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Pulmonary tumor embolism and lymphangitic carcinomatosis in adults: Diagnostic evaluation and management

Pulmonary tumor embolism and lymphangitic carcinomatosis in adults: Diagnostic evaluation and management
Literature review current through: Jan 2024.
This topic last updated: Oct 03, 2023.

INTRODUCTION — Pulmonary tumor emboli and lymphangitic carcinomatosis are rare, end-stage manifestations of malignancy that have a poor prognosis. Recognition of either of these problems should lead to a frank discussion of treatment options and/or re-evaluation of goals of care.

The clinical features, diagnosis, and treatment of pulmonary tumor embolism and pulmonary lymphangitic carcinomatosis are reviewed here. The epidemiology, etiology, and pathogenesis of these syndromes, as well as the diagnosis and management of venous thromboembolism, and embolism of air, amniotic fluid, fat, or foreign material, are discussed separately. (See "Pulmonary tumor embolism and lymphangitic carcinomatosis in adults: Epidemiology, etiology, and pathogenesis" and "Epidemiology and pathogenesis of acute pulmonary embolism in adults" and "Air embolism" and "Amniotic fluid embolism" and "Fat embolism syndrome" and "Foreign body granulomatosis".)

TERMINOLOGY — The terminology for both disorders is often used interchangeably by clinicians. However, pulmonary tumor embolism refers to the identification of tumor within pulmonary arteries and/or capillaries on pathologic lung samples, whereas pulmonary lymphangitic carcinomatosis refers to the identification of tumor in pulmonary lymphatic vessels. Since both entities are similarly evaluated and treated, distinguishing one from the other has little clinical significance. (See "Pulmonary tumor embolism and lymphangitic carcinomatosis in adults: Epidemiology, etiology, and pathogenesis", section on 'Terminology'.)

While any malignancy can cause both disorders, the risk appears to be the greatest in patients with renal cell and hepatocellular carcinoma, as well as adenocarcinoma of the breast, stomach, colon, and lung (table 1). The etiology and pathogenesis of these disorders are discussed separately. (See "Pulmonary tumor embolism and lymphangitic carcinomatosis in adults: Epidemiology, etiology, and pathogenesis", section on 'Etiology' and "Pulmonary tumor embolism and lymphangitic carcinomatosis in adults: Epidemiology, etiology, and pathogenesis", section on 'Pathogenesis'.)

CLINICAL PRESENTATION — The clinical manifestations of pulmonary tumor emboli and lymphangitic carcinomatosis are nonspecific, with the majority of patients presenting with subacute, progressive, unexplained dyspnea [1-7]. Consequently, the diagnosis often remains unsuspected and not made until autopsy. Traditionally, it is thought that pulmonary tumor embolism is more likely to present with features suggestive of pulmonary hypertension (PH) or venous thromboembolism (dyspnea, hypoxemia, right heart strain, and clear lungs) while pulmonary lymphangitic carcinomatosis is more likely to present with the features of interstitial lung disease (eg, fever, bilateral infiltrates on chest imaging). However, clinical and pathological overlap between the entities is common. (See 'Definitive pathologic diagnosis' below.)

Symptoms and signs — Progressive, unexplained dyspnea is the most common symptom that occurs in up to 60 percent of cases [1,2,8-14]. Dyspnea is often subacute (over weeks) but can be rapid (over days). Rarely, patients present suddenly with overwhelming shock and acute respiratory failure from acute massive tumor embolism resulting in acute PH [15].

Pleuritic chest pain can occur, particularly in patients with lymphangitic carcinomatosis when obstructed pleural lymphatics or blood vessels are involved with tumor.

Cough, hemoptysis, fatigue, and weight loss occur less commonly. While some of these symptoms may be explained by tumor embolism or lymphangitis, they may also be due to the underlying cancer.

A diagnosis of cancer is usually, but not always, present and patients may have advanced, metastatic, or occult disease [8-12].

Patients are rarely asymptomatic. Case reports of patients with imaging features suggestive of either embolization or lymphangitis found incidentally during surveillance for known cancer have been reported [16,17].

The physical examination usually reveals tachypnea, tachycardia, and low-grade fever. Signs of PH and cor pulmonale, such as an increase in the pulmonic component of the second heart sound, a right ventricular lift, cyanosis, and jugular venous distention, may be more likely in patients with tumor emboli than lymphangitis. Crackles or adventitious sounds are unusual but may be more likely to be heard in patients with lymphangitic carcinomatosis than in tumor emboli syndrome [18].

Imaging — Most imaging studies are insensitive for the diagnosis of pulmonary tumor embolism and lymphangitic carcinomatosis. However, many of these imaging modalities are performed because venous thromboembolism or other etiologies are suspected. Importantly, these tests are usually not diagnostic, and up to 50 percent of patients have normal imaging, particularly in the early phase. In an autopsy series, imaging detected only 20 to 30 percent of cases of pulmonary tumor embolism, although higher rates of detection of lymphangitic carcinomatosis by both positron emission tomography (PET) and high resolution chest computed tomography (CT) were reported (approximately 73 percent) [14,19]. However, imaging studies may provide subtle clues to help raise the clinical suspicion for underlying tumor embolism or lymphangitis in the event that other more common etiologies are ruled out. (See 'Differential diagnosis' below.)

Imaging may show features of one or both entities and include the following:

Chest radiography – Chest radiography is often initially normal, but as the disease progresses, it may show diffuse reticular and nodular infiltrates, coarse bronchovascular markings, or Kerley B lines suggestive of lymphangitic edema [1,2,20]. Occasionally, lymphadenopathy and pleural effusions are also seen.

The signs of PH may indicate elevated pulmonary pressures from pulmonary tumor embolism (eg, enlarged pulmonary arteries, enlarged right heart) but can also be less commonly seen in lymphangitic carcinomatosis [1,13].

Ventilation-perfusion (V/Q) lung scintigraphy – V/Q lung scans may be normal or demonstrate multiple, small, peripheral, subsegmental perfusion defects ("mottled" or "beaded" appearance) with normal ventilation [21,22]. This pattern is similar to that seen in fat embolism or idiopathic pulmonary arterial hypertension, but different from the pattern typically seen with venous thromboembolism.

Computed tomography – CT findings of smooth or irregularly thickened interlobular septum ("nodular" appearance) (image 1A-B) are more characteristic of lymphangitic carcinomatosis than tumor embolism. While some experts believe that nodular septae may help distinguish lymphangitic carcinomatosis from other interstitial disorders, in general, overlap with other diseases including sarcoidosis and asbestosis is not uncommon [3]. Some cases may have ground glass densities that may represent interstitial edema. Hilar adenopathy and effusions may occasionally be present. In contrast, a dilated, beaded or tree-in-bud appearance of pulmonary arteries on CT pulmonary angiography may be more characteristic of tumor embolism than lymphangitic carcinomatosis [16,23].

Conventional pulmonary angiography – Older reports from an era where conventional pulmonary angiography was more commonly performed in patients with suspected pulmonary embolism (PE) report subtle abnormalities such as subsegmental filling defects, pruning and tortuosity of the third to fifth order vessels, or delayed filling of segmental arteries [8,24,25]. However, these findings are neither sensitive nor specific for the diagnosis of tumor embolism or lymphangitic carcinomatosis. In addition, conventional pulmonary angiography is no longer commonplace in the diagnostic evaluation patients with suspected PE.

Other – PET and endobronchial ultrasound (EBUS) are not routinely performed for the diagnosis of tumor embolism or lymphangitic carcinomatosis but case reports suggest abnormalities in rare cases.

PET – Rare case reports have described 18F-2-deoxy-2-fluoro-D-glucose (FDG) uptake in the lungs (eg, during serial PET surveillance) when presumably tumor deposits are large enough to be FDG avid [17,19,26-28]. However, it is unlikely that smaller tumor deposits can be detected with this modality.

EBUS – Rare case reports also describe the identification of filling defects in the major or central pulmonary arteries using EBUS [29-31]. However, it is unlikely that EBUS can locate filling defects in more distal vessels (eg, beyond the second order) and cannot readily distinguish between tumor and clot.

Laboratory — Most routine laboratory tests including complete blood count and chemistries are unhelpful and are not diagnostic. A mild leukocytosis is not unusual and may represent a stress response to disseminated tumor. One case report described elevated circulating eosinophils in a patient with lymphangitic carcinomatosis, but in our experience this finding is unusual and likely to be due to a paraneoplastic phenomenon [32].

D-dimer levels may be elevated in patients who have evidence of acute PH and acute right heart failure. However, an elevated D-dimer is nonspecific as it may be elevated in many other conditions (table 2). (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Laboratory tests'.)

Arterial blood gas — As the disease progresses, arterial blood gas analysis generally shows hypoxemia, a respiratory alkalosis, and an elevated alveolar-arterial oxygen gradient (calculator 1). If shock ensues, then patients may develop lactic acidosis. However, these are nonspecific findings and can be found in many of the competing diagnoses. (See "Arterial blood gases" and "Simple and mixed acid-base disorders" and 'Differential diagnosis' below.)

Pulmonary function tests — Pulmonary function tests may be normal but may reveal a restrictive pattern with reduced lung volumes and reduced diffusing capacity as the disease progresses. (See "Overview of pulmonary function testing in adults".)

Electrocardiography and echocardiography — Electrocardiography may be normal but typically reveals tachycardia as the disease progresses. Other rhythm disturbances including atrial fibrillation and bradycardia and evidence of right heart strain due to PH may also be present. Similarly, echocardiography may be normal or show signs consistent with right ventricular hypertrophy or strain from PH, the details of which are discussed separately. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Electrocardiography' and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Echocardiography' and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Echocardiography' and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Electrocardiography'.)

DIAGNOSTIC APPROACH — The optimal diagnostic approach is unknown. In our experience, multiple imaging tests are often performed, during which time patients typically progress, increasing the risk of invasive procedures. Consequently, the diagnosis is often delayed and not made until autopsy.

When to suspect tumor emboli or lymphangitic carcinomatosis — Progressive unexplained dyspnea and hypoxemia in a patient with malignancy should raise the clinical suspicion for pulmonary tumor embolism or lymphangitic carcinomatosis; however, patients with microscopic tumor emboli may be asymptomatic. These syndromes should be considered in those suspected to have pulmonary embolism (PE; acute or subacute dyspnea, hypoxemia, chest pain, low grade fever) and/or pulmonary hypertension (PH; dyspnea, loud second heart sound, elevated jugular venous pressure, lower extremity edema, right ventricular dilation) in whom testing or an etiology is unrevealing.

Dyspnea is often subtle and initially occurs in the setting of a normal chest radiograph or a radiograph with nonspecific infiltrates. In our experience, patients are often treated empirically with antibiotics for presumed bronchitis or pneumonia but fail to respond and continue to progress.

Details regarding the clinical signs and symptoms of pulmonary tumor embolism and lymphangitic carcinomatosis are provided above. (See 'Symptoms and signs' above.)

Initial diagnostic tests — Other than lung biopsy, most diagnostic tests are nonspecific but help to raise the clinical suspicion for tumor embolism or lymphangitic carcinomatosis, and prompt invasive testing (see 'Pursuing a histologic diagnosis' below and 'Choosing among the tests' below). Nonetheless, we suggest the following tests be performed in the routine evaluation of patients suspected of having either pulmonary tumor embolism or lymphangitic carcinomatosis:

Chest radiograph (see 'Imaging' above)

Chest CT, CT pulmonary arteriogram, and/or ventilation-perfusion lung scanning (see 'Imaging' above)

Laboratory studies including complete blood count and differential, serum chemistries, and liver function tests (see 'Laboratory' above)

Arterial blood gas analysis (see 'Arterial blood gas' above)

Electrocardiography (see 'Electrocardiography and echocardiography' above)

Echocardiography (see 'Electrocardiography and echocardiography' above)

Positron emission tomography (PET), pulmonary angiography, or endobronchial ultrasound (EBUS) are not routinely performed for the diagnostic evaluation of this population. However, PET and EBUS may be appropriate on a rare case-by-case basis if it is considered that additional imaging would help guide further diagnostic testing (eg, a patient with an intensely positive tumor by PET scan or a patient in whom central emboli are suspected and biopsy options are limited). (See 'Imaging' above.)

Pursuing a histologic diagnosis — Additional testing is aimed at a cytologic or histologic diagnosis (picture 1). In general, many experts prefer to obtain a transbronchial lung biopsy (TBBX); if TBBX is negative and the clinical suspicion remains, or if TBBX is contraindicated, then proceeding with surgical lung biopsy may be appropriate in select cases. Alternatively, aspiration of pulmonary artery blood using a right heart catheter (RHC) may be appropriate as the initial test, particularly in those with suspected PH or for those who are too ill to undergo lung biopsy; if negative, then proceeding to lung biopsy is appropriate for patients well enough to undergo biopsy. (See 'Choosing among the tests' below.)

Right heart catheterization — A pulmonary artery catheter (PAC) is typically placed for the diagnostic evaluation of patients with suspected PH and/or for the acquisition of a wedged sample of pulmonary artery blood. Only the latter can provide material for cytologic diagnosis.

Pulmonary hypertension — The identification of PH on PAC is not diagnostic of tumor embolism or lymphangitis, but rather confirms or refutes the presence of PH. The presence of PH increases the risk of lung biopsy (eg, hemorrhage and cardiovascular collapse). (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'Surgical or periprocedural care'.)

Acute PE is unlikely to result in mean pulmonary artery pressures >50 mmHg, whereas mean pulmonary artery pressures >50 mmHg can be found in patients with tumor embolism and in PH due to other causes [8,24,33-35]. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Right heart catheterization' and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Echocardiography' and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Echocardiography'.)

The presence or absence of PH does not influence the decision regarding whether or not to proceed with withdrawing blood from the pulmonary artery when either of these conditions are suspected. (See 'Pulmonary artery catheter aspiration' below.)

Pulmonary artery catheter aspiration — Pulmonary artery blood is not routinely aspirated during RHC for the evaluation of PH. However, RHC is less invasive when compared with lung biopsy, and cancer cells can be identified on aspirated blood from a wedged PAC sample. Thus, if these conditions are strongly suspected and the PAC is in place, a sample should be simultaneously drawn for diagnostic purposes without increasing the risk of the procedure. In the absence of a suspicion for PH, the decision to insert a PAC solely for the acquisition of aspirated pulmonary artery blood should be individualized. (See "Pulmonary artery catheterization: Indications, contraindications, and complications in adults" and 'Choosing among the tests' below.)

The diagnostic accuracy of cytologic examination of blood aspirated from a wedged PAC is unknown with case reports suggesting that it is helpful in up to 90 percent of patients [36,37]. However, it is considered by most experts as insensitive such that negative pulmonary artery blood cytology is insufficient to definitively exclude the diagnosis [33,37]. In addition, false-positive results may be a consequence of megakaryocytes being mistaken for malignant cells because of their large size, multilobulated nuclei, densely staining chromatin, and prominent nucleoli [1,38]. Thus, it is imperative that the specimen is read by an experienced cytopathologist to avoid erroneous interpretations. Given these limitations, patients who undergo cytologic examination of blood aspirated from a wedged PAC often end up still undergoing lung biopsy, when feasible.

We suggest the following technique for sample aspiration:

The PAC is placed in the wedged position (see "Pulmonary artery catheters: Insertion technique in adults")

Approximately 10 to 15 mL of blood is slowly aspirated and discarded

Then, another 5 to 10 mL of blood is slowly aspirated, placed into a heparinized tube, and sent to the laboratory for cytologic analysis

Bronchoscopy — In this population, bronchoscopy with TBBX is typically the diagnostic test of choice to obtain lung tissue for histopathologic diagnosis. However, bronchoscopy is often performed for multiple concurrent indications. As an example, bronchoalveolar lavage (BAL) is commonly also obtained for the evaluation of pulmonary infiltrates of unclear etiology or as part of the evaluation in a patient with suspected lung cancer. (See "Flexible bronchoscopy in adults: Associated diagnostic and therapeutic procedures", section on 'Diagnostic'.)

Bronchoalveolar lavage fluid — Although case reports suggest that cancer cells can be observed in patients with lymphangitic carcinomatosis on BAL fluid collected during bronchoscopy, it is not generally a procedure associated with high diagnostic yield such that a negative BAL does not rule out the diagnosis [39,40]. It is generally considered by most experts as complementary to lung biopsy. (See "Flexible bronchoscopy in adults: Associated diagnostic and therapeutic procedures", section on 'Diagnostic'.)

If BAL is negative, most experts would prefer to proceed with lung biopsy, if not already performed. The identification of cancer cells on BAL confirm that cancer is present in the alveolar space but are not markers of tumor within the lymphatic or vascular space. Ideally, further tissue may still be required (eg, patients without a prior known malignancy or for immunohistochemical or genetic fingerprinting so that targeted therapy can be administered). Occasionally, a positive BAL may be sufficient to proceed with antitumor therapies.

One case report described lymphangitis masquerading as acute eosinophilic pneumonia with elevated eosinophils on BAL. However, CT findings suggestive of lymphangitic carcinomatosis prompted a lung biopsy confirming the diagnosis [2]. It was suggested that the eosinophils seen on BAL were likely a paraneoplastic phenomenon. (See "Overview of pulmonary eosinophilia" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)

Transbronchial biopsy — Lung biopsy is the diagnostic test of choice for pulmonary tumor emboli and lymphangitic carcinomatosis (picture 1). TBBX is preferred since it is less invasive compared with surgical lung biopsy and has a lower risk of pneumothorax compared with transthoracic needle biopsy. However, it is not always feasible (eg, contraindication), such that other methods need to be considered. (See "Flexible bronchoscopy in adults: Associated diagnostic and therapeutic procedures", section on 'Transbronchial biopsy' and "Flexible bronchoscopy in adults: Indications and contraindications", section on 'Contraindications' and "Overview of minimally invasive thoracic surgery" and "Diagnostic evaluation of the incidental pulmonary nodule", section on 'Transthoracic needle biopsy'.)

The diagnostic yield of TBBX is unknown but considered high, particularly when diffuse disease is suspected from lymphangitic carcinomatosis. Similarly, the diagnostic yield for pulmonary tumor emboli is also unknown but probably lower than that for lymphangitic carcinomatosis. If a TBBX is negative and the suspicion remains, then surgical lung biopsy should be considered. (See "Role of lung biopsy in the diagnosis of interstitial lung disease" and "Overview of minimally invasive thoracic surgery".)

Choosing among biopsy options is dependent upon the assessed risks and benefits of each procedure which is discussed separately. (See 'Choosing among the tests' below.)

Surgical lung biopsy — Surgical lung biopsy has the highest procedural risk but also has the highest diagnostic yield and may be considered in those in whom bronchoscopy is contraindicated or has failed to establish a diagnosis (picture 1). Choosing among these options is dependent upon the assessed risks and benefits of each procedure, which is discussed separately. (See 'Choosing among the tests' below and "Overview of minimally invasive thoracic surgery".)

Details regarding the technical aspects and complications of these procedures are provided separately. (See "Flexible bronchoscopy in adults: Preparation, procedural technique, and complications" and "Flexible bronchoscopy in adults: Associated diagnostic and therapeutic procedures" and "Overview of minimally invasive thoracic surgery".)

Other — Rare case reports suggest that EBUS may be used to obtain cytological samples from visualized filing defects in the central pulmonary arteries [29-31,41]. However, it is unlikely that EBUS can sample filling defects in peripheral vessels or lung tissue. Theoretically, transthoracic needle aspiration/core biopsy may also be a feasible method for obtaining lung tissue for cytology/histology, but the risk of pneumothorax is high. (See "Endobronchial ultrasound: Technical aspects" and "Endobronchial ultrasound: Indications, contraindications, and complications" and "Bronchoscopy: Transbronchial needle aspiration" and "Diagnostic evaluation of the incidental pulmonary nodule", section on 'Transthoracic needle biopsy'.)

Choosing among the tests — The definitive diagnosis of pulmonary tumor embolism or lymphangitic carcinomatosis depends upon the identification of tumor cells in the pulmonary vasculature or lymphatics, respectively. This can be accomplished via lung biopsy. We typically perform TBBX first, but surgical biopsy may be pursued in those in whom TBBX has failed to be diagnostic or bronchoscopy is contraindicated. The cytologic demonstration of malignant cells on aspirated blood from a wedged PAC is an alternative for those in whom a PAC is indicated for the diagnosis of PH or in whom lung biopsy is considered too risky. (See 'Surgical lung biopsy' above and 'Pulmonary artery catheter aspiration' above and 'Other' above.)

The decision about how aggressively to pursue the histologic diagnosis of pulmonary tumor embolism is generally individualized and depends upon the nature of the underlying tumor, the severity of illness, the presence or absence of PH, goals and preferences of the patient, and the benefits and risks of each procedure in the context of its diagnostic yield.

In general, the following principles apply:

Lung biopsy, usually TBBX or video-assisted thoracoscopic biopsy, are best performed in patients who are stable enough to tolerate an invasive procedure. Lung biopsy procedures are more risky but associated with a better diagnostic yield compared with cytologic examination of blood from a PAC. Transbronchial biopsy is associated with a lower likelihood of complications than a surgical biopsy but is not always feasible (eg, if a patient is mechanically ventilated) and likely has a lower diagnostic yield. Lung biopsy should be performed early in the patient's course but should be avoided if significant PH is suspected. (See 'Bronchoscopy' above and 'Surgical lung biopsy' above.)

Aspiration of blood from a wedged PAC may be appropriate in those who are assessed as too ill to undergo biopsy or in those who decline biopsy. It may also be useful in a patient who presents with PH in whom a PAC is already indicated for the diagnosis. The clinician should be aware that patients who have PH are at increased risk of complications from lung biopsy. (See "Pulmonary artery catheterization: Indications, contraindications, and complications in adults" and 'Pulmonary artery catheter aspiration' above and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'Surgical or periprocedural care'.)

Invasive diagnostic testing may not be preferred for patients with malignancies that have no available antitumor therapies where histologic confirmation in such cases is unlikely to alter the patient's outcome [3,42]. In contrast, for patients with a chemotherapy-sensitive tumor or a suspected (but unconfirmed) malignancy, more aggressive efforts to confirm the diagnosis may be warranted so that proceeding with antitumor therapy can be justified. (See 'Therapy' below.)

Options should be discussed in detail with the patient or their health care provider to evaluate their preferences. As an example, patients with aggressive end-stage malignancy may prefer to avoid invasive procedures and elect to be treated with supportive therapies or comfort therapies. (See "Ethics in the intensive care unit: Responding to requests for potentially inappropriate therapies in adults" and "Communication in the ICU: Holding a meeting with families and caregivers" and "Palliative care: Issues in the intensive care unit in adults".)

DIFFERENTIAL DIAGNOSIS — The major competing diagnoses are pulmonary embolism (PE), pulmonary hypertension (PH; including pulmonary veno-occlusive disease [PVOD]), and interstitial lung disease (ILD). Pneumonia, heart failure, acute respiratory distress syndrome (ARDS), and other embolization syndromes (amniotic, fluid, fat, foreign body) may also be considered on the differential.

Although pulmonary tumor embolism is more likely to present with features suggestive of PH, and lymphangitic carcinomatosis with the features of ILD, the entities are not clinically distinct and overlap can exist. While the distinction between both disorders is largely made pathologically, clinically distinguishing the disorders is less significant as both are evaluated and treated in a similar fashion. (See 'Clinical presentation' above.)

Venous thromboembolism — The findings of dyspnea, hypoxemia, right heart strain, and clear lungs may suggest PE or tumor embolism. Differentiating these entities clinically may be difficult, as illustrated by a study that compared 56 patients with solid tumors and PE to 17 patients with solid tumors and tumor embolism [42]. The only difference was that cough was significantly more common among patients with pulmonary tumor embolism. There were no differences at presentation in the respiratory rate, heart rate, white blood cell count, bilirubin, lactate dehydrogenase, or the frequency of dyspnea, pleuritic or nonpleuritic chest pain, hemoptysis, fever, or cyanosis.

The concomitant finding of deep vein thrombosis may increase the suspicion for PE.

Ventilation-perfusion (V/Q) scans and/or CT pulmonary angiography are often needed to rule out PE. If negative, the suspicion for tumor embolism or lymphangitic carcinomatosis should be further increased. (See 'Imaging' above.)

A positron emission tomography (PET) scan that is diffusely positive in the lung is unlikely to be due to venous thromboembolism, although such testing is rarely performed during the evaluation for suspected PE, tumor embolism, or lymphangitic carcinomatosis.

Assuming there is no predisposing PH, elevations in mean pulmonary arterial pressure (mPAP) on echocardiography tend to be mild in patients with acute PE (typically <40 mmHg) compared with patients who have pulmonary tumor emboli. However, this finding is not specific and hypoxemia secondary to other etiologies in patients with underlying PH may also increase pulmonary pressures. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Echocardiography'.)

The clinical features and diagnosis of PE are discussed separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults".)

Pulmonary hypertension — Dyspnea, hypoxemia, right heart strain, and clear lungs may also suggest PH. However, patients with PH are more likely to have dyspnea that is chronic rather than subacute or acute in its progression. In addition, patients generally do not have underlying malignancy, although patients with rare forms of PH (eg, PVOD) may have a history of malignancy or have undergone therapy that puts the patient at risk for PH.

Right heart catheterization is diagnostic of PH but there are no pathognomic features that distinguish tumor emboli (or lymphangitic carcinomatosis) from other more common etiologies of PH. Higher mPAP (>50 mmHg) suggests a chronic etiology for PH but the mPAP level does not clearly distinguish one etiology from the other.

The mottled pattern on V/Q scanning typical of tumor emboli can also be seen with idiopathic pulmonary arterial hypertension. (See 'Imaging' above.)

The clinical features and diagnosis of PH and PVOD are discussed separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults" and "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults" and 'Right heart catheterization' above and 'Electrocardiography and echocardiography' above.)

Interstitial lung disease — Patients with ILD may also present with subacute progressive dyspnea and infiltrates on CT, although a history of malignancy is not typically present.

The acute or subacute forms of ILD include acute eosinophilic pneumonia, cryptogenic organizing pneumonia, connective tissue disease (CTD)-associated ILD, and, rarely, hypersensitivity pneumonitis and sarcoidosis (table 3). Although supportive clinical features of ILD (eg, crackles, eosinophilia, underlying CTD) or classic CT findings (eg, nodular septa associated with lymphangitic carcinomatosis, or thickened septa in tumor emboli syndrome) may help distinguish these etiologies, in general, overlap is common [3]. However, lung biopsy will typically definitively distinguish these entities from each other. (See "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing" and "Role of lung biopsy in the diagnosis of interstitial lung disease" and 'Imaging' above.)

Others — Amniotic fluid, air, fat, and foreign body embolism may also present with progressive dyspnea and hypoxemia, and have a mottled pattern on V/Q scan. However, predisposing causes should be identifiable (eg, pregnancy, trauma, drug injection use). (See "Amniotic fluid embolism" and "Air embolism" and "Fat embolism syndrome" and "Foreign body granulomatosis".)

Other etiologies in the differential when abnormal infiltrates are present include acute or subacute infectious processes such as atypical infectious pneumonias or fungal pneumonia, which may present with diffuse radiographic opacities, mild leukocytosis, and fever. Bronchoscopy may be useful in distinguishing infectious etiologies from tumor embolism or lymphangitic carcinomatosis. (See 'Bronchoscopy' above.)

Similarly, lymphangitic carcinomatosis may mimic heart failure, which may present with crackles and abnormal infiltrates, and mimic ARDS, which can develop subacutely with hypoxemia and abnormal infiltrates, following an inciting event. (See "Mycoplasma pneumoniae infection in adults" and "Approach to the immunocompromised patient with fever and pulmonary infiltrates" and "Heart failure with preserved ejection fraction: Clinical manifestations and diagnosis" and "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults".)

DIAGNOSIS — Definitive diagnosis of pulmonary tumor embolism or lymphangitic carcinomatosis is made histopathologically, most often on autopsy (picture 1). While older series suggested these conditions were commonly encountered on autopsy [42,43], one 2006 autopsy series of 65,181 cancer patients identified tumor embolism in 0.19 percent and tumor invasion into a large vein in 0.11 percent [44]. The incidence of lymphangitic carcinomatosis was not reported in that study, but other series confirm that the majority of cases (up to two-thirds) are also diagnosed post mortem [2,45].

In our experience, antemortem diagnosis is rare. An antemortem diagnosis is generally dependent upon a high clinical suspicion (see 'When to suspect tumor emboli or lymphangitic carcinomatosis' above) that prompts lung biopsy or pulmonary artery catheter blood draw early in the course of the disease (see 'Choosing among the tests' above). Delay in obtaining a lung biopsy will often lead to continued progression and an inability to obtain tissue for histopathological examination because the procedural risk is too high.

However, while definitive histologic diagnosis is ideal (see 'Definitive pathologic diagnosis' below), we acknowledge that there is a role for a presumptive diagnosis in patients who are too ill to undergo tissue sampling to justify antitumor therapy. (See 'Presumptive diagnosis' below.)

Definitive pathologic diagnosis — A definitive diagnosis of tumor embolism or lymphangitic carcinomatosis can be made histopathologically on tissue derived from transbronchial or surgical lung biopsy, or from tissue obtained at autopsy (picture 1). They are separate pathologic entities, although both are commonly encountered in the same sample and up to 70 percent of cases have coexisting solid lung metastases [2,13,46]. (See 'Pulmonary tumor embolism' below and 'Lymphangitic carcinomatosis' below.)

Pulmonary tumor embolism — Gross examination of the lung may be normal or reveal cords or clusters of tumor within visible pulmonary arteries. Histologic examination typically demonstrates the embolized tumor cells within large and/or small arteries and capillaries (picture 1). Tumor cells are often mixed with thrombus and associated with an obliterative arteritis. Tumor cells typically do not migrate through or invade the vessel wall or surrounding interstitium. Degeneration of tumor cells within pockets of organized thrombus is also sometimes observed. The process typically involves both lungs diffusely but involvement may also be discrete.

Tumor emboli have been grouped into four categories [46]:

Tumor emboli that are microscopic and occlude small pulmonary arteries and arterioles (most common) (picture 2)

Tumor emboli that occlude large, proximal pulmonary arteries (picture 3)

Tumor emboli characterized by diffuse microvascular invasion, which may also include lymphatic obstruction

Combinations of the above

Occasionally, tumor embolization is associated with pulmonary hemorrhagic infarction distal to the occlusion [13].

Pulmonary tumor thrombotic microangiopathy (PTTM) is an associated phenomenon [47]. It is a pulmonary hypertensive arteriopathy that is thought to be due to activation of the coagulation system at the surface of the tumor emboli and intimal proliferation in small pulmonary arteries. PTTM may explain why some cases of pulmonary tumor embolism are associated with pulmonary arterial hypertension and an elevated D-dimer level [48,49]. (See 'Clinical presentation' above.)

Right ventricular hypertrophy and dilatation may also be seen in cases that present with pulmonary hypertension (PH).

Concomitant pulmonary metastases may also be seen in up to 70 percent of cases but is not always present [13].

Lymphangitic carcinomatosis — Macroscopically, the lungs may appear normal or may show fine white linear markings on the pleural and cut surfaces of the lung representing lymphatic vessel distension by tumor. Occasionally, the same linear markings may extend from the hilum to the lung periphery. Histologic obstruction and distension of lymphatics by tumor cells is the hallmark microscopic feature of pulmonary lymphangitic carcinomatosis [2]. Pleural, peribronchial, perivascular, and subpleural lymphatics can be involved. Vessel wall invasion is not typically seen.

Obstruction of lymphatics may lead to lymphatic dilation, interstitial edema, bronchovascular bundle, and septal thickening, as well as fibrosis. However, overt chylous accumulations are not typically seen.

Occasionally, parenchymal tumor nodules are seen, but it is not clear whether this is due to local spread of tumor into adjacent lung; tissue invasion is not generally seen.

Presumptive diagnosis — Some experts make a presumptive diagnosis in patients who are too ill to undergo lung biopsy. The advantage of such an approach is that patients are spared the risks of invasive diagnostic testing. As an example, the identification of tumor cells on lavage fluid or right heart catheter in the correct clinical context (ie, typical presentation in a patient with malignancy in whom venous thromboembolism is excluded) may be sufficient to allow clinicians to proceed with management decisions including chemotherapy or discuss prognosis with the patient and/or their health care provider. (See 'Bronchoscopy' above and 'Right heart catheterization' above.)

THERAPY

Antitumor — Definitive therapy for pulmonary tumor embolism and lymphangitic carcinomatosis is directed at treating the primary tumor. This may involve surgical resection, systemic chemotherapy, radiation therapy, or any combination thereof. In some patients, therapy is sufficient to wean patients from supportive forms of treatment including oxygen and, occasionally, mechanical ventilation. It is generally not curative, and in nearly all cases, the malignancy will likely recur or progress despite therapy, although some reports have described prolonged remission with treatment [50]. (See 'Prognosis' below.)

Complete resection of the primary tumor has resulted in gradual resolution of the tumor emboli without any specific therapy in cases of atrial myxoma and renal cell carcinoma [9,20,51]. However, tumor that invades a major pulmonary artery cannot be resected due to the high risk of catastrophic bleeding.

Chemotherapy is more likely to be effective in patients with chemo-responsive tumor such as Wilms tumor or a trophoblastic malignancy [52].

Supportive — Supportive therapy frequently involves the administration of oxygen, mechanical ventilation, and inotropic support, when needed. Supportive care is generally administered while diagnostic testing and definitive therapies are ongoing. They can be continued until a response to antitumor therapy is demonstrated or death occurs. (See "Long-term supplemental oxygen therapy" and "Overview of initiating invasive mechanical ventilation in adults in the intensive care unit".)

Historically, intravenous hydrocortisone (eg, 50 to 100 mg every six to eight hours) is administered by many experts while investigations are ongoing, although there are no data to support this practice. Anecdotally, transient and subjective improvements have been observed in breathlessness (eg, patients with lymphoma) with this approach.

Antibiotics and anticoagulants are not routinely administered unless another indication is present.

For patients who present with pulmonary hypertension (PH) and signs of decompensated right heart failure or shock, supportive therapy with diuretic, inotropic support and/or inhaled nitric oxide may also be appropriate. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'General measures and supportive therapy'.)

Embolectomy and inferior vena cava filter placement have been employed in rare patients suffering from large, central emboli due to infradiaphragmatic tumors [9,53]. (See "Placement of vena cava filters and their complications".)

PROGNOSIS — Pulmonary tumor emboli and lymphangitic carcinomatosis are typically end-stage manifestations of malignancy. As such, the prognosis with or without therapy is generally poor [20]. Although rare case reports suggest prolonged remission in some cases, cure is typically not possible, with most patients dying within 3 to 12 months after presentation [50]. It is likely that prognosis also relates to the responsivity of the underlying tumor to antitumor therapy.

SUMMARY AND RECOMMENDATIONS

Terminology – Pulmonary tumor emboli and lymphangitic carcinomatosis are rare, end-stage manifestations of malignancy that have a poor prognosis. Prompt recognition is critical so that therapy can be initiated in a timely fashion. Although the syndromes overlap, pulmonary tumor embolism refers to the identification of tumor within pulmonary blood arterial vessels on pathologic lung samples, whereas pulmonary lymphangitic carcinomatosis refers to the identification of tumor in pulmonary lymphatic vessels. The causes are listed in the table (table 1). (See 'Introduction' above and 'Terminology' above.)

Clinical features – The clinical manifestations are nonspecific with the majority of patients presenting with subacute, progressive, unexplained dyspnea. Traditionally, it is thought that pulmonary tumor embolism is more likely to present with features suggestive of pulmonary hypertension (PH) or venous thromboembolism (eg, dyspnea, hypoxemia, right heart strain, and clear lungs), while pulmonary lymphangitic carcinomatosis is more likely to present with the features of interstitial lung disease (ILD; eg, fever, bilateral infiltrates on chest imaging (image 1A and image 1B)). However, clinical and pathological overlap between the entities is common. (See 'Clinical presentation' above and 'When to suspect tumor emboli or lymphangitic carcinomatosis' above.)

Diagnostic evaluation – The optimal diagnostic approach is unknown. Other than lung biopsy, most diagnostic tests are nonspecific but help to raise the clinical suspicion and prompt invasive testing. (See 'Diagnosis' above and 'Initial diagnostic tests' above.)

We suggest the following tests be performed in the routine evaluation of patients suspected of having either pulmonary tumor embolism or lymphangitic carcinomatosis: chest radiography, chest CT (including CT pulmonary angiography), ventilation-perfusion (V/Q) imaging, routine chemistries, arterial blood gas analysis, electrocardiography, and echocardiography.

Additional testing is aimed at a cytologic or histologic diagnosis. In general, many experts prefer to obtain a transbronchial lung biopsy (TBBX); if TBBX is negative and the clinical suspicion remains, or if TBBX is contraindicated, then proceeding with surgical lung biopsy is appropriate. Alternatively, aspiration of pulmonary artery blood using a right heart catheter may be appropriate as the initial test, particularly in those with suspected PH or for those who are too ill to undergo lung biopsy; if negative, then proceeding to lung biopsy is appropriate for patients well enough to undergo biopsy. (See 'Pursuing a histologic diagnosis' above.)

The decision about how aggressively to pursue the histologic diagnosis of pulmonary tumor embolism generally is individualized and depends upon the nature of the underlying tumor and likely success of treatment, the severity of illness, the presence or absence of PH, goals and preferences of the patient, and the benefits and risks of each procedure in the context of its diagnostic yield. (See 'Choosing among the tests' above.)

The major competing diagnoses are pulmonary embolism (PE), PH, and ILD. Pneumonia, heart failure, and acute respiratory distress syndrome, and other embolization syndromes (amniotic, fluid, fat, foreign body) may also be considered on the differential. (See 'Differential diagnosis' above.)

Definitive diagnosis of pulmonary tumor emboli or lymphangitic carcinomatosis is made histopathologically, most often on autopsy (picture 1). While definitive diagnosis is ideal, we acknowledge that there is a role for a presumptive diagnosis in patients who are too ill to undergo tissue sampling to justify antitumor therapy. (See 'Diagnosis' above.)

Treatment – Definitive therapy is directed at treating the primary tumor. This may involve surgical resection, systemic chemotherapy, radiation therapy, or any combination thereof. In some patients, therapy is sufficient to wean patients from supportive forms of treatment including oxygen and, occasionally, mechanical ventilation. Importantly, therapy is not curative, and in many cases, the malignancy will likely recur or progress despite therapy. (See 'Therapy' above.)

Prognosis – Pulmonary tumor emboli and lymphangitic carcinomatosis are typically end-stage manifestations of malignancy. As such, the prognosis with or without therapy is generally poor. Most patients die within 3 to 12 months after presentation. (See 'Prognosis' above.)

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Topic 8252 Version 24.0

References

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