A variety of rare malignant and benign tumors that develop in the lung, the pleura, and the mediastinum, may have a propensity to mimic orphan lung diseases at some level of examination, as they may share with these clinical, imaging, pathological, and even molecular and genomic features. Lung cancer is by far the most frequent intrathoracic malignancy, and it is then the rst diagnosis to consider when facing a rapidly growing lesion involving the lung, the pleura, and/or the mediastinum, especially in smokers [1, 2]. However, physicians may be aware of uncommon and rare neoplastic and non-neoplastic disorders, that have a propensity to mimic other pulmonary diseases at some level of examination, especially rare, orphan entities that are less frequent for physicians who may not be aware of differential diagnoses [3–5]. Several frequent and rare intrathoracic tumors are associated with a peculiar phenotype, as such entities may share some of the clinical, radiological, pathological, and even molecular and genomic features of non-­ neoplastic orphan lung diseases. Numerous disorders may be considered, but the challenges in the differential diagnosis are well illustrated through the examples of bronchioloalveolar carcinoma, as well as primary pulmonary lymphomas and vascular sarcomas. All of these entities are rare, which may hamper rapid and accurate diagnosis.

Pseudotumors have further been described in the thorax, historically also referred to as pseudoneoplasms, but currently restricted to a speci c heterogeneous group of diseases characterized by a circumscribed brous tissue associated with infammatory and myo broblastic cells, which may be observed in multiple diseases [6]. Among those, neoplastic/non-neoplastic borderline disorders have been identi ed, such as infammatory myo broblastic tumor with clonal proliferation, thus nowadays considered as a true

N. Girard (*)

Institut du Thorax Curie-Montsouris, Institut Curie, Paris, France EURACAN Network, Centre Léon Bérard, Lyon, France

UVSQ, Paris Saclay University, Versailles, France e-mail: nicolas.girard2@curie.fr

malignancy with treatment opportunities that include standard anticancer therapies [6]. Molecular, oncogenic alterations that are observed in pulmonary carcinomas may be shared by borderline orphan lung diseases. Other rare pulmonary disorders are emerging as borderline neoplastic-non-­ neoplastic entities, which require multidisciplinary expertise both in the eld of orphan pulmonary diseases and in thoracic oncology, including, for example, amyloidosis or Langerhans cell histiocytosis. Some of these entities are discussed elsewhere in this book.

Here, our objective is to provide the reader with a practical overview of these disorders. Key points for clinical practice are the identi cation of possible suggestive clinical and radiological features, a cautious interpretation of radiological or metabolic imaging, recommendations for speci c pathological and molecular analyses on often small-size biopsies, and ultimately dedicated multidisciplinary expert discussion and networking to ensure expertise for the clinical decision-making.

Cancer Mimicking Orphan Lung Disease at

Imaging

Malignant disorders may mimic some of landmark orphan lung diseases, as these may present radiologically as organizing pneumonia, interstitial lung disease, or even multiple cysts. Awareness of clinicians is key, as well as strict pretreatment workup, that may include molecular and genomic analyses.

Cancer Mimics of Organizing Pneumonia

Organizing pneumonia presents a classical diagnostic pitfall for lung cancer evaluation, as it may occasionally present as a solitary mass-like lesion, leading to unnecessary diagnostic procedures and even surgical resection, especially in heavy smokers who harbor a chronic lesion [7]. The landmark fea-

ture of this condition consists of intra-alveolar broblast and myo broblast, connective matrix organization that lls the alveolar spaces, the alveolar ducts, and the respiratory bronchioles. In patients treated for malignancies, cytotoxic drugs may induce organizing pneumonia. Although usually not presenting as a focal lesion, organizing pneumonia may mimic multiple pulmonary metastases as well. This has especially been reported historically with bleomycin treatment for germ-cell testicular cancer, embryonal tumors, and Hodgkin lymphoma, but is nowadays far more frequent with the use of immunotherapy with immune checkpoints inhibitors [8, 9]. Even in patients with a history of cancer, differential diagnosis is a clinical challenge, and may require multidisciplinary expert discussion to distinguish organizing pneumonia and recurrent cancer.

Conversely, the organizing pneumonia imaging pattern is shared with some primary lung malignancies, including bronchioloalveolar carcinoma and primary pulmonary lymphoma, that are characterized by tumor cell spread in the alveolar spaces, leading to a common radiological pattern of alveolar opacities with air bronchograms [7].

Lung Adenocarcinoma/Bronchioloalveolar Carcinoma

Bronchioloalveolar carcinoma has extensively been described elsewhere [10, 11]. It has actually been a term referring to several clinical-radiological-pathological entities of lung adenocarcinoma, which to varying degrees share a non-invasive lepidic cell growth pattern—a proliferation of tumor cells that progressively develops within the alveolar walls, lling the alveolar spaces without disturbing the normal lung architecture, with no pleural, stromal, or vascular invasion. These include: (1) mixed-type invasive adenocarcinoma with predominant lepidic growth, which has a very similar clinical and radiological presentation to other non-­ small cell lung carcinomas, (2) adenocarcinoma in situ—a pure lepidic growth proliferation, and (3) pneumonic-type lung adenocarcinoma, that is a distinct clinical-radiological-­ pathological entity. As stated above, the lling of alveolar spaces is a landmark feature of typical organizing pneumonia. The 2015 World Health Organization classi cation of lung adenocarcinoma deleted the term “bronchioloalveolar carcinoma” from the nomenclature to avoid historical misunderstanding [11].

Adenocarcinoma in situ, formerly known as pure bronchioloalveolar carcinoma, usually presents as a localized coin-like lesion, 3 cm or less in size, showing a predominant ground-glass pattern usually surrounding a solid lesion, pos-

sibly with air bronchograms, and located at the periphery of the lung parenchyma [11].

Molecularly, these tumors frequently harbor epidermal growth factor receptor (EGFR) mutations; KRAS mutations are frequently found in cases of mucin producing tumors [11]. These tumors may preferentially develop in non-­ smokers. Patients are usually asymptomatic. The lesion may show normal metabolic activity at 18-fuoro-2-desoxy-d-­ glucose Positron Emission Tomography (18-FDG PET) [12]. Given the localized nature of adenocarcinoma in situ, treatment usually consists of upfront surgery, producing a 95–100% disease-free survival rate. Metastatic progression is not observed, however, patients may present with multiple independent synchronous and metachronous tumors.

Pneumonic-type lung adenocarcinoma (PTLA) is a clinical-­radiological-pathological entity that is not strictly de ned in the histopathologic adenocarcinoma classi cation [13]. Histologically, PTLA is a heterogeneous disease, usually corresponding to mixed-type lung adenocarcinoma with predominant lepidic growth pattern, combined with papillary and acinar features, a desmoplastic brotic stromal reaction, and nodal, pleural, and vascular invasion. The clinical criteria to make a diagnosis of PTLA were the following: (1) evidence of a pneumonia-like consolidation, de ned as a homogenous opacity in the lung characterized by little or no loss of volume, disappearance of blood vessel shadows and, sometimes, and the presence of an air bronchogram (Clinical Vignette) and (2) no concomitant bacterial pneumonia or obstructive pneumonia due to an exophytic lesion occluding the lumen of the main or lobar bronchi. The tumor is usually multifocal (65% of cases), slow growing with rare metastatic disease (5% of cases). It is associated with highly productive cough and progressive restrictive respiratory failure [13]. The epidemiology of PTLA differs from that of other non-­small cell lung cancers, with less important epidemiologic links with tobacco smoking, an increased frequency in women and younger patients, and a better outcome (with a 5-year survival of 60%). Current treatment is based on recommendations established for other lung non-small cell carcinomas, including surgery for localized lesions and chemotherapy for disseminated tumors; the role for limited surgical resection is debated. Chemosensitivity is actually limited given the slow-growing pattern [14]. Molecular alterations are observed in about half of the patients [15], that may include

EGFR, KRAS mutations, as well as ROS1, RET, NTRK gene fusions: these alterations predict the ef cacy of targeted agents that are marketed or under investigation [15].

Clinical Vignette

a

b

A 66-year-old former smoker woman presented with progressive cough, and dyspnea. Chest radiography showed bilateral alveolar opacities, leading to prescribe antibiotics. Given the absence of symptom improvement, CT-scan imaging was done, and showed multiple bilateral alveolar condensation-like masses with irregular margins, some of which containing air bronchograms (a). Two subsequent lines of antibiotics were delivered, in the hypothesis of pulmonary infection. Ultimately, the patient presented with weight loss, and worsening of dyspnea. 18-fuoro-2-desoxy-d-­ glucose positron emission tomography scan showed hypermetabolism of all the lesions (b). Transparietal biopsy was performed, and pathological analysis showed adenocarcinoma cells with lepidic growth pattern and papillary architecture. No EGFR mutation was detected, nor other oncogene alteration at next-­ generation sequencing on DNA. The patient received platinum-based chemotherapy, leading to stable disease. Progression-free survival was 18 months. The patient subsequently received three lines of systemic

therapies, including immune checkpoint inhibitors and antiangiogenic agents. Rebiopsy was then performed, leading to nally identify RET fusion. The patient currently receives RET inhibitor, leading to partial response. The patient is currently alive, 5 years after initial diagnosis

Primary Pulmonary Lymphoma

Pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma is referred to as nodal marginal zone B cell lymphoma, with similar cytopathologic features to other MALT lymphomas, especially gastric lymphoma [16]. These low-­ grade lymphomas account for 70% to 90% of primary pulmonary lymphomas. At pathologic examination, MALT lymphoma appears as a diffuse in ltrate of small monomorphic lymphoid cells, with a typical lymphangitic growth pattern spreading along the bronchovascular bundles and interlobular septa, and forming solid nodules that ll the alveolar spaces and obliterate the normal lung architecture. Immunohistochemistry forms the basis of the subtype classi cation, with the expression of the pan-B-markers CD20 and CD79 and the absence of staining for CD5 and CD10 [16]. The proliferation is monotypic, with surface and/or cytoplasmic expression of immunoglobulin (Ig) M and, less frequently, IgG and IgA. Light chain restriction can be detected in the plasmacytic component using fow cytometry. MALT lymphomas are associated with unique chromosomal translocations, such as the t(11;18)(q21,q21) resulting in a fusion of the API2 and MALT1 genes, the t(1;14) (p22;q32) involving the BCL10 and IgH genes— which is overall much less frequent, more speci c to lung locations, and never found in high-grade lymphoma—and the t(14;18)(q32;q21) involving the IgH and MALT1 genes [17]. In cases with the t(1;14) (BCL10/IgH) translocation, immunohistochemistry on paraf n-embedded tissues can detect the strong nuclear overexpression of BCL10. Ampli cation of the IgH gene from paraf n-embedded or cytologic samples with polymerase chain reaction (PCR)-based assays was demonstrated to be a reliable method to detect monoclonality in more than 60% of MALT lymphomas. Contrary to extrapulmonary MALT lymphomas, for which a strong relationship has been established with chronic bacterial infammation related to

Helicobacter pylori in the stomach and to Chlamydia psittaci in the ocular adnexa, no chronic infectious condition has been associated with pulmonary MALT lymphoma. MALT is absent in the normal bronchial tree and is thought to develop only after long-term infammation secondary to smoking or to an autoimmune condition.

Clinically, MALT lymphoma has mainly been observed in patients older than 45 years, with a slight male predomi-

a

b

Fig. 43.1  Pulmonary primary MALT lymphoma in a 56-year-old man. (a, b) Chest radiography and computed tomography scan show persistent alveolar opacities in the right lower lobe, despite prolonged antibiotic therapy. Pathological examination of surgical biopsy showed lymphoplasmacytic-like cells of the marginal zone lymphoma associated with amyloid deposits. The patient received treatment with chlorambucil, which led to complete regression of the lesion

nance, but it may also arise in younger patients with underlying immunosuppression, especially related to human immunode ciency virus (HIV) infection, or with infammatory conditions such as Sjögren disease or rheumatoid arthritis, or in association with Epstein–Barr virus (EBV) infection [18, 19] (Fig. 43.1). Less than 50% of patients are symptomatic, with nonspeci c symptoms including cough, dyspnea, and chest pain. Unlike the situation with other lymphomas, systemic signs such as fever, swelling, and weight loss are uncommon. Association with IgM or IgG blood monoclonal gammopathy is observed in 30% of cases.

Radiologically, MALT lymphoma exhibits three imaging patterns on chest radiography and computed tomography (CT), which are challenging for differential diagnosis: (1)

the most frequent and suggestive is the “pneumonia-like” alveolar consolidation with air bronchograms typically localized in the middle lobe; (2) a “tumor-like” appearance with a solitary circumscribed nodular opacity (30% of cases) and possible central air bronchogram; and (3) the “in ltrative” pattern with diffuse poorly de ned ground-glass opacities, assumed to represent early-stage disease before tumor cells invade alveolar spaces [20]. The combination of a nodular opacity with peripheral peri-bronchovascular ground-glass attenuation halo is common. Pleural effusion is unusual. Multiple cystic lesions may be observed, which may be associated with light chain deposition disease. Hence, differential diagnosis may be challenging with infection, cancer or interstitial diseases leading to frequent misdiagnosis if a complete workup is not conducted.

About a third of MALT lymphomas are multifocal at the time of diagnosis, a presentation that may hamper the determination of the primary pulmonary origin of the disease [18–20]. Pulmonary MALT lymphomas are associated with tumor locations in the gastric mucosa in 10% to 20% of patients and in the bone marrow in 15% to 20% of patients. Gastroscopy and bone marrow biopsy are then recommended; 18-FDG PET imaging may not be sensitive enough to exclude extrathoracic disease. The Ann Arbor staging system, although not designed for extranodal lymphoma, may be applied in pulmonary MALT lymphoma, which would be staged as IE (one site, extranodal) in case of lung unilateral or bilateral involvement, IIE (two sites, both above the diaphragm, extranodal) in case of hilar or mediastinal lymph nodes, or IV in case of multiple sites.

Pathological diagnosis actually requires a large, possibly surgical lung biopsy, because cytologic examination of bronchoalveolar lavage or ne-needle biopsy may show the CD20-positive B-cell in ltration but fail to exclude differential diagnoses, such as reactional lymphoid proliferation, follicular bronchiolitis, or lymphoid interstitial pneumonia. MALT1 gene rearrangements may be identi ed on bronchoalveolar lavage [17].

Therapeutic options are based on the degree of tumor extension. Surgical resection ensures both the diagnosis and the treatment of nodular lesions, but MALT-type histology is usually unexpected when approaching a lesion thought to be NSCLC. In asymptomatic patients, a watch-and-wait attitude may be preferred to aggressive treatment. In the majority of patients MALT lymphoma requires more aggressive management, and standard-of-care is the combination of rituximab, an anti-CD20 antibody, with chlorambucil [21]. Several alternative options have been described, from single-­ agent therapy with chlorambucil, fudarabine, or rituximab to combined cytotoxic agents used for diffuse large-B cell lymphomas. Whether genomic pro les should drive the chemotherapy regimen is unclear, even if rituximab alone may be effective in case of t(11;18) translocation [21].

Prognosis of MALT lymphomas is usually excellent, with an indolent and localized prolonged course, and response to chemotherapy. Historical series reported 5-year survival rates