV-8 (27). Pyothorax-associated lymphoma develops in the pleural cavity after decades of chronic pyothorax, and it is strongly associated with EBV, not HHV8. It can occur in those with a history of chronic inflammation or secondary to artificial pneumothorax for tuberculosis, and it can present as a pleural mass with or without effusion (28).

Parenchymal and tracheobronchial disease

Hematologic malignancies can affect lung parenchyma as primary site of disease or spread via infiltration. Both leukemia and lymphoma can present with discrete masses, nodules or diffuse infiltrates, and both may mimic infectious or inflammatory processes (Figure 2).

Lymphoma

Lymphoma involving lung parenchyma may be primary or secondary, and these may present as nodules, masses, consolidation or diffuse interstitial infiltrates (29). Clinical presentation may be variable and range from asymptomatic with only radiographic findings to mild or significant respiratory symptoms. Diagnosis requires tissue sampling with immunohistochemistry and flow cytometry for definitive classification.

Primary pulmonary lymphoma

Primary pulmonary lymphomas are rare and account for less than 1% of all NHL (30). They have no extra-thoracic manifestations at the time of diagnosis or for three months following diagnosis (7). The most common form is pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma, comprising 80% of primary pulmonary lymphomas. The presence of underlying autoimmune disease, particularly Sjogren syndrome, has been correlated with pulmonary MALT lymphoma. MALT lymphoma presents with a wide variety of radiographic findings, which can mimic sarcoidosis, organizing pneumonia, lymphoid interstitial pneumonia or adenocarcinoma. Patients typically respond well to treatment, which includes clinical observation, surgical resection and radiation therapy for localized cases, or systemic treatment with single agent chemotherapy or rituximab (8,30). Less common primary pulmonary lymphoproliferative disorders include pulmonary lymphomatoid granulomatosis, primary effusion lymphoma, and intravascular large B cell lymphoma (30).

Secondary pulmonary lymphoma

Secondary pulmonary involvement is more common and can occur with both NHL and HL. NHL comprises 80–90% of secondary lymphoma, and 50% will present with thoracic involvement and 24% with parenchymal disease (31). HL represents 10–15% of secondary pulmonary lymphoma and nearly 85% present with thoracic involvement with 38% having parenchymal disease (31). Imaging findings are variable, but three distinct patterns have been described including lymphangitic, nodular, and alveolar (7). In HL, pulmonary parenchymal disease is almost always associated with hilar and/or mediastinal lymphadenopathy, whereas isolated pulmonary involvement may occur with NHL (32). Histological patterns can include 5 different variations: peribronchial, perivascular, nodular alveolar, interstitial, and pleural (33).

Leukemia

Leukemia can manifest via direct infiltration of leukemic cells or leukostasis, acute lysis pneumopathy, and differentiation syndrome. Presence of mass like lesions can occur as myeloid sarcoma as well.

Leukemic pulmonary infiltration

Leukemic pulmonary infiltration is characterized by extravascular collections of leukemic cells in the lung parenchyma with no other identifiable cause for their presence (2). This most frequently occurs in the pretreatment phase and the terminal stages of disease (10). Thickening of the bronchovascular bundles and interlobular septa or reticulations may be suggestive of leukemic infiltration, as leukemic cells tend to distribute along the lymphatic vessels (34,35). Leukemic infiltration can also rarely present as nodules and be seen in a peribronchovascular, centrilobular, or random distribution. Radiographic infiltrates are reported in less than 7% of patients with leukemia but may be underdiagnosed, as histologic evidence of leukemic infiltration at autopsy ranges from 38% to 60% (35). Due to nonspecific symptoms and radiologic findings, leukemic pulmonary infiltration is difficult to distinguish from infection or pulmonary edema (36). Definitive diagnosis may be limited due to hematologic parameters, but radiographic findings and exclusion of other processes can help generate a clinical consensus. Rapid initiation of chemotherapy can produce significant clinical improvement in these cases. Hydroxyurea, judicious use of blood transfusions, and intravenous isotonic fluid infusion should all be considered if hyperleukocytosis is present.

Leukostasis

Leukostasis is a clinical diagnosis, defined as end-organ hypoperfusion in the setting of hyperleukocytosis, most commonly at 100×10³ /mm³ or greater. The prevalence of leukostasis is highest in myeloid leukemias, particularly in AML, due to decreased blast deformity and increased blast size (37). The accumulation of leukocytes in small vessels increases serum viscosity and ultimately leads to microvascular occlusion. Increased cytokine release triggers increased vascular permeability, contributing to extravasation of leukemic cells into the interstitium and alveoli (38). Treatment involves supportive care and emergent cytoreduction, which may be done with chemotherapy, hydroxyurea, or leukapheresis (39).

Leukemic cell lysis pneumopathy

Leukemic cell lysis pneumopathy is caused by diffuse lysis of tumor cells, leading to diffuse alveolar damage, pulmonary hemorrhage, and picture like acute respiratory distress syndrome (ARDS). It generally occurs within 48 hours after starting chemotherapy, most commonly in patients with ALL. Acute lysis pneumopathy is associated with leukocyte counts greater than 200×10³/mm³ with 70–90% blasts, although it has been described in patients with fewer than 50×10³ leukocytes/mm (7,40,41). The role of chemotherapy cessation is unclear, and treatment is supportive care.

Differentiation syndrome

Differentiation syndrome can be triggered by treatment of acute promyelocytic leukemia with all-trans retinoic acid (ATRA) and/or arsenic trioxide with migration and infiltration of differentiating leukemic cells in the lungs, prompting an inflammatory response and respiratory compromise (42). It has also been described in AML patients after isocitrate dehydrogenase enzyme inhibitors and a small fraction of those treated with gilteritinib (43,44). The pathogenesis is not completely understood, but it is linked to the production of inflammatory cytokines and a large burden of maturing myeloid cells as well as endothelial damage with capillary leak syndrome and occlusion of microcirculation. The onset can range from days to weeks after beginning treatment but can occur earlier in those with significant disease. Symptoms include dyspnea, fever, pericardial and pleural effusion, weight gain, hypotension and erythematous rash (45,46). Prompt clinical response to dexamethasone is supportive of the diagnosis.

Myeloid sarcoma

Myeloid sarcoma is an extramedullary presentation of myeloid malignancy, also referred to as a chloroma (21). It is differentiated from benign extramedullary hematopoiesis by the presence of blasts and the absence of trilineage hematopoiesis. Within the thorax, it may present as a mass lesion within the lung parenchyma, endobronchial tumor or pleural based disease (10,21,47). The diagnosis is confirmed by biopsy, and bone marrow biopsy should be done to rule out concomitant AML.

Tracheobronchial disease

In lymphoma, endobronchial disease is most seen in HL or in cases of primary pulmonary lymphoma, whereas in leukemia, endobronchial involvement has been described with CLL and myeloid sarcoma (2,48). Common symptoms include cough, wheezing, chest pain and occasional hemoptysis, and potentially recurrent infections. Bronchoscopy can reveal airway narrowing and nodularity, and tissue samples with immunohistochemistry are often needed for diagnosis. Evaluation for localized tracheobronchial intervention by interventional pulmonary can be considered along with systemic treatment.

Pulmonary vascular disease

Pulmonary hypertension (PH)

PH has rarely been associated with hematologic malignancies, but it has been described in each category of PH based on the WHO. Right heart catheterization is integral to the diagnosis and appropriate treatment of PH (49). Pulmonary vasodilator therapy may be considered, but consultation with a PH center of excellence is recommended.

Group 1 pulmonary arterial hypertension (PAH)

Targeted therapies can result in PAH. Dasatinib has a definite association with PAH, and possible associations with other TKIs (bosutinib, ponatinib), alkylating agents (cyclophosphamide, mitomycin C) via pulmonary veno-occlusive disease, and selective proteasome inhibitors (carfilzomib, bortezomib) have been described (49,50). Drug cessation along with pulmonary vasodilator therapies are often required (Figure 3).

Figure 3 Pulmonary arterial hypertension related to dasatinib. Young woman with chronic myeloid leukemia treated with dasatinib presented with shortness of breath, lower extremity edema, and hypoxia (85%) on room air. Chest radiograph (A) revealed cardiomegaly with enlarged pulmonary artery (arrow). Echocardiogram (B) showed right ventricular dilatation, flattened septum (arrowheads), and depressed right ventricular systolic function. She underwent right heart catheterization which revealed pulmonary hypertension. She was treated with combination pulmonary vasodilator therapy, macitentan and sildenafil, for approximately 23 months. She was titrated off therapy and chest radiograph (C) and echocardiogram (D) demonstrated resolution of pulmonary hypertension. Written informed consent from the patient for the publication of this article and accompanying images was waived as the images are retrospectively collected. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

Group 2 PH associated with left heart disease

Heart disease may also be prevalent in patients with hematologic malignancies given age of onset. For example, a study of hemodynamic parameters in patients with MPN-associated PH demonstrated an increased prevalence of group 2 PH in patients with CML, potentially related to other co-morbid conditions (51). Similarly, in a retrospective single center cohort screening for PH in myelofibrosis (MF) patients suggested cardiac etiology may be an underestimated contributor (52).

Group 3 PH associated with lung disease

Patients treated with anti-neoplastic therapies prone to drug-induced pneumonitis can develop PH due to underlying lung injury, as has been described with busulfan (53).

Group 4 PH associated with pulmonary artery obstructions

Mechanisms for PH in MPN include chronic thromboembolic pulmonary hypertension (CTEPH) particularly in with polycythemia vera and essential thrombocytosis (54). Further in population-based studies, the incidence of venous thromboembolic disease in hematological malignancies is comparable to that of solid organ tumors, and retrospective study in acute leukemia demonstrated thromboembolic disease even in those with thrombocytopenia (55-57). Thus, this population may be prone to CTEPH as well.

Group 5 PH with unclear and/or multifactorial mechanisms

PH in those with MPN can meet criteria for PAH, but these are classified in Group 5 due to unclear mechanisms (54). Some reports of resolution of MF-associated PH after treatment of disease with allogeneic hematopoietic transplantation have been reported (58). Low dose radiotherapy has also been reported to improve symptoms and hemodynamic parameters including PH and hypoxia in case series and cohorts in those thought to have extramedullary hematopoiesis from MPN (59,60).

SVC syndrome

SVC syndrome results from the intrinsic or extrinsic compression of the SVC, which is most frequently caused by lung cancer. NHL accounts for 10% of cases and manifests as superior mediastinal mass causing extrinsic compression (2). Rapid obstruction at or above the level of the azygos vein typically causes more severe symptoms, with upper extremity and chest wall edema, headache and cough. Rare life-threatening complications of SVC syndrome include cerebral and laryngeal edema, leading to neurologic and respiratory compromise respectively (61).

Pseudohypoxemia

Pseudohypoxemia, or hypoxemia out of proportion to pulmonary symptoms, may be observed in patients with hyperleukocytosis or thrombocytosis due to rapid oxygen consumption by immature leukocytes after collection, called leukocyte larceny. Cooling blood specimens on ice does not reliably improve accuracy of partial pressure of oxygen (PaO₂) measurements, therefore routine arterial blood gases should not be monitored in these patients. Pulse oximetry is the preferred method of monitoring of oxygenation (62).

Therapy-related complications

Pulmonary sequelae of chemotherapeutic agents such as bleomycin, busulfan, and cyclophosphamide have been well described. As treatments continue to evolve, adverse pulmonary manifestations may continue to emerge.

Immune checkpoint inhibitors (ICIs)

ICIs have revolutionized cancer treatment with the ability to target T cell-mediated destruction of cancer cells. Although the efficacy of ICIs has been long established in solid organ tumors, their use in hematologic malignancies has been limited to relapsed and refractory HL, but the role in other continues to evolve (63). Immune-related adverse events (irAEs) impacting the respiratory system can range from mild to severe. For example, in a cohort of relapsed/refractory lymphoma patients, the incidence of ICI-pneumonitis was 5% and typically low grade (64). Symptoms can range from cough, dyspnea, fatigue or wheezing. Radiographic findings most commonly include organizing pneumonia, but ground-glass opacities and less commonly acute interstitial pneumonia (65,66). Classification of pneumonitis symptoms based on the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) helps guide appropriate interventions (Table 3) (67). Diagnostic workup to evaluate for opportunistic infection is important especially in those with hematologic malignancy.

TKIs

Pleural effusions are the most reported TKI-associated pulmonary toxicity, followed by drug-related pneumonitis and PH (68).

Radiation

Radiation therapy may be an adjunct for treatment of diseases with intrathoracic disease burden. Acute lung injury from radiation occurs through diffuse alveolar damage, inflammation or organizing pneumonia through and proximal to radiation fields (69). After exclusion of other potential etiologies, those that are symptomatic and with temporal and radiographic correlation, corticosteroids may alleviate symptoms (70). Chronic radiation changes can include volume loss, traction bronchiectasis, and architectural distortion in the geographic region of radiation (71). Radiation recall may occur within previously treated radiation fields after exposure to certain chemotherapy (taxanes, anthracyclines, alkylating agents or pyrimidine analogs), immunotherapy, or other medications (tamoxifen, simvastatin, levofloxacin, or isoniazid) (72,73).

Chimeric antigen receptor T-Cell therapy (CAR-T)

The most common noninfectious pulmonary complication is cytokine release syndrome (CRS). CRS is a systemic inflammatory syndrome which promotes inappropriate cytokine release and widespread inflammation. Patients may experience fever, rashes, fatigue, hypoxemia, or vasodilatory shock (74). It can manifest as hypoxemia, pulmonary edema, pleural effusion and in severe cases, ARDS. Late complications of CAR-T therapy include recurrent respiratory infections due to bronchiectasis (75).

Conclusions

Hematologic malignancies can affect the thorax in a myriad of ways. As incidence and recognition of these manifestations evolve, additional data will emerge, however many of these are rare and a paucity of literature exists. These manifestations may be an initial presentation or a sign of recurrent disease, and a high clinical suspicion can help facilitate prompt diagnosis and appropriate interventions. Therapy-related sequelae may continue to emerge as treatment modalities evolve.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://atm.amegroups.com/article/view/10.21037/atm-25-139/rc

Peer Review File: Available at https://atm.amegroups.com/article/view/10.21037/atm-25-139/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-25-139/coif). S.A.F. serves as an unpaid editorial board member of Annals of Translational Medicine from June 2025 to June 2027. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Written informed consent from the patients for the publication of this article and accompanying images was waived as the images are retrospectively collected.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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