Intrathoracic Pseudotumors

Pseudotumors represent a wide range of etiological, pathological, and clinical-radiological disorders, that all share some degree of reactive infammation and may present with some cancer-related molecular hallmarks. Pseudotumors may mimic the clinical and radiological features of various intrathoracic diseases.

In ammatory Myofbroblastic Tumor

Infammatory myo broblastic tumor (IMT) is the most representative of the pulmonary pseudotumors [6, 38] and encompasses a wide spectrum of lesions previously called “infammatory pseudotumor,” “ broma,” “ broxanthoma,” “ brous histiocytoma,” “plasma cell/mast-cell/solitary granuloma,” “plasma cell histiocytoma complex,” or “pseudosarcomatous tumor.” IMT has a prevalence of 0.04% of resected pulmonary neoplasms in a surgical series of the Mayo Clinic.

IMT appears as an intraparenchymal, well-circumscribed mass of variable size (Fig. 43.3) [38, 39]. Histologically, the tumor is composed of an irregular proliferation of broblasts and myo broblasts intermixed with an in ltrate of infammatory cells, mainly lymphocytes and plasma cells. Three distinct histologic patterns are usually recognized:

\1.\ Plasma cell variant, also called the “lymphoplasmacytic” variant, which is composed of infammatory myxoid proliferation with fascicles of spindled broblasts or myo -

Fig. 43.3  Infammatory myo broblastic tumor. Computed tomography scan of a 31-year-old man who presented with persistent cough and hemoptysis following infectious pneumonia. A spiculated mass is located in the left lower lobe. Transparietal biopsy showed polymorphic infammation without tumor cells. 18-fuoro-desoxy-glucose positron emission tomography showed focal hypermetabolism of the mass. Surgical resection was performed. The patient did not receive adjuvant treatment. No recurrence was observed after a 1-year follow-up

broblasts, abundant lymphocytes and plasma cells, and minimal brous connective tissue.

\2.\ Fibrohistiocytic type, which appears as a compact spindle cell pattern simulating brous histiocytoma that is characterized by a myxoid proliferation of broblasts and myo broblasts associated with polyclonal plasma cells, xanthoma cells, and rare giant cells.

\3.\ Organizing pneumonia-like type, which has a hypocellular pattern characterized by dense collagen with sparse spindle cells.

The proliferating myo broblastic cells show no cellular atypia, no necrosis, and only rare mitotic gures. The myo - broblastic cells usually stain for vimentin and smooth muscle actin.

The concept of IMT as a proliferating neoplasm has been questioned [6]. More recently, clonal gene rearrangements have been observed [40–42], especially involving the anaplastic lymphoma kinase (ALK) gene. ALK overexpression is observed in 40% to 70% of IMTs at immunohistochemistry, but ALK rearrangement is identi ed in less than 30% of pulmonary IMT cases, and most frequently consists of t(1;2) (q21;p23) translocation implicating the tropomyosin 3 gene [40–42]. Other translocations have been reported, including ROS1 translocation [42]. Given the oncogenic nature of ALK activation, these data lead some authors to consider IMT as a true malignant neoplasm. Other elements further reinforce this concept, including the presence of vascular invasion, local recurrence rate as high as 25%, and the existence of multifocal lesions. IMT is also a consequence of immunologic disorders. IgG4 expression in polyclonal plasma cells extracted from intrathoracic IMTs has been associated sclerosing pancreatitis and retroperitoneal and mediastinal brosis, and IgG4-related disease. Overlap exists between IMT, IgG4-related disorders, and prototypic, high-grade infammatory brosarcoma that exhibits prominent cellular atypia and necrosis. Finally, EBV and human herpesvirus 8 infected myo broblastic cells can be found in IMTs.

Pulmonary IMTs usually appear before the fourth decade, accounting for more than 50% of pulmonary tumors in children Contrary to its presentation at extrathoracic locations, the pulmonary IMT is usually solitary, and often forms a well-circumscribed peripheral mass, ranging from 2 to 15 cm in size. Calci cations are observed in 15% of cases. Stability in size over time is an important imaging feature that helps differentiation of IMT from more aggressive tumors. Mediastinal invasion is frequent but multifocal and bilateral IMTs are usually hypermetabolic on 18-FDG-PET scan.

Even if historically considered a benign lesion with possible spontaneous regression, IMT is usually treated by surgical resection due to its tendency to grow, to provoke local complications including hemoptysis and infection, and to relapse occasionally with lung/pleural and/or mediastinal

invasion (15–25% of cases and 3–5% of cases, respectively). The need for adjuvant treatment in case of incomplete resection has not been evaluated. In nonoperable patients, focal conformation radiotherapy or corticosteroids may represent an alternative. Corticosteroids are reported to induce objective responses in as many as 50% of cases, especially in predominantly plasma cell tumors and IgG4positive tumors. In recurrent or multifocal lesions, chemotherapy may be based on regimens used for soft tissue sarcomas. ALK inhibitors are effective in case of ALK- rearranged IMT [42].

Sclerosing Mediastinitis and Hyalinising

Granuloma

Similar to IMT, sclerosing mediastinitis and hyalinising granuloma both consist of tissue in ltration by dense collagen brosis forming lamellar bands, interspersed with lymphocytes and plasma cells [43–45]. These two entities differ by the primary anatomic location: sclerosing mediastinitis predominantly involves the mediastinum, with possible extension to the lung parenchyma; hyalinising granuloma occurs within the lung parenchyma without contiguous involvement of the mediastinum (Fig. 43.4). Overlap exists between these entities and other brosing disorders such as IMT, retroperitoneal brosis, and other IgG4-related disorders.

Borderline Neoplastic-Non Neoplastic

Disorders

Excluded from this chapter are benign tumors and pre-­ neoplastic conditions of the lung, which have extensively been reviewed elsewhere [4]. Borderline neoplastic and non-­ neoplastic disorders include entities that are considered benign despite being associated with true neoplasms or presenting with some pathological or molecular characteristic of neoplasia, including clonal proliferation. These disorders may also present as pulmonary nodules or in ltrative disease, mimicking bronchogenic carcinoma or interstitial pneumonias, respectively.

Respiratory Papillomatosis

Some lesions thought to be benign may have a borderline presentation and outcome. One relevant example is recurrent respiratory papillomatosis. Papillomas usually present in the upper respiratory tract but may rarely spread to the lung parenchyma (less than 5% of cases) [46]. Histologically, squamous papillomas are usually exophytic with an epithelial layer covering a central brovascular core that forms a frondlike architecture protruding into the lumen of the airway. Papillomas may exhibit imaging features similar to those of lung cancer, including heterogeneous, cavitating, or poorly de ned masses.

Fig. 43.4  Sclerosing mediastinitis. (a) Computed tomography scan of a 32-year-old woman who presented with progressive dyspnea and superior vena cava syndrome. Connective tissue proliferation in ltrates the entire mediastinum. Surgical biopsy was performed to make the

diagnosis. (b) At magnetic resonance angiography, the caliber of the superior vena cava is reduced (arrow). An endoprosthetic tube was placed for palliation

Pulmonary papillomas may be solitary or multiple; if multiple, these are associated with multiple papillomas of the upper respiratory and aerodigestive tract. As in other locations, the pathogenesis of squamous papillomas is linked with human papillomavirus (HPV) infection, often acquired at birth [47]. Speci cally, HPV type 11 infection has been reported to bear a high-risk of transformation of papilloma to squamous cell carcinoma. Molecularly, loss of the tumor suppressor genes TP53, RB, and P21 has been reported in squamous cell carcinomas originating from papillomas. Mutation of HPV-11 with duplication of promoter and oncogene regions has been described in a case responding to vorinostat. 18-FDG-PET scanning may not be useful given the mild hypermetabolism of high-grade papillomas. Given this uncertain malignant potential and the dif cult differential diagnosis with lung cancer, complete resection of papillomas is recommended though not always possible in the setting of multiple and bilateral lesions. The role of vaccines, antiangiogenic agents, and antiviral treatment in preventing evolution of pulmonary papillomas is unclear.

Amyloid and Non-amyloid Immunoglobulin

Deposition Disorders

Amyloidosis is characterized histopathologically by tissue in ltration with amorphous eosinophilic material consisting of brillar protein with a β-sheet structural conformation, speci cally stained by Congo red with a yellow-green birefringence under polarized light [48]. Amyloidosis has a highly variable clinical-radiological presentation. The lung parenchyma is involved in 30–80% of cases. Pulmonary amyloidosis may be localized or associated with systemic amyloidosis.

Pulmonary amyloidosis may present either as tumor-like lesions consisting of amyloid deposits, generally associated with peripheral lymphoplasmacytic in ltrate and multinucleated giant cells, or as an in ltrative parenchymal disease. Pulmonary amyloid nodules usually consist of AL (“amyloid light chain”) amyloid, which is the most common subtype of amyloidosis deposits, consisting of lambda light chains. AL amyloidosis is primary in more than 80% of cases and associated with infammatory or lymphoproliferative disease in 20% of cases. Serum and/or urinary monoclonal gammopathy is frequent.

Nodular amyloidosis is observed in patients in their seventh decade, without gender predominance [48–51]. Patients are usually asymptomatic. The lesion is solitary in about 30% of cases, corresponding to the so-called amyloidoma. When multiple nodules are present, symptoms may include

cough, hemoptysis, or pleuritic chest pain due to pleural effusion. Radiologically, pulmonary nodules are rounded and sharply delimited usually mimicking neoplastic growth. Most nodules are peripheral and located in the lower lobes. The nodules may range from 5 mm to more than 15 cm, and are calci ed in 20–50% of cases. The radiological differential diagnosis includes primary and secondary neoplasia, and granulomatous disease. Nodules have shown moderately increased activity at FDG-PET scan. Fine-needle biopsy may provide pathologic diagnosis. Pulmonary amyloid nodules may remain stable for years. Surgical resection is usually performed to obtain a de nite diagnosis, but recurrence is frequent.

Besides nodular amyloidosis, diffuse parenchymal amyloidosis typically manifests as interstitial linear or nodular subpleural opacities. In the context of systemic amyloidosis, lymphadenopathy can be widespread and can affect hilar and mediastinal lymph nodes in the thorax. The enlarged lymph nodes may exhibit punctiform calci cation. Dyspnea and cough are the most common symptoms. The prognosis of diffuse parenchymal amyloidosis presenting with clinical symptoms is poor. In one series, the median survival of patients with primary systemic amyloidosis affecting the lung was 16 months [49]. Most patients show progression to respiratory failure within 2 years, irrespective of whether the disease is limited to the lungs or affects additional organs. However, many patients also present with concomitant cardiac amyloidosis, which can be associated with rapid heart failure and death. Treatment of any underlying hematologic disease usually leads to regression of the monoclonal peak but has little effect on existing deposits.

Like amyloidosis, nonamyloidotic monoclonal immunoglobulin deposition disease (NAMIDD) initially described in the kidney where it is referred to as Randall disease, was recently reported to occur in the lung [51]. NAMIDD (also known as Light Chain Deposition Disease) presents with deposits that are not stained by Congo red dye and do not demonstrate birefringence under polarized light. These deposits most usually consist of light chains, frequently of kappa isotype, or more rarely of single heavy chains or of mixed light and heavy chains. Pulmonary NAMIDD most frequently presents as multiple parenchymal nodules or as a unique mass without functional consequences; deposition is usually limited to the lung without systemic involvement. NAMIDD may also present as multiple cysts or diffuse bronchiectasis with functional impairment, which may be severe [51]. Approximately half of the cases are associated with hematologic malignancies, mostly of lymphoplasmacytic nature [51]. Pulmonary NAMIDD may bene t from lung transplantation in cases of severe respiratory failure and in the absence of an underlying hematologic disorder [51].

Pulmonary Langerhans Cell Histiocytosis

Pulmonary Langerhans cell histiocytosis (PLCH) is a heterogeneous disease de ned by the proliferation of Langerhans cells, corresponding to CD1a-positive histiocytes exhibiting Birbeck granules on electron microscopy [52]. These cells of dendritic lineage derive from CD34-positive bone marrow stem cells. If the lung is the sole location of the disease, it is called “pulmonary LCH.” In less than 15% of cases, LCH in adults is associated with multisystem disease, corresponding to “acute disseminated LCH” involving the lung as well as the bone, the skin, and the pituitary gland. The pathogenic concepts about LCH mostly involve an uncontrolled immune response to a yet undetermined stimulus, leading to the recruitment of Langerhans cells in the lung parenchyma. Smoking exposure is found in the majority of patients developing pulmonary LCH which is thought to stimulate this process effects on the bronchiolar epithelium [52]. The true nature of LCH remains elusive. Strongly favoring the hypothesis of a neoplastic disorder is the observation that Langerhans cells, isolated from patients with either pulmonary or disseminated LCH, are clonal [53], and may harbor activating BRAF mutations, as well as mutations of the MAP2K1 pathway [53, 54]. However, the limited proliferation of Langerhans cells, the absence of cellular atypia, the low number of Langerhans cells in high-stage lesions, and the possibility of spontaneous regression argue against a truly cancerous nature of LCH.

Pathologically, LCH lesions are made of Langerhans cells that proliferate and aggregate to form stellate nodules in the interstitium, with a bronchiolocentric pattern and linear distal and proximal spread. High-stage lesions are characterized by disappearance of Langerhans cells, increased amounts of brosis, and cavitation of the nodules leading to cyst formation [52].

Clinically, pulmonary LCH develops in young smokers who present with nonspeci c respiratory symptoms, including dyspnea, cough, and chest pain. Pneumothorax may herald the disease in 15% of patients; 10–25% of patients are asymptomatic. The most typical imaging feature is the combination of pulmonary multiple cysts and micronodules sparing the lower zones of the lung. Nodules, ranging from 5 mm to 2 cm in size, are centrilobular and may be solid or cavitated with smooth or irregular margins. LCH is an active process, with predominant nodular presentation at early stages of the disease, evolving to cavitated nodules, cysts of variable wall thickness, and confuent cystic lesions over time. Lesions of different ages are usually observed within the same subject. Rarely, pulmonary LCH presents as a single nodule, localized consolidation, or mediastinal disease. Increased uptake on 18-FDG-PET scanning is frequent.

Smoking cessation may lead to regression in as many as 25% of patients. No other treatment has been con rmed to be useful in pulmonary LCH, which may also regress spontaneously. Patients with progressive or multiorgan disease may bene t from chemotherapy with cladribine, which produced a 75% objective response rate in a landmark study of 13 patients [55]; cladribine may also reduce the growth and development of cystic lesions. BRAF mutations are associated with resistance to chemotherapy, but may predict the ef cacy of RAF/MEK inhibitors [56]. Supporting the neoplastic hypothesis, pulmonary LCH can recur following lung transplantation.

Lessons Learned: Rare Tumors Vs. Orphan

Lung Diseases

When facing a pulmonary tumor-like lesion, the primary hypothesis for clinicians should remain that the lesion represents lung cancer, the main differential diagnosis of rare pulmonary malignancies. The absence of a tobacco smoking history, especially in men, is more frequently seen for rare lung tumors and pseudotumors than for bronchogenic carcinoma (60% vs. 15%, respectively). Young age at diagnosis is another characteristic to consider, because more than 50% of rare tumors present before the fourth decade. Given the frequent initial suspicion of lung cancer, most patients undergo complete oncologic workup. 18-FDG-PET scan is usually not helpful for differential diagnosis. Preoperative biopsies and intraoperative frozen sections may not be suf ciently representative of the tumor to ensure accurate histopathologic diagnosis, especially in biphasic or composite tumors, for which small-size samples may identify only one cellular component. Frozen specimen collection and storage is mandatory to preserve the tumor for additional analyses.

Sophisticated molecular studies, including fow cytometry and genomic and cytogenetic analyses, play an increasingly important role in the accurate diagnosis of rare pulmonary tumors vs. orphan lung diseases, as morphology may not be suf cient for classi cation and evaluation of tumor grade. This is especially mandatory for lymphoma, IMT, or sarcomas. Systematic high-throughput genomic analyses, including DNA/RNA sequencing—possibly whole exome sequencing, is used to identify deregulated molecular pathways, which is not possible based on targeted, panel-­ based analyses designed for frequent tumors. These data may facilitate decisions regarding potential treatment strategies based on targeted agents. Family history is of interest to understand possible predispositions, and occupational/professional questionnaires may identify potential carcinogens;