CONTENTS
- Approach to pulmonary dysfunction in a patient with cancer
- Specific disorders
- Iatrogenic:
- Other topics:
- Questions & discussion
abbreviations used in the pulmonary section: 4
- ABPA: Allergic bronchopulmonary aspergillosis 📖
- AE-ILD: Acute exacerbation of ILD 📖
- AEP: Acute eosinophilic pneumonia 📖
- AFB: Acid Fast Bacilli
- AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
- ANA: Antinuclear antibody 📖
- ANCA: Antineutrophil cytoplasmic antibodies 📖
- ARDS: Acute respiratory distress syndrome 📖
- ASS: Antisynthetase Syndrome 📖
- BAL: Bronchoalveolar lavage 📖
- BiPAP: Bilevel positive airway pressure 📖
- CEP: Chronic eosinophilic pneumonia 📖
- CF: Cystic fibrosis 📖
- COP: Cryptogenic organizing pneumonia 📖
- CPAP: Continuous positive airway pressure 📖
- CPFE: Combined pulmonary fibrosis and emphysema 📖
- CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
- CTEPH: Chronic thromboembolic pulmonary hypertension 📖
- DAD: Diffuse alveolar damage 📖
- DAH: Diffuse alveolar hemorrhage 📖
- DIP: Desquamative interstitial pneumonia 📖
- DLCO: Diffusing capacity for carbon monoxide 📖
- DRESS: Drug reaction with eosinophilia and systemic symptoms 📖
- EGPA: Eosinophilic granulomatosis with polyangiitis 📖
- FEV1: Forced expiratory volume in 1 second 📖
- FVC: Forced vital capacity 📖
- GGO: Ground glass opacity 📖
- GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
- HFNC: High flow nasal cannula 📖
- HP: Hypersensitivity pneumonitis 📖
- IPAF: Interstitial pneumonia with autoimmune features 📖
- IPF: Idiopathic pulmonary fibrosis 📖
- IVIG: Intravenous immunoglobulin 📖
- LAM: Lymphangioleiomyomatosis 📖
- LIP: Lymphocytic interstitial pneumonia 📖
- MAC: Mycobacterium Avium complex 📖
- MCTD: Mixed connective tissue disease 📖
- NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
- NSIP: Nonspecific interstitial pneumonia 📖
- NTM: Non-tuberculous mycobacteria 📖
- OHS: Obesity hypoventilation syndrome 📖
- OP: Organizing pneumonia 📖
- OSA: Obstructive sleep apnea 📖
- PAP: Pulmonary alveolar proteinosis 📖
- PE: Pulmonary embolism 📖
- PFT: Pulmonary function test 📖
- PLCH: Pulmonary Langerhans Cell Histiocytosis 📖
- PPFE: Pleuroparenchymal fibroelastosis 📖
- PPF: Progressive pulmonary fibrosis 📖
- PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
- RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
- RP-ILD: Rapidly progressive interstitial lung disease 📖
- TNF: tumor necrosis factor
- UIP: Usual Interstitial Pneumonia 📖
differential diagnosis
Differential diagnosis depends heavily on history, presentation, and radiological findings. Patients who are status post bone marrow transplantation require numerous additional considerations. 📖 Some considerations include the following:
parenchymal lung disease
- Tumor itself:
- Lymphangitic carcinomatosis.
- Parenchymal lung metastases.
- Leukemia:
- Pulmonary leukostasis.
- Pulmonary leukemic infiltrates.
- Iatrogenic:
- Radiation pneumonitis.
- Drug-induced pneumonitis, e.g.:
- Chemotherapy.
- Checkpoint-inhibitor pneumonitis.
- TRALI (transfusion related acute lung injury).
- Pneumonia:
- Community acquired pneumonia.
- Opportunistic infections, e.g.:
- Pneumocystis.
- Fungal pneumonia.
- Aspiration (due to neurological involvement).
- DAH (diffuse alveolar hemorrhage):
- Acute promyelocytic leukemia.
- Following bone marrow transplantation.
pleural disease
- Effusion due to pulmonary embolism.
- Malignant pleural effusion.
pulmonary vascular disease
- Pulmonary embolism.
- Pulmonary tumor emboli.
cardiovascular
- Myocardial infarction (e.g., following thoracic radiotherapy).
- Myocardial dysfunction, e.g.:
- Anthracycline chemotherapy.
- Checkpoint inhibitor myocarditis.
- Malignant pericardial effusion.
neuromuscular disease (rare)
- Checkpoint inhibitor-related myasthenia gravis.
- Paraneoplastic neuropathy or myopathy.
airway disease (rare)
- Airway metastases.
- Bronchiolitis obliterans (e.g., due to chemotherapy).
initial investigations to consider
- CT scan of the chest with contrast (evaluates parenchyma, large airways, larger pulmonary arteries).
- Echocardiography.
- Bedside pulmonary function tests (forced vital capacity, negative inspiratory force).
epidemiology
- Lung metastases often occur in the context of known systemic malignancy.
- Relative propensity of various tumors to metastasize to the lungs:
- Choriocarcinoma (~80%).
- Osteosarcoma (~75%).
- Kidney (~75%).
- Thyroid (~70%).
- Melanoma (~65%).
- Breast (~55%).
- Prostate (~45%).
- Nasopharyngeal, gastrointestinal, gynecological (~20%).
- The most common sources of metastasis from extrathoracic malignancy are breast, colon, kidney, uterus, prostate, and head/neck cancers.
- Cancers which are more likely to present initially with lung metastasis: Choriocarcinoma, testicular carcinoma, renal cell carcinoma, thyroid carcinoma.
symptoms
- Metastatic lesions tend not to cause symptoms until they are quite advanced. Nodules tend to displace lung tissue, leaving patients minimally symptomatic despite extensive radiographic disease.
- Dyspnea, cough, or chest pain may occur.
- Metastatic lesions may cause more symptoms under the following conditions: (Murray 2022)
- Tumor infiltrates the lung parenchyma (lymphangitic carcinomatosis).
- Tumor involves the large airway(s).
- Large pleural effusion occurs.
radiology
(#1) usually, lesions have a nodular configuration
- Typical features of metastatic lesions:
- Metastases are often round lesions with smooth (well-demarcated) borders.
- Lesions may tend to distribute in the lung base and periphery.
- Nodules often vary in size.
- Occasionally, additional features may be seen that can provide additional information:
- Hemorrhagic lesions may generate a halo sign, for example:
- Choriocarcinoma.
- Angiosarcoma.
- Melanoma.
- Renal cell carcinoma.
- Kaposi sarcoma.
- Profuse miliary, micronodular lesions may occur with some types of cancer:
- Thyroid carcinoma.
- Renal carcinoma.
- Bone sarcoma.
- Trophoblastic disease.
- Melanoma.
- Cavitation (may rarely predispose to pneumothorax):
- Squamous cell neoplasms have a tendency to cavitate (including head/neck or cervical cancer primary sites).
- Sarcomas cavitate more often than carcinomas (but they are overall less common).
- More common adenocarcinomas causing cavitation include: uterine, cervical, colon carcinoma, and transitional cell carcinoma.
- Calcification of metastatic lesions is uncommon, but may occur with:
- Osteosarcoma, chondrosarcoma, synovial cell sarcoma.
- Carcinoma of the colon, ovary, breast, or thyroid.
- Metastatic disease status post treatment.
- Classic “cannonball” lesions (with large, well-defined nodules):
- Sarcoma.
- Gastrointestinal malignancy (especially colon).
- Testicular tumors.
- Uterine carcinoma.
- Solitary metastatic lesion is most common with: (Walker 2019)
- Kidney.
- Testicle.
- Breast.
- Colon.
- Sarcomas (especially osteosarcomas).
- Melanoma.
(#2) occasionally, metastatic disease may spread within the alveoli
- ~15% of metastatic lesions grow within the alveoli in a lepidic pattern. This will radiographically mimic invasive mucinous adenocarcinoma of the lung (previously called mucinous bronchoalveolar carcinoma). The most common causes of this metastatic pattern are adenocarcinoma of the pancreas, colon, breast, stomach, or kidney. (32768080)
- Radiographic appearance may vary, including: (32768080)
- Nodules (which may be poorly defined, for example with a halo sign).
- Ground-glass attenuation.
- Consolidation.
differential diagnosis
- If only a single lesion is present, the differential often centers around metastasis versus primary lung cancer.
evaluation
- CT chest/abdomen/pelvis, and/or PET scan may be helpful in unclear situations:
- Extensive metastatic disease beyond the lung would support the diagnosis of metastatic malignancy. This may also help to discover potential sites for tissue biopsy (which may be less invasive than lung biopsy).
- Absence of cancer activity outside the lung may suggest a primary lung cancer, or nonmalignant diagnosis.
- Tissue biopsy may be needed if diagnostic uncertainty persists and a diagnosis would change management. Options will depend on the nature of the lesion (often involving either CT-guided percutaneous biopsy or excisional surgical biopsy).
treatment
- Management is complex. Ideally a multidisciplinary tumor board may help coordinate various disciplines.
- Treatment may center around systemic therapy for the underlying malignancy.
- Germ cell tumors, neuroblastoma, lymphoma, choriocarcinoma, and osteosarcoma may be curable despite the presence of lung metastasis. (Murray 2022)
- Rarely, a solitary pulmonary metastatic lesion may be surgically resected (metastasectomy). This may be considered if the primary tumor is controlled, there is no other evidence of extrathoracic metastatic disease, and complete resection is possible.
- Stereotactic ablative radiotherapy (SABR) may extend survival in selected patients with oligometastatic disease.
definitions:
- Leukostasis refers to elevated white blood cell counts that cause impaired tissue perfusion due to elevations in blood viscosity.
- Hyperleukocytosis refers to a peripheral white blood cell count >100,000/uL. Hyperleukocytosis may or may not cause clinical leukostasis.
epidemiology
- Leukostasis occurs when very high levels of white blood cells increase blood viscosity, impairing perfusion.
- There is no accepted minimum leukocyte count for the diagnosis of leukostasis. However, leukostasis should be considered more strongly when the white blood cell count is >100,000/uL with >20% blasts. (30037446)
risk varies depending on the type of leukemia
- AML (Acute myeloid leukemia):
- Highest risk of leukostasis.
- Leukostasis can occur even if WBC is <50,000/uL. Myeloid blasts are larger than immature lymphocytes or mature granulocytes, causing the greatest risk of leukostasis. (33280778)
- Leukostasis usually occurs within the context of a blast crisis.
- In APL (acute promyelocytic leukemia), ATRA (all-trans retinoic acid) and/or arsenic trioxide may cause treatment-emergent hyperleukocytosis as a component of differentiation syndrome. (35357988)
- ALL (acute lymphocytic leukemia): Low-moderate risk of leukostasis.
- CML (chronic myeloid leukemia): Low risk of leukostasis.
- CLL (chronic lymphocytic leukemia): Very low risk of leukostasis; leukostasis is almost exclusively seen at WBC >1,000,000/uL. (35357988)
presentation & clinical manifestations
pulmonary manifestations
- Dyspnea.
- Cough.
- Diffuse alveolar hemorrhage can occur. (35357988)
- Hypoxemia (frequently requiring intubation).
neurologic manifestations
- Symptoms may vary:
- Neuroimaging findings are nonspecific (e.g., neuroimaging may show ischemic and hemorrhagic areas, edema, or masses). (27018197)
- Differential diagnosis: parenchymal infiltration by leukemic cells. (35357988)
cardiac effects
- Heart failure.
- Chest pain.
- Myocardial infarction. (35357988)
other manifestations
- Fever occurs in most patients. (35357988)
- Renal failure (including renal vein thrombosis).
- Acute limb ischemia; bowel ischemia.
- Deep vein thrombosis.
- Priapism. (30037446)
radiology
- Chest radiograph may be normal, or may show an alveolar pattern of infiltrates. (27018197)
- Imaging findings resemble those of pulmonary edema (e.g., septal thickening).
evaluation
laboratory evaluation should generally involve:
- Complete blood count with manual differential.
- Electrolytes, Ca/Mg/Phos, uric acid.
- INR, PTT, fibrinogen, D-dimer (to evaluate for DIC).
three laboratory artifacts often occur in hyperleukocytosis:
- (1) Pseudohyperkalemia: Measurement of potassium using a portable bedside blood gas analyzer may be more accurate. More on pseudohyperkalemia here: 📖
- (2) Pseudohypoxemia on arterial blood gas specimens (“leukocyte larceny”). Pulse oximetry is generally a more accurate modality for assessing oxygenation.
- (3) Hyperleukocytosis may cause overestimation of reported platelet counts, since leukemic cell fragments may be interpreted by automated hemocytometers as platelets. Manual smear review may help reveal the diagnosis of thrombocytopenia. (35357988)
other diagnostics to consider:
- Chest radiograph.
- Neuroimaging, as clinically indicated.
- Bone marrow biopsy is often needed.
treatment
volume status & transfusion
- Blood transfusion should be avoided if possible, as this may increase blood viscosity.
- Volume resuscitation with crystalloid should be utilized for patients with hypovolemia. Among hypovolemic patients, crystalloid administration will dilute the blood and thereby improve the viscosity. (30037446)
prophylaxis/management of TLS (tumor lysis syndrome)
- Background:
- Spontaneous tumor lysis syndrome may occur in ~10% of patients with leukostasis, even before the initiation of chemotherapy. (30037446)
- The risk of tumor lysis syndrome following chemotherapy is high.
- Prophylaxis for TLS is essential for patients with leukostasis (discussed here: 📖).
- If TLS occurs, it should be treated: 📖.
aggressive investigation and treatment for infection
- Despite elevated white blood cell count, patients may be neutropenic (either with a reduced absolute number of neutrophils, or “functional neutropenia” due to a lack of normal neutrophils).
- Early empiric initiation of antibiotics may be reasonable, if infection is suspected. (27018197)
management of thrombocytopenia and/or DIC (if present)
- Patients with definite or suspected APL (acute promyelocytic leukemia) should be started empirically on all-trans retinoic acid (ATRA): 📖.
- Thrombocytopenia may result from bone marrow infiltration and/or disseminated intravascular coagulation. Platelet transfusion may reduce the risk of intracranial hemorrhage (more on the management of thrombocytopenia here: 📖).
steroid
- Potential roles of steroid therapy:
- In ALL or CLL, steroid may reduce the lymphocyte count.
- Steroid may reduce expression of leukocyte adhesion molecules, thereby allowing leukocytes to pass more easily through capillaries. (35357988)
- Steroid may reduce secondary inflammation and cytokines that cause tissue damage (e.g., ARDS). (35357988)
- One retrospective review of outcomes at a single center found a reduction in all-cause mortality after routine implementation of dexamethasone 10 mg BID for three days for patients with AML and hyperleukocytosis. (29519869)
measures to reduce the white cell count
- ⚠️ Leukostasis is a hematologic emergency – hematology should be consulted immediately.
- Cytoreductive chemotherapy is the key intervention (often beginning with hydroxyurea, before precise identification of the leukemia type allows for more definitive chemotherapy).
- Leukapheresis is controversial, lacking any robust evidentiary basis. (29519869)
- Leukapheresis removes cells from the blood but doesn't remove proliferating blasts from the bone marrow. Consequently, leukapheresis without chemotherapy will generally fail (effects will be minimal and/or transient). On the other hand, early chemotherapy alone may provide sufficient therapy for cytopenias – thereby eliminating any additional benefit from mechanical cytoreduction. (29519869)
- Leukapheresis shouldn't be used for patients with acute promyelocytic leukemia, as this may trigger worsening coagulopathy. (31483060; 27018197) Other risks of leukapheresis may include complications from vascular access insertion, immunologic reactions, citrate-mediated hypocalcemia, and platelet loss. (29519869)
basics
- Leukemic infiltrates are often seen on pathology specimens without clinical or radiological findings. Consequently, the detection of leukemic infiltrates doesn't necessarily indicate that these are responsible for the patient's deterioration. (33280778)
clinical manifestations
- Symptoms may include cough, dyspnea, and/or low-grade fevers.
radiology findings are highly variable, including:
- Thickening of interlobular septa and bronchovascular bundles is often a prominent feature.
- Septal thickening may be either smooth or nodular. (Walker 2019)
- Small nodules are commonly seen, which may include centrilobular nodules in a tree-in-bud pattern. (29884276)
- Areas of ground-glass opacification or consolidation may occur, often in a peribronchial distribution. (29184595)
diagnosis
- Diagnosis generally requires lung biopsy (either bronchoscopic, transthoracic CT-guided, or surgical). (29884276)
management
- Treatment of the underlying leukemia.
more common causes
- Most common: (ERS handbook, 3rd ed.)
- Colorectal carcinoma.
- Renal cell carcinoma.
- Lung cancer.
- Breast cancer.
- Melanoma.
- Gastric carcinoma.
- Prostate carcinoma.
- Hodgkin lymphoma.
- Cervical cancer.
- Sarcoma.
symptoms
- Dyspnea.
- Cough: (Rosado-de-Christenson 2022)
- Hemoptysis (especially with hypervascular tumors, such as melanoma and renal cell carcinoma).
- Rarely, tissue fragments may be expectorated.
- Obstructive atelectasis:
- Lobar collapse.
- Postobstructive pneumonia.
diagnosis
chest radiograph
- Atelectasis may be seen.
- Lesion(s) themselves are rarely visible.
CT scan
- Endoluminal soft tissue lesions may be seen.
- Tumors may have a polypoid or finger-in-glove appearance with bronchial dilation.
- Typically, lesions will enhance with IV contrast administration, especially renal carcinoma. (Walker 2019; ERS handbook 3rd ed.)
- Consequences of airway obstruction may be notable:
- Atelectasis.
- Fluid-filled bronchi distal to the obstruction (drowned lung).
- Other evidence of metastatic cancer may be present (e.g., parenchymal lung metastases).
bronchoscopy
- Melanoma may produce black endobronchial lesions.
- ⚠️ Endobronchial biopsy may provoke bleeding, especially with renal cell carcinoma. This is generally unwise (unless rigid bronchoscopy is immediately available to control any bleeding).
management
- Radiation may be used for radiosensitive tumors.
- Interventional pulmonology techniques may be useful, especially in radioresistant tumors (e.g., laser, physical debridement, argon plasma coagulation). (Murray 2022)
Lymphangitic carcinomatosis involves tumor infiltration and growth within the pulmonary lymphatic system.
epidemiology
- Lymphangitic carcinomatosis follows hematogenous dissemination to the lungs, usually due to adenocarcinoma:
- Lung adenocarcinoma (may occur ipsilateral or contralateral to the primary tumor).
- Other adenocarcinomas (including breast, gastric, pancreas, colon, liver, prostate, ovarian, cervix, kidney).
- (Less often, malignancy may spread from mediastinal and hilar lymph nodes outwards, into peripheral lymphatics.)
clinical presentation
- Severe, rapidly progressive dyspnea and hypoxemia. This usually progresses much faster than other interstitial lung diseases.
- Dry cough.
- Chest pain may occur. (ERS handbook 3rd ed.)
radiology
chest radiograph
- Lymphangitic carcinomatosis can mimic heart failure.
- Septal thickening may produce Kerley B lines.
- Reticular or reticulo-nodular parenchymal abnormalities may occur.
CT scan
- Thickening of the interlobular septa, fissures, and bronchovascular bundles are characteristic. This may be smooth or nodular.
- Nodularity suggests malignancy rather than heart failure, if this is seen.
- (Further discussion of septal thickening and nodularity here: 📖)
- Areas of ground-glass opacity.
- Pleural effusion (~50% of cases). (Shepard 2019, Walker 2019)
- Centrilobular nodules may occur due to thickened interstitium surrounding the bronchovascular bundles (figure below).
- Hilar and mediastinal lymphadenopathy may occur in ~40% (especially in lymphangitic carcinomatosis due to lung cancer).
distribution
- Extrathoracic malignancy may tend to involve the bilateral lungs.
- Lung cancer may tend to cause lymphangitic carcinomatosis in a single lung, ipsilateral to the primary tumor.
diagnosis
- For patients with known malignancy and typical CT findings, this may be sufficient to reach a provisional diagnosis. Since there is no specific therapy for lymphangitic carcinomatosis, it may not be worth subjecting the patient to an invasive procedure in order to prove the diagnosis.
- Bronchoscopy may yield the diagnosis (e.g., based on malignant cells found in the bronchoalveolar lavage). Transbronchial biopsy increases diagnostic yield, at the cost of increased procedural risk. (25237994)
- In some patients with malignancy, it may be difficult to differentiate between lymphangitic carcinomatosis versus heart failure. A trial of diuretic therapy may be reasonable – if this causes clinical and radiological improvement, then the diagnosis of heart failure is secured.
management
- Treatment may involve various systemic therapies directed towards the underlying malignancy.
prognosis
- Prognosis is generally poor. For example, one review found a median survival of 3 weeks following hospital admission with lymphangitic carcinomatosis. (34872679)
basics
- Tumor cells within the pulmonary vasculature incite fibrin deposition and fibrocellular intimal proliferation.
- Radiologically, this may produce a pattern of centrilobular nodules (discussed further below).
- This can occasionally coexist with lymphangitic carcinomatosis (discussed above).
epidemiology
overall epidemiology
- Pulmonary tumor emboli generally occurs in the context of known malignancy. However, occasionally pulmonary tumor emboli may be the presenting manifestation of cancer.
- Among patients dying of malignancy, ~2% have pulmonary tumor thrombotic microangiopathy (based on autopsy studies). Rates may be higher among gastric adenocarcinoma (perhaps ~15%). (27502464)
- However, pulmonary tumor thrombotic microangiopathy is difficult to diagnose, so the frequency of antemortem diagnosis is <1%.
usually caused by mucin-secreting adenocarcinomas
- #1) Gastrointestinal cancer (gastric >> pancreatic, esophageal, liver, gallbladder).
- #2) Bronchogenic adenocarcinoma.
- Breast cancer.
- Prostate cancer.
- Choriocarcinoma.
clinical presentation is dominated by subacute pulmonary hypertension
- Dyspnea is the most common symptom (usually subacute and progressive over a period of weeks).
- Nonproductive cough may occur. (34022028)
- Hypoxemia eventually will emerge.
- Eventually, right ventricular failure (cor pulmonale) causes peripheral edema and reduced cardiac output.
laboratory studies
- Consumptive coagulopathy may result from chronic disseminated intravascular coagulation:
- Elevated D-dimer.
- Thrombocytopenia.
- Elevated INR.
- Microangiopathic hemolytic anemia (MAHA) can occur: (35103561)
- Schistocytes present on blood smear.
- Anemia.
- Elevated LDH (lactate dehydrogenase).
radiology
(1) radiographic features of pulmonary hypertension
- Dilation of the right ventricle and pulmonary artery.
- Contrast reflux into the inferior vena cava.
(2) pulmonary tumor thrombotic microangiopathy (PTTM):
- (1) Tree-in-bud pattern may occur:
- Centrilobular nodules may be diffusely distributed, or they may have a more focal distribution.
- Individual nodules are often larger than most tree-in-bud patterns (e.g., those seen with bronchiolitis). Additionally, serial imaging may reveal progressive enlargement of the nodules. (31042088)
- (2) Surrounding ground-glass opacities can be seen (likely reflective of interstitial or airspace edema). (33160547)
- (3) Smooth septal thickening may occur, due to obstruction of pulmonary venules causing hydrostatic edema.
- (4) CT angiogram may reveal dilated and beaded peripheral pulmonary arteries in some patients. (25940260)
(3) ventilation-perfusion (VQ) scan
- VQ scan may show multiple peripheral subsegmental perfusion defects that are evenly distributed throughout both lungs (whereas the ventilation scan should be normal). (33160547, 32023378) This pattern may also occur in pulmonary vasculitis, fat emboli, or idiopathic pulmonary arterial hypertension. (28763265)
- Differentiation of PTTM vs. CTEPH (chronic thromboembolic pulmonary hypertension): (35103561)
- Wedge-shaped infarcts and a mosaic pattern on CT scan may suggest CTEPH.
- Cough is usually seen in PTTM, but atypical of CTEPH.
- PTTM is usually subacutely progressive, whereas CTEPH is more stable over time.
hemodynamic investigations
serial echocardiography
- Serial echocardiography may show rapidly progressive pulmonary hypertension and right ventricular failure.
pulmonary artery catheterization
- Pulmonary artery catheterization generally shouldn't be performed for the sole purpose of identifying tumor emboli (since the performance is poor). Nonetheless, it's possible that a pulmonary artery catheterization may be performed mostly for another indication.
- Pulmonary artery wedge aspiration cytology may reveal malignant cells. However, the performance is poor:
- Malignant cells may sometimes be found in patients without significant pulmonary hypertension.
- Malignant cells may be confused with megakaryocytes that reside within the pulmonary capillary lumen.
- To perform this test: wedge the pulmonary artery catheter, discard 10-15 ml of blood, then send 10 cc of blood in a heparinized tube for cytology.
surgical lung biopsy
- This may be required to obtain the diagnosis, particularly in the context of a patient without any known primary tumor.
- Among patients with known advanced malignancy, there is little rationale for performing a surgical biopsy (since this will not alter management).
- If there is substantial pulmonary hypertension or coagulopathy, these will increase the risk of any lung biopsy procedure. (35103561)
treatment
- Treatment generally focuses on management of the underlying malignancy. Unfortunately, at the time of diagnosis, many patients don't have adequate performance status to receive chemotherapy. (32023378)
- (1) Some cancers may be sensitive to chemotherapy, targeted therapy, or immunotherapy.
- (2) The primary tumor may rarely be eligible for surgical resection (e.g., atrial myxoma or renal cell carcinoma). If possible, resection might theoretically prevent ongoing embolization.
- Anticoagulation has no proven benefit.
- It's possible that in-situ thrombosis could aggravate pulmonary tumor emboli among patients with pulmonary tumor microangiopathy. This condition is too rare to investigate rigorously.
- Pulmonary hypertension may be treated supportively (e.g., with pulmonary vasodilators). (32023378)
prognosis
- Pulmonary tumor emboli is almost uniformly fatal.
- Survival tends to be measured in one or a few months.
basics
- This usually involves multiple noninvasive/nonaggressive, well-circumscribed metastases from a uterine leiomyoma (aka fibroids). Tumors are composed of differentiated smooth muscle cells.
- BML usually involves the lungs and lymph nodes, but it can occur elsewhere (e.g., mediastinum, retroperitoneum, bone, heart, spine, soft tissues, abdomen, skeletal muscle).
clinical presentation
- Pulmonary symptoms:
- BLM is usually asymptomatic (discovered as an incidental imaging finding).
- Symptoms can occur (including cough, wheezing, dyspnea, pleuritic chest pain).
- Cysts and pneumothorax can occur (causing confusion with a diagnosis of lymphangioleiomyomatosis).
- Symptomatic uterine fibroids may cause uterine bleeding, pelvic discomfort, and reproductive dysfunction. (Fishman 2023)
epidemiology
- BML is extremely rare (with reported cases numbering only in the hundreds).
- Premenopausal women account for most active disease cases. However, BML may not be diagnosed until decades later (so it's diagnosed among women ~30-75 years old).
- Most patients have a history of uterine myomectomy or hysterectomy for management of known leiomyoma(s).
radiology
- Usually, numerous well-circumscribed nodules are seen in a random distribution (consistent with hematogenous dissemination).
- Nodules may undergo cavitation, ultimately leading to the formation of cysts.
- If PET/CT is performed, lesions should have minimal uptake (because they are very indolent and metabolically quiescent). (35913461)
diagnosis
- Tissue biopsy is generally needed (given the rarity of this syndrome, other possibilities may be statistically more likely).
- Histology shows well-differentiated, spindle-shaped cells.
- Immunohistochemical staining is often positive for desmin, actin, vimentin, caldesmon, estrogen-receptors, and progesterone-receptors.
- The mitotic index should be low (<5 mitoses per ten in a high-powered field).
- It may be difficult to distinguish BML from more aggressive diseases (e.g., leiomyosarcoma).
treatment
- Prognosis is generally favorable.
- BML tumors may respond to hormonal manipulations that reduce estrogen levels (e.g., gonadotropin releasing hormone analogs, progesterone therapy, aromatase inhibitors). However, BML is often asymptomatic, so it is unclear whether such treatments are truly beneficial.
epidemiology & risk assessment
overall risk
- PD-1 inhibitors (~4%) > PD-L1 inhibitors (~2%) >> CTLA-4-inhibitors (<1%). (32541313, 31584861, ESMO 2022 36270461)
- PD-1 inhibitors: nivolumab, pembrolizumab, cemiplimab.
- PD-L1 inhibitors: atezolizumab, avelumab, durvalumab.
- CTLA-4 inhibitors: ipilimumab, tremelimumab. (35332071)
- Use of multiple checkpoint inhibitors increases the risk (10% vs. ~3%), even if given sequentially rather than simultaneously. (32187473, 32880733)
- Other risk factors:
- Preexisting interstitial lung disease.
- Underlying lung or renal cell cancer.
- Radiotherapy, chemotherapy, or EGFR-TKI (epidermal growth factor receptor – tyrosine kinase inhibitor)(discussed further below).
timing
- Median onset after ~3-8 months. (31584861, 32187473, 34724392)
- Onset ranges from 1 week – 2 years. (34724392; 33594904)
clinical presentation
Severity ranges from subclinical to frank respiratory failure.
common symptoms
- Dyspnea (50%).
- Dry cough (35%).
- Productive cough usually doesn't occur. (29162153)
- Fever occurs in ~15% of patients. (33929306)
- Chest pain (7%). (27646942)
differential diagnosis includes:
alternative diagnoses
- Heart failure (e.g., checkpoint-inhibitor induced myocarditis).
- Infection (including opportunistic infection such as pneumocystis, if immunosuppressed by steroid or chemotherapy).
- Pulmonary embolism (both malignancy and checkpoint-inhibitors increase risk).
- Progression of malignancy:
- Lymphangitic infiltration of the lung.
- Lung metastases.
- Pulmonary tumor emboli.
- Pseudoprogression: Inflammation may cause tumor present in the lungs to enlarge. This may mimic progression of malignancy, but it actually reflects a favorable treatment response.
- Neuromuscular weakness (e.g., checkpoint inhibitor-induced myasthenia gravis, myositis, or Guillain-Barre Syndrome).
hybrid diagnoses
- Immune checkpoint inhibitors may augment pneumonitis due to other causes:
- Radiation pneumonitis.
- Pneumonitis due to chemotherapy.
- Flare of underlying interstitial lung disease.
- The overall result of a checkpoint inhibitor plus one of these processes may produce a hybrid condition that may represent some combination of checkpoint inhibitor pneumonitis plus a second type of pneumonitis. Clinically it may be difficult to discern the dominant process.
- Two examples are discussed below:
- Hybrid ICI + EGFR-TKI.
- Hybrid ICI + radiotherapy.
hybrid checkpoint inhibitor pneumonitis plus EGFR-TKI (epidermal growth factor receptor – tyrosine kinase inhibitor) pneumonitis
- EGFR-TKI medications may themselves cause pneumonitis. Co-administration of a checkpoint inhibitor plus EGFR-TKI may lead to synergistically elevated rates of pneumonitis. For example, when osimertinib was combined with durvalumab (a PD-L1-inhibitor), the incidence of interstitial lung disease was as high as 22% – causing the TATTON trial to be terminated prematurely. (33466795)
- Hybrid checkpoint inhibitor pneumonitis + EGFR-TKI pneumonitis may result from co-administration or administration of EGFR-TKI after checkpoint inhibitors (noting that checkpoint inhibitor pneumonitis may be substantially delayed following exposure to checkpoint inhibitors). (33594904)
- Pneumonitis due to EGFR-TKI is frequently associated with radiologic features that are largely indistinguishable from checkpoint inhibitor pneumonitis (e.g., patterns that resemble NSIP, OP, or DAD). (33466795)
- The treatment for checkpoint inhibitor pneumonitis + EGFR-TKI pneumonitis is not well defined. Steroid is front-line therapy for both checkpoint inhibitor pneumonitis as well as for EGFR-TKI pneumonitis, so this is a logical place to start. For EGFR-TKI pneumonitis some case reports have described patients who failed to respond to moderate-dose steroids but did respond to 500-1000 mg/day methylprednisolone for three days, so this could be a consideration. (33466795) Other potential therapies for checkpoint inhibitor pneumonitis should be considered as well (discussed below).
hybrid checkpoint inhibitor pneumonitis plus radiation pneumonitis
- Prior or ongoing lung radiotherapy is often considered a risk factor for checkpoint inhibitor pneumonitis.
- Immune checkpoint inhibitors may cause “radiation recall,” wherein ground-glass or consolidative opacities occur that are confined to a prior radiation field.
radiology
basics
- Chest radiograph has a sensitivity of only ~75%. (27646942)
- CT scan is required. Consider using contrast to evaluate for pulmonary embolism.
- Red flags: Some features aren't commonly seen (cavitation, pleural effusion). These should arouse suspicion for an alternative diagnosis.
- Radiographic and pathological patterns are variable, mimicking an array of interstitial diseases. The most common patterns are OP (organizing pneumonia), NSIP (nonspecific interstitial pneumonia), or DAD (diffuse alveolar damage). On average a DAD pattern is associated with highest disease severity, an OP pattern is associated with intermediate severity, and NSIP or HP patterns are associated with less severe disease. (33594904)
OP (organizing pneumonia) pattern is most common
- Radiological features:
- Bilateral peribronchovascular and subpleural ground-glass and airspace opacities.
- Mid-lung to lower-lung predominance.
- May also see: Reversed halo or atoll sign, pulmonary nodules/masses, reticular opacities.
- Differential diagnosis may include:
- Progression of malignancy.
- Infection, including fungal.
NSIP (nonspecific interstitial pneumonitis) pattern
- Radiological features:
- Relatively symmetric ground-glass and reticular opacities with a basilar predominance.
- Immediate subpleural sparing.
- May be associated with volume loss and traction bronchiectasis. (33594904)
- Differential diagnosis may include: Other causes of NSIP, infection.
DAD (diffuse alveolar damage)
- Radiologic findings: 📖
- Diffuse or multifocal ground-glass opacities or consolidation. The majority of the lung, or even the entire lung, may be involved (both OP or DAD may cause ground-glass opacities, but in DAD the ground-glass opacities are more widespread).
- Often associated with lung volume loss and traction bronchiectasis. (33594904)
- Interlobular septal thickening with a crazy-paving pattern may be present.
- Pathology in some cases has revealed diffuse alveolar damage. (32880733)
- Differential diagnosis: Cardiogenic pulmonary edema, ARDS due to other etiologies, pulmonary hemorrhage, infection including pneumocystis.
other patterns that have been reported:
- Hypersensitivity pattern (HP):
- Diffuse or centrilobular ground-glass nodules with a mid-to-upper lobe predominance.
- Air trapping may occur.
- (Differential diagnosis: Exposure-related hypersensitivity pneumonitis, follicular bronchiolitis, atypical infection.)
- Bronchiolitis:
- Centrilobular nodules with tree-in-bud nodularity.
- May visualize adjacent ground-glass opacities and/or consolidation (but this shouldn't be the predominant finding).
- (Differential diagnosis: Aspiration, infection.)
- Sarcoidosis mimic: 📖
basic evaluation
radiology
- Chest CT scan should be performed.
- CT angiography should be done if pulmonary embolism is a possibility.
laboratory studies
- Noninfectious workup:
- D-dimer may be considered.
- BNP (brain natriuretic peptide) may be considered.
- Blood cultures.
- Sputum culture and Gram stain (if productive cough – note that sputum expectoration would be unusual for checkpoint inhibitor pneumonitis).
- Procalcitonin.
- MRSA nares PCR.
- Nares PCR for viral pathogens (e.g., COVID, influenza, extended viral panel).
- Urine pneumococcal and Legionella antigens.
- If concern for fungal infection:
- Beta-D-glucan serum level.
- Urine antigens for Histoplasma, Blastomyces.
- Serum cryptococcal antigen (CrAg).
- (Further discussion of noninvasive infectious evaluation here: 📖).
other tests
- Bedside pulmonary function tests: If concern for neuromuscular weakness, check negative inspiratory force (NIF) and forced vital capacity (FVC).
- Echocardiography to evaluate for myocarditis.
bronchoscopy
role of bronchoscopy?
- The utility of bronchoscopy in suspected checkpoint inhibitor pneumonitis currently unknown. (30189190) While some authors promote the use of bronchoscopy, others report treating patients empirically without bronchoscopy. (26865455)
- There is no finding on bronchoscopy that proves the diagnosis of checkpoint inhibitor pneumonitis.
- The role of bronchoscopy is primarily to exclude infection (especially pathogens that require specific antibiotic therapy such as fungi, tuberculosis, or pneumocystis). Thus, bronchoscopy is most important among patients with immunocompromise or imaging features suggestive of fungal/mycobacterial infection (e.g. nodular infiltrates, cavitation).
should unstable patients be intubated solely to facilitate bronchoscopy?
- Many patients are encountered who are doing OK, yet are too unstable for bronchoscopy (e.g., on 60-80% FiO2 via high-flow nasal cannula). A classic conundrum is whether to intubate such patients in order to facilitate bronchoscopy.
- For each patient, the benefits of bronchoscopy must be weighed against the risks of intubation and mechanical ventilation. This should involve an informed discussion with the patient, including risks/benefits of various strategies.
- From an evidentiary standpoint, bronchoscopy has never been shown to improve mortality (not even among immunosuppressed pneumonia patients). Meanwhile, intubation of critically ill patients has repeatedly been demonstrated to carry a small, yet real, mortality of ~2%. (22174463) Intubation also increases the risk of delirium and ventilator-associated pneumonia. This makes intubation solely for the purpose of bronchoscopy difficult to justify.
- A reasonable compromise may be to initiate empiric therapy and consider delayed bronchoscopy after 1-2 days (by which point the patient will often have improved). Delaying bronchoscopy will reduce the yield for bacterial pathogens, but Pneumocystis and fungal studies are likely to remain positive. Sometimes lab tests will return within this time frame, which make bronchoscopy unnecessary (e.g., positive urine pneumococcal antigen).
grading
- Grade 1:
- Definition:
- Asymptomatic.
- Confined to one lobe of the lung, or <25% of lung parenchyma.
- Clinical or diagnostic observations only.
- Management:
- Hold checkpoint inhibitor.
- Carefully follow patient, including serial imaging.
- If there is clinical improvement, may resume checkpoint inhibitor.
- If no improvement, treat as Grade 2 (discussed below).
- Definition:
- Grade 2 definition:
- Symptomatic, with limitation in the instrumental activities of daily living.
- Involves more than one lobe of the lung or 25-50% of the lung parenchyma.
- Medical intervention is indicated.
- Grade 3 definition:
- Severe symptoms, requiring hospitalization and limiting self-care activities of daily life.
- Involves all lobes or >50% of the lung parenchyma.
- Oxygen therapy is needed.
- Grade 4 definition:
- Life-threatening respiratory compromise.
- Urgent intervention indicated (e.g., intubation).
treatment of Grade 2-4 toxicity
antimicrobial therapy
- It is rarely possible to be entirely certain of the diagnosis of checkpoint inhibitor pneumonitis immediately, so patients will often be covered with antibiotics. As laboratory tests return and the diagnosis becomes clear, these antibiotics should be discontinued.
- 1) Antibacterial therapy
- Most patients will be treated initially to cover pneumonia (e.g. ceftriaxone plus azithromycin, or trimethoprim-sulfamethoxazole plus azithromycin).
- 2) Pneumocystis therapy
- Pneumocystis can cause radiographic patterns that look exactly like checkpoint inhibitor pneumonitis (e.g., diffuse, patchy, ground-glass opacification).
- Empiric therapy with trimethoprim-sulfamethoxazole may be reasonable if the patient is at risk for Pneumocystis and has a CT scan which is consistent with Pneumocystis.
- 3) Antifungal therapy (e.g., Histoplasma, Blastomyces, Cryptococcus neoformans)
- Checkpoint inhibitor pneumonitis with an organizing pneumonia (OP) pattern may resemble fungal pneumonia (with dense nodules and patchy consolidation).
- For patients at risk for fungal pneumonia (due to immunosuppression or exposure) and with a CT scan consistent with fungal pneumonia, empiric coverage with voriconazole or isavuconazonium may be reasonable while awaiting microbiologic data.
steroid
- Steroid is the mainstay of therapy. 85% of patients will respond to this within a few days. (30189190)
- Initial dose:
- Taper steroid over 4-6 weeks. However, <2% of patients may develop chronic pneumonitis and require a longer taper. (ASCO 2021 34724392)
second immunosuppressive agent
- ~15% of patients respond poorly to steroid. Ideal treatment for these patients is unknown. Historically they tend to do poorly. (30189190)
- If no improvement is observed after 48-72 hours of steroid, consider adding an additional immunosuppressive agent (with continuation of steroid). (ASCO 2021 34724392; 36270461 ESMO 2022)
- Preferred: Infliximab 5 mg/kg or tocilizumab 8 mg/kg +/- IVIG. (36270461 ESMO 2022)
- May consider on an individual basis:
epidemiology
overall epidemiology
- Radiation pneumonitis affects roughly ~10-30% of patients who receive radiotherapy for lung cancer, esophageal cancer, or mediastinal lymphoma. Radiotherapy for breast cancer is associated with a lower risk. (32427626)
- Timing:
- Pneumonitis usually develops ~1-3 months following therapy. (Walker 2019)
- However, pneumonitis may occasionally occur during the course of intense chemoradiation, or hyperfractionated accelerated radiation protocols. (Fishman 2023) Alternatively, in some cases, onset may be delayed by up to two years.
risk factors
- Type of malignancy being treated: (30998908)
- Lung cancer: ~5-25% risk.
- Mediastinal lymphoma: ~5-10% risk.
- Breast cancer: ~1-5% risk.
- Dose of radiation:
- At any given location within the lung:
- <30 Gray is usually well tolerated.
- >40 Gray usually causes radiographic changes. (30998908)
- >50 Gray often causes symptomatic pneumonitis.
- Parameters that increase risk of pneumonitis: (30998908)
- Mean lung dose >20 Gray.
- % lung receiving >20 Gray (V20) >30%.
- % lung receiving >5 Gray (V5) >65%.
- Absolute volume spared >5 Gray (AVS5) < 500 ml.
- Fractionation: More fractions divide the dose over time, reducing the risk of injury.
- Prior irradiation increases risk.
- At any given location within the lung:
- Other risk factors:
- Chemotherapeutics:
- Agents known to cause lung injury increase risk (e.g., doxorubicin, bleomycin, busulfan).
- Chemoradiation for lung cancer often involves lower doses of radiation – so the overall risk may be reduced. (32427626)
- Age >50. (32427626; 30998908)
- Underlying interstitial lung disease (especially idiopathic pulmonary fibrosis). (32427626)
- Former or current smoker. (30998908)
- Chemotherapeutics:
symptoms
- Onset is usually subacute. An exception to this is that acute onset can occur if steroids were recently discontinued (which may cause abrupt unmasking of subacute radiation pneumonitis).
- ⚠️ Abrupt onset usually suggests an alternative diagnosis (such as infection). (Walker 2019)
- Most common symptoms:
- Dyspnea.
- Dry cough.
- Low-grade fever.
- Other symptoms may include chest tightness and pleuritic chest pain.
imaging
general principles:
- Radiographic abnormalities are frequently more dramatic than clinical symptoms.
- Abnormalities are confined to the field of irradiation. However:
- With SBRT (stereotactic body radiotherapy 📖), the margins may be less well-defined.
- Newer methods of delivering radiation can cause radiation pneumonitis at unusual locations, away from the primary tumor (especially if lymph nodes were being targeted). If available, anatomic dose mapping from radiotherapy planning are essential to understand the distribution of radiation pneumonitis. (Walker 2019)
- The stages below are commonly seen, but not always. Nonetheless, it is useful to conceptualize this process as having three components.
#1/3) acute radiation pneumonitis
- Parenchymal abnormalities:
- Ground-glass opacification is usually the initial finding. This can occur as early as a few weeks after completion of radiotherapy. (Walker 2019)
- Consolidation may subsequently occur.
- Septal thickening may occur, which in combination with ground-glass opacities can generate a crazy-paving pattern.
- Nodular opacities may occasionally occur, which may simulate tumor spread. Over time, these lesions usually coalesce into areas of consolidation. (Walker 2019)
- Traditionally, sharply demarcated borders were often seen. However, with more sophisticated radiotherapy techniques, borders may be less well-defined.
- Pleural effusion may occur, ipsilateral to the radiation pneumonitis.
- Effusion is usually small, often persisting for months.
- Concerning signs for the possibility of malignant pleural effusion include: if the effusion develops after 6 months, continues to increase in size, or is large. (Walker 2019)
#2/3) chronic radiation fibrosis
- Fibrosis often develops within 6-12 months (although pneumonitis can resolve without causing fibrosis). Radiographic features may include: (Shepard 2019; Walker 2019)
- Traction bronchiectasis.
- Linear scarring.
- Persistent contracted areas of consolidation.
- Architectural distortion, volume loss.
- Cavitation is not expected; if cavitation occurs this suggests superimposed infection or malignancy. (Walker 2019)
#3/3) recurrent tumor
- Signs of tumor recurrence may include the following:
- (1) Previously stable, fibrotic lesion starts to enlarge in size.
- (2) Previously aerated air bronchogram gets filled in by tumor.
differential diagnosis: other postradiation syndromes
AEP (acute eosinophilic pneumonia)
bilateral lymphocytic alveolitis (“sporadic radiation pneumonitis”)
- Rarely, high-dose radiotherapy causes diffuse radiographic changes (not confined to the radiation port).
- This occurs relatively early, typically 2-6 weeks after completion of therapy.
- Can be severe, causing respiratory failure.
OP (organizing pneumonia)
- OP most often occurs in the first months after tangential field radiotherapy for breast cancer.
- Criteria for diagnosing radiation-induced OP: (Walker 2019)
- Radiotherapy within the prior 12 months.
- Symptom duration of at least 2 weeks.
- Airspace opacities outside the radiation treatment field.
- Exclusion of other causes.
CEP (chronic eosinophilic pneumonia)
- More likely in patients with a history of allergy or asthma.
- Tends to occur ~4-10 months after completion of radiotherapy. (Murray 2022)
(More complete differential diagnosis of lung disease in the context of cancer: 📖)
treatment of radiation pneumonitis
- No controlled studies are available on the treatment of radiation pneumonitis. Steroid causes transient improvement in symptoms, but it is unclear whether steroid improves long-term outcomes (i.e., prevention of radiation fibrosis).
- Acute radiation pneumonitis:
- Most patients with radiation pneumonitis have mild symptoms and require no therapy (or, perhaps, inhaled steroid).
- Steroid is effective in more severe, acute disease (often 60 mg/day for 1-2 weeks, followed by a gradual taper over 3-12 weeks). (Fishman 2023)
- There is no role for steroid in the post-acute or chronic setting. (Shah 2019)
- Infection is the most common.
- Drug toxicity.
- Malignant pleural effusion.
- Pulmonary leukostasis.
- Leukemic pulmonary infiltration. 📖
- Upper airway obstruction (due to airway wall infiltration or compression due to lymphadenopathy).
- Richter syndrome/transformation.
To keep this page small and fast, questions & discussion about this post can be found on another page here.
Guide to emoji hyperlinks
- = Link to online calculator.
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- = Link to IBCC section about a drug.
- = Link to IBCC section covering that topic.
- = Link to FOAMed site with related information.
- 📄 = Link to open-access journal article.
- = Link to supplemental media.
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