higher than 80%, and the more recent availability of rituximab may improve these results. Still patients may present with recurrences leading to sequential treatment; parenchymal or bronchial sequelae may ensue, leading to chronic obstructive disease or pulmonary brosis. Local and systemic recurrences develop in about 50% of cases, but are usually controllable with chemotherapy. Evolution to high-­grade B-cell lymphoma is seen in less than 5% of cases.Young age at diagnosis is the most signi - cant favorable prognostic factor.

Cancer Mimics of Interstitial Lung Diseases

Besides lymphangitis carcinomatosis, several rare intrathoracic tumors may present with an interstitial and/or a micronodular pattern, such as epithelioid hemangio-­ endothelioma and lymphomatoid granulomatosis.

Lymphangitic Carcinomatosis

Pulmonary lymphangitic carcinomaosis is a metastatic lung disease characterized by the diffuse in ltration and obstruction of the pulmonary parenchymal system by tumor cells [22, 23]. Pulmonary lymphangitic carcinomatosis accounts for up to 10% of all thoracic metastases. Patients are usually diagnosed in their fth decade. Dyspnea is usually the chief symptom [22, 23]. Weight loss is also frequent, as well as cough. Hypoxemia is observed in 70% of patients.

Even if histologically con rmed, chest radiography may be normal in up to 30–40% of cases. High-resolution computed tomography (CT)-scan may show (1) uneven thickening of bronchovascular bundles, from the hilum to periphery, that resembles Kerley B lines, (2) a more limited or diffuse peripheral interlobular septal thickening producing polygonal arcades, and/or (3) a radiographic pattern referred to as “beaded chain” or “string of pearls” thickening of interlobular septa [22]. These features may be diffuse or localized, unior bilateral, and symmetric or not. Micronodules may be observed within the thickened septa. Rapidly progressive asymmetric lymph node involvement is found in 30% of patients. 18-FDG-PET scan shows diffuse parenchymal hypermetabolism in diffuse lymphangitic carcinomatosis, or a more linear or hazy area of FDG uptake.

Diagnosis is usually obtained through bronchial, transbronchial or open lung biopsy; percutaneous biopsy may also provide lung tissue materials allowing the diagnosis to be made. Pathological examination shows multiple tumor thrombi within the lymphatic vessels, associated with a desmoplastic reaction caused by tumor proliferation and lymphatic dilatation around the interlobular septa and peribronchovascular bundles. Tumor cells of adenocarcinoma type are the most likely to produce lymphangitic carcinomatosis, originating from the following primary anatomic locations: breast (33%), stomach (29%), lung (15%), pan-

creas (4%), and prostate (3%) [22]. Survival is usually poor, ranging from 3 to 6 months [21, 22].

Differential diagnosis includes other in ltrative lung diseases, sarcoidosis, as well as bacterial or fungal infections, such as pneumocystis jirovecii pneumonia (PJP), especially when immunosuppressive cytotoxic agents are employed for treatment of the primary cancer. Bronchoalveolar lavage is the key to making the diagnosis of PJP. Lymphangitic carcinomatosis may also be confused with drug-induced interstitial lung disease especially in patients receiving chemotherapy or targeted agents or immunotherapy, immune checkpoint inhibitors or antibodies (drug-conjugated or not). Imaging patterns are nonspeci c and may include ground-glass opacities and interlobular septal thickening. Multiple forms of interstitial lung disease may occur within individual cancer patients.

Epithelioid Hemangio-Endothelioma

Epithelioid hemangio-endothelioma (EHE) is a lowto intermediate-­grade mixed epithelioid, endothelial, and vascular tumor [24, 25]. Lung is the most frequent extrahepatic location (10% of cases); EHE can also arise from the liver (63% of cases), the bone (8% of cases), and the skin (6% of cases) [24, 25]. EHE is characterized by polypoid nodules, with a central sclerotic paucicellular zone, growing into the alveolar spaces with an angiocentric distribution. Lymphangitic spread may mimic metastatic carcinoma. Around 90% of EHEs are caused by the fusion of transcriptional co-activator with a PDZ-motif (TAZ) with calmodulin binding transcription activator 1 (CAMTA1), a central nervous system-speci c transcription activator; the 10% of EHEs that lack the TAZ-CAMTA1 fusion instead have a fusion of yes-associated protein (YAP) and transcription factor E3 (TFE3) genes (YAP-TFE3) [26]. EBV RNA sequences are detected in 90% of cases. Overlapping entities with IgG4-related disease have been described. Clinically, 80% of cases of EHE are diagnosed in white females [24–26]. The tumor is asymptomatic in 50% of cases; when present, symptoms are nonspeci c and include pleuritic chest pain, nonproductive cough, dyspnea, and rarely hemoptysis. By CT imaging, EHE presents either with bilateral slow-growing perivascular multiple nodules, usually located adjacent to small vessels or bronchi, or with predominant in ltrative ground-glass opacities with a micronodular pattern, mimicking lymphangitic carcinomatous. EHE nodules usually range from 3 to 50 mm, and their numbers vary from 10 to 20 lesions. Nodules in patients with EHE may show increased uptake on 18-FDG PET scan. Although there are a few reports of spontaneous remission, the complete resection of all pulmonary nodules is the only curative treatment for EHE. Surgery remains effective even in cases of localized recurrence. In contrast, EHE is generally insensitive to chemotherapy (cisplatin-based) or radiotherapy. Treatment with rituximab or antiangiogenic kinase inhibitors, such as

sorafenib or bevacizumab, have been reported to be effective in isolated case reports [27]. In most cases, EHE is a slow-­ growing tumor that rarely metastasizes and is associated with a median survival of 5–6 years. Endobronchial spread, pleural effusion, and extended endovascular disease have been identi ed as unfavorable prognostic factors.

Angiosarcoma is a high-grade primary pulmonary vascular sarcoma that is considered to be a counterpart of EHE, although no direct transformation from EHE to angiosarcoma has been reported. Clinical features of angiosarcoma are similar to EHE, but massive hemoptysis is more frequent. Radiologic features of angiosarcoma include multiple nodules with a typical surrounding halo of ground-glass attenuation, and a characteristic “caulifower-like” appearance on T2-weighted MRI [28]. This aspect may be shared by other disorders, including malignancies (e.g., adenocarcinoma with lepidic pattern (e.g., bronchioloalveolar carcinoma), metastatic sarcomas, choriocarcinoma, melanoma, lymphoma), infectious diseases (e.g., mycobacteriosis, aspergillosis, cytomegalovirus infection), granulomatosis with polyangiitis, and eosinophilic conditions. Distinguishing primary pulmonary angiosarcoma from extrathoracic angiosarcoma metastatic to the lung can be challenging. Management of angiosarcoma is not established: surgical resection is rarely possible owing to local and regional invasion and radiotherapy and chemotherapy are typically ineffective as seen in other locations of angiosarcoma. In immunocompromised patients, reduction of immunosuppressive agents may lead to reduce the burden of the disease.

Lymphomatoid Granulomatosis

Lymphomatoid granulomatosis (LG), previously called “angiocentric lymphoma,” is a malignant B cell angiocentric and angiodestructive lymphoproliferative disorder [28– 30]. For a long time, LG was considered an infammatory granulomatous disease owing to a presentation similar to other granulomatosis, such as granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis. Now, LG is recognized as a true EBV-related lymphoid malignancy. Differential diagnosis also includes allergic bronchopulmonary aspergillosis. The lung is the most frequent location, but the disease may also involve the brain, the skin, and the liver [28–30].

Pathologically, LG forms multiple and confuent nodules composed of an atypical, angiocentric, and polymorphous lymphoid in ltration involving the vascular walls, from the subendothelium to the adventitial zones, with focal lumen obliteration. By immunohistochemistry, these lymphoid cells are characterized mostly as CD4+ T-lymphocytes, with scattered atypical B cells. Large B cells are infected with EBV in 65% of cases, and EBV status correlates with the grade of the lesion. Pulmonary biopsy is required in most cases to exclude other granulomatoses.

LG arises in middle-aged patients between 40 and 50 years old, with a male predominance. Nearly all patients present with respiratory and systemic symptoms, consisting of cough, dyspnea, hemoptysis, chest pain, fever, and weight loss. Peripheral and mediastinal lymphadenopathy is absent. Prolonged immunosuppression is a frequent underlying condition. Hypereosinophilia may be observed in the blood and/ or in the bronchioalveolar lavage. The typical radiologic presentation consists of multiple smooth bilateral nodules ranging from 2 to 10 cm mainly localized in the lower lobes, exhibiting a peribronchovascular pattern and mimicking multiple metastases. As in other granulomatoses, convergent nodules may migrate and form cavitated pseudotumoral masses.

LG is considered a low-grade or early-stage lymphoma, and a histopathologic grading system has been developed based on the degree of cellular atypia and necrosis to predict the risk of evolution to high-grade lymphoma and to select patients for early aggressive treatment [30]. Chemotherapy based on the use of cyclophosphamide with high-dose steroids is the most frequently reported treatment. The additional use of rituximab has been reported [30]. The overall prognosis is grim, with a 5-year survival of 30% to 40%, owing to progression to nodal diffuse aggressive lymphoma in 20% to 50% of patients.

Cancer Mimics of Multiple Cystic/Cavitary Lung

Disorders

Cystic Tumors

Multiple cystic lung disease (MCLD) is de ned by the presence of multiple rounded well-de ned lucencies of low-­ attenuating area in the lung parenchyma that have a wall thickness lower than 2 mm [31]. MCLD may lead to the development of spontaneous recurrent pneumothorax. As discussed elsewhere in this book, MCLD may be caused, among various disorders, by lymphangioleiomyomatosis, Langerhans cell histiocytosis, Sjögren disease or Birt-Hogg-­ Dubé syndrome.

Metastatic cancers of extrapulmonary origin may mimic MCLD when metastasizing to the lung, especially soft tissue sarcomas including angiosarcomas [32, 33], leiomyosarcomas, osteosarcomas, and synovial sarcoma. Primary tumor locations include soft tissues, bones, the scalp or the uterine endometrium. The occurrence of spontaneous pneumothoraces, which may be bilateral and recur in more than 40% of cases, is more frequent in angiosarcoma, and is associated with worse outcomes. Metastatic cysts may be associated with small-size nodules. In cases for which the information is available, pathological examinations have shown tumor cells in the wall of the cysts. Several case reports describe patients for whom metastatic sarcoma was ultimately diag-

nosed on lung biopsies, or even explanted lungs, after an initial diagnosis of lymphangioleiomyomatosis or pulmonary Langerhans cells histiocytosis [33].

In addition to sarcomas, MCLD-like metastases have been reported in bronchioloalveolar carcinoma, metastatic or primary germ-cell tumors, colorectal and pancreatic cancer.

Cavitating Tumors

The radiological features of cavities overlap with those of cysts. A cavity is a gaslled space, seen as a lucency or low-­ attenuation area within a parenchymal nodule, focus of consolidation or mass [34]. Cavitation is a classical feature of pulmonary involvement by granulomatosis with polyangiitis, in combination with multiple bilateral pulmonary nodules. Cavitation is also a common feature of bronchogenic carcinoma, especially of squamous cell histology, and typically is not associated with extrapulmonary manifestations in the head and neck area, the skin, the joints or the kidney [34]. Serum proteinase 3-speci c, cytoplasmic antineutrophil cytoplasmic antibodies (C-ANCA) are not elevated in patients with cancer. Granulomatosis with polyangiitis rarely presents with a solitary lung lesion; most solitary necrotising granulomas are actually of infectious nature and require histology in addition to typical clinical ndings to support the diagnosis.

Cancer Mimics of Pulmonary Hypertension:

Pulmonary Artery Sarcoma

Pulmonary artery sarcoma presents as an endoluminal polypoid or nodular mass, which spreads along the intima of the pulmonary artery. Histologic features consist of an undifferentiated spindle cell proliferation, with marked cellular pleomorphism and high mitotic index Leiomyosarcoma is the most frequent subtype (60% of cases) [35]. Pulmonary artery sarcomas mainly develop in patients in their fth to sixth decade [35]. Symptoms may mimic pulmonary embolism, with dyspnea, chest pain, cough, and hemoptysis. Failure of anticoagulants to resolve the vascular obstruction in this setting, as well as the presence of symptoms of weight loss and fever (arising in 40% of cases), may suggest the diagnosis. Imaging ndings also help differentiate between pulmonary artery sarcoma and pulmonary embolism: CT scanning may show a polypoid lling defect in the pulmonary artery but, in contrast to thromboembolic disease, sarcoma forms a contiguously soft, smooth, tapering tissue mass, sometimes accompanied by extravascular nodular spread in the parenchyma (40% of cases) and localized

Fig. 43.2  Primary pulmonary artery sarcoma. Contrast enhanced computed tomography scan of a 79-year-old woman, which shows complete obstruction and enlargement of the pulmonary artery trunk. Hypermetabolism is detected at 18-fuoro-2-desoxy-d-glucose positron emission tomography scan. The patient underwent pulmonary endarteriectomy, complete resection of the tumor, and extensive left pneumonectomy. The patient died 25 months after surgery

ground-glass opacities (Fig. 43.2) [36]. Sarcoma also presents with a heterogeneous appearance including areas of necrosis and hemorrhage, and with intense hyperactivity on 18-FDG-PET scanning. Magnetic resonance imaging (MRI) shows intermediate to mildly increased signal on T1-weighted images, often with heterogenous enhancement. T2-weighted images may reveal intermediate to diminished signal intensity relative to skeletal muscle, but in some cases may show enhancement of the intravascular mass, a feature not typically encountered with uncomplicated thromboembolic disease. Surgery is the only potentially curative treatment and, even if performed emergently in the setting of acute right-sided heart failure, is amenable to attempted resection in only 60% to 75% of cases [35– 37]. Alternatively, heart and lung transplantation may be an option for unresectable tumors, but has rarely been reported. A slight improvement of overall survival has also been reported following adjuvant chemotherapy and/or radiotherapy. Contrary to soft tissue sarcoma, prognosis is mainly related to tumor location, because half of the patients die as a result of the progressive obstruction of the pulmonary trunk [37]. In case of recurrence, reoperation is feasible in 30% of cases and radiation therapy and chemotherapy can be partially effective. However, in recent series, the overall median survival has remained low at 6–12 months.