Introduction
Rare lung tumors are defined as lung tumors with low prevalence and unusual histology. Overall, these tumors account for less than 1% of all primary lung tumors, whereas they correspond to more than 100 different histologic, clinical, radiologic, and prognostic entities. Some rare lung tumors are specific to the lung, whereas others represent tumors more frequently found in other organs that are only rarely detected in the lungs. It is estimated that about 60% of rare primary pulmonary tumors correspond to benign and low-grade lesions and that 40% are malignant. The rare tumors are characterized by their low incidence, but also by poor clinical and imaging descriptions, by the low number of experienced specialists for each tumor subtype, and by the limited amount of specific therapeutic data. Recognition of rare lung tumors relies on characteristic clinical and radiologic signs, on a modified diagnostic and imaging strategy, and on the determination of their primary or secondary nature. Interestingly, some of the rare lung tumors may have a propensity to mimic lung carcinoma as well as benign orphan lung diseases, because they may share clinical, imaging, pathologic, and even molecular features.
Pseudotumors have further been described in the thorax, historically referring to any pseudoneoplasm, but currently restricted to a specific heterogeneous group of diseases characterized by circumscribed fibrous tissue associated with inflammatory and myofibroblastic cells. Among those, borderline neoplastic/non-neoplastic disorders have been identified, such as inflammatory myofibroblastic tumor with clonal proliferation, thus emerging as a true neoplasm. Other rare pulmonary disorders are emerging as borderline neoplastic/non-neoplastic disorders, which require multidisciplinary expertise both in the field of orphan pulmonary diseases and in thoracic oncology, including, for example, amyloidosis or Langerhans cell histiocytosis.
Here our objective is to provide the reader with a practical overview of these disorders. Selected lesions of special interest with relatively high incidence are discussed to illustrate specific issues regarding the overall diagnostic and therapeutic management of rare malignant primary pulmonary tumors and borderline entities. In a closely related chapter, Chapter 56 , some of the same entities are discussed when they have overlap between benign and malignant behavior.
Characterization of Rare Lung Tumors
Although accounting for less than 1% of lung malignancies, rare lung tumors correspond to a large array of histopathologic, clinical, radiologic entities. Prevalence may also range from merely uncommon lesions, such as carcinoids, which account for 0.15% of primary lung tumors, to extremely unusual tumors, such as primary pulmonary melanoma, with fewer than 50 reported cases. Overall, the most frequent rare malignant primary lung tumors are, in decreasing order of frequency: carcinoid, mucosa-associated lymphoid tissue (MALT) lymphoma, and pneumoblastoma.
Most rare lung tumors develop from orthotopic tissues, constitutive of the normal lung parenchyma, and from hematopoietic tissues, whereas tumors derived from ectopic tissues, including melanoma and meningioma, are more uncommon. Some rare tumor subtypes, such as lymphomatoid granulomatosis (LG), arise specifically within the lung, whereas others, such as blastomas and perivascular epithelioid cell tumors, arise in many different tissues of the body including the lung and are infrequent wherever they are located. Furthermore, some primary tumors that are uncommon within the lung may be frequent in other locations, including lymph node lymphomas and soft tissue sarcomas, which present with specific histopathologic differentiation when originating in the lung, such as MALT lymphoma and angiosarcoma, respectively.
From a clinical point of view, the hallmarks of rare lung tumors may be, more than their actual low frequency, the absence of comprehensive clinical data, the low number of specialized groups for the care of each tumor subtype, and the lack of specific therapeutic recommendations. More than 90% of rare lung tumor observations are published as case reports or small series including fewer than five patients. Currently, only carcinoids and large cell neuroendocrine carcinoma, as the most frequent of the rare tumor subtypes, have been characterized regarding their clinical, therapeutic, and prognostic features in large retrospective and prospective studies.
Patients with rare lung tumors, like many patients with cancer, tend to go through several stages of grief, including depression, uncertainty, hope, disappointment, and in most cases, physical degradation and social isolation. The rarity of the tumor may also enhance these feelings, owing to the relative lack of information and the increased feeling of isolation, the geographic disparity in access to specific care, the longer duration of the pretherapeutic workup, the involvement of multiple specialists, a feeling of injustice especially in young and never-smoking patients, and the complex management undertaken in a state of uncertainty. As a result, patients with rare lung tumors may not receive equal care and some may feel “orphaned,” being incompletely integrated in the process of care of patients with the more frequent bronchogenic carcinoma.
Primary Pulmonary Lymphoma and Other Lymphoproliferative Diseases
Primary pulmonary lymphoma is defined as a lymphoma affecting one or both lungs, without evidence of extrapulmonary involvement or bone marrow disease at the time of diagnosis and during the subsequent 3 months. For clinicians, pulmonary lymphomas associated with small-size satellite mediastinal and/or systemic nodes are also regarded as originating from the lung. Even including these tumors, primary pulmonary lymphomas are rare, representing 0.4% of all lymphomas. The most frequent subtypes are MALT-type lymphoma and LG. Other subtypes are found only in immunocompromised patients ( eFig. 90-33 , eFig. 90-34 , eFig. 90-35 , eFig. 90-36 , eFig. 90-37 , eFig. 91-16 , eFig. 91-17 ). Primary pulmonary lymphoproliferative disorders may present with a wide range of radiologic features, mimicking organizing pneumonia, interstitial diseases, or lung cancer.
Mucosa-Associated Lymphoid Tissue Lymphoma
Pulmonary MALT lymphoma is referred to as nodal marginal-zone B-cell lymphoma, with similar cytopathologic features to other MALT lymphomas, especially gastric lymphoma. These low-grade lymphomas account for 70% to 90% of primary pulmonary lymphomas. At pathologic examination, MALT lymphoma appears as a diffuse infiltrate of small monomorphic lymphoid cells, with a typical lymphangitic growth pattern spreading along the bronchovascular bundles and interlobular septa, and forming solid nodules that fill the alveolar spaces and obliterate the normal lung architecture ( Fig. 54-1C and D ). Immunohistochemistry forms the basis of the subtype classification, with the expression of the pan-B-markers CD20 and CD79 and the absence of staining for CD5 and CD10. The proliferation is monotypic, with surface and/or cytoplasmic expression of immunoglobulin (Ig) M and, less frequently, IgG and IgA (see Fig. 54-1E and F ). Light chain restriction can be detected in the plasmacytic component using flow 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 specific to lung locations, and never found in high-grade lymphoma—and the t(14;18)(q32;q21) involving the IGH and MALT1 genes. The precise mechanisms leading to the development of these translocations remain unknown, but they all appear to result in an inhibition of apoptosis and a survival advantage to the cells. In cases with the t(1;14) ( BCL10/IGH ) translocation, immunohistochemistry on paraffin-embedded tissues can detect the strong nuclear overexpression of BCL10, thought to have prosurvival functions. Amplification of the IGH gene from paraffin-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 inflammation 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, although concurrent evolution with chronic hepatitis C has been described. However, MALT is absent in the normal bronchial tree and is thought to develop only after long-term inflammation secondary to smoking or to an autoimmune condition.
MALT lymphoma has mainly been observed in patients older than 45 years, with a slight male predominance, but it may also arise in younger patients with underlying immunosuppression, especially related to human immunodeficiency virus (HIV) infection, or with inflammatory conditions such as Sjögren disease or rheumatoid arthritis, or in association with Epstein-Barr virus (EBV) infection. Less than 50% of patients are symptomatic, with nonspecific 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. 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 (see Fig. 54-1A and B ) that is typically localized in the middle lobe; (2) a “tumor-like” appearance with a solitary circumscribed nodular opacity (30% of cases) ( eFig. 54-1 ) and possible central air bronchogram; and (3) the “infiltrative” pattern with diffuse poorly defined ground-glass opacities ( eFig. 54-2 ), assumed to represent early-stage disease before tumor cells invade alveolar spaces. The combination of a nodular opacity with peripheral peribronchovascular ground-glass attenuation halo is frequent. Pleural effusion is unusual.
About a third of MALT lymphomas are multifocal at the time of diagnosis, a presentation that may hamper the determination of the primary site. 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 frequently performed as a pretreatment workup. 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scanning may not be sensitive enough in MALT lymphoma 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, and IIE (two sites, both above the diaphragm, extranodal) in case of hilar or mediastinal lymph nodes.
The diagnosis often requires a surgical lung biopsy, because cytologic examination of bronchoalveolar lavage or fine-needle biopsy may show the CD20-positive B-cell infiltration but fail to exclude differential diagnoses, such as reactional lymphoid proliferation, follicular bronchiolitis, or lymphoid interstitial pneumonia. MALT1 gene rearrangements may be diagnosed on bronchoalveolar lavage.
Therapeutic options are based on the degree of tumor extension. Surgical resection ensures both the diagnosis and the treatment of nodular lesions. In asymptomatic patients, a watch-and-wait attitude may be preferred to aggressive treatment. More advanced MALT lymphoma requires more aggressive management, and several options have been described, from resection to radiotherapy, or single-agent chemotherapy with chlorambucil, fludarabine, or rituximab; chlorambucil may produce the best results. Rituximab, an anti-CD20 antibody, is particularly effective and well tolerated and may represent an alternative to chemotherapy, especially in the case of t(11;18) translocation. Current data favor systemic treatments in MALT lymphomas, considering that these tumors may represent the early-stage manifestation of a systemic disorder of mucosal immunity. Furthermore, the fact that surgical resection has not been shown to improve prognosis in some series is an additional argument against local treatments. Recently, the addition of rituximab to chlorambucil demonstrated asignificant effect on survival in patients with MALT lymphoma. Prognosis of MALT lymphomas is excellent, with an indolent and localized prolonged course. Historical series reported 5-year survival rates higher than 80%, and the more recent availability of rituximab may even improve these results. 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 is the most significant favorable prognostic factor.
Lymphomatoid Granulomatosis
Lymphomatoid granulomatosis (LG), also called “angiocentric lymphoma,” is a malignant B-cell angiocentric and angiodestructive lymphoproliferative disorder. For a long time, LG was considered an inflammatory granulomatous disease owing to a clinical presentation similar to other granulomatoses, such as granulomatosis with polyangiitis (formerly Wegener disease) and eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome). 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.
LG forms multiple and confluent nodules composed of an atypical, angiocentric, and polymorphous lymphoid infiltration 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 cells of B phenotype. Large B cells are infected with EBV in 65% of cases, a fact that 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 ( eFigs. 54-3 and 54-4 ). As in other granulomatoses, convergent nodules may migrate and form cavitated pseudotumoral masses. Ground-glass opacities may be present. Peripheral and mediastinal lymphadenopathy is absent. Lung biopsy is required in most cases to make the diagnosis.
Chemotherapy based on high-dose steroids with cyclophosphamide is the most frequently reported treatment. The additional use of rituximab may increase the efficacy of these cytotoxic agents. 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. As in lymphoma, the main prognostic factors are age, extension of the lesions, and response to first-line chemotherapy. LG is increasingly 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.
Other Lymphomas and Lymphoproliferative Diseases
Other primary pulmonary malignant lymphoproliferative diseases are very rare and include high-grade diffuse large B-cell lymphoma, intravascular large cell lymphoma, Hodgkin lymphoma, and plasmacytoma.
Primary pulmonary diffuse large B-cell lymphoma is likely underrecognized owing to its rapid spread to mediastinal nodes and other extrathoracic sites, which may hide its pulmonary origin. Histologically, it shows characteristics similar to those of diffuse large B-cell lymphomas at other sites, with diffuse infiltration of large blastic lymphoid cells, expressing pan-B antigens (CD20 and CD79a). Primary pulmonary high-grade B-cell lymphomas typically develop in immunocompetent patients in their sixth to seventh decade. In younger patients, large B-cell lymphoma may be caused by latent EBV infection, which may develop following drug-induced immunosuppression, as from methotrexate or antilymphocyte antibodies in transplant recipients, or following HIV-related immunosuppression. In patients with HIV infection, the availability of highly active antiretroviral therapy led to the near disappearance of primary pulmonary high-grade lymphomas, which are now less frequent than MALT lymphomas in these patients. Patients often present with marked respiratory and systemic symptoms. Radiologic studies usually show multiple well-defined rounded solid masses of various sizes, more frequently in the subpleural areas of the lower lobes (see eFig. 90-33 , eFig. 90-34 , eFig. 90-35 ). Chemotherapy is based on the same multiagent regimens as those used in high-grade nodal lymphomas, including doxorubicin (Adriamycin), prednisone, and rituximab. The overall prognosis is much worse than for MALT lymphoma, with a 5-year survival lower than 20%.
Intravascular large cell lymphoma is a variant of non-Hodgkin lymphoma, in which neoplastic lymphoid cells proliferate within the lumen of small and intermediate-sized blood vessels, resulting in thrombotic and ischemic complications. Clinical manifestations are multiple, but lymphadenopathy is usually absent. Pulmonary imaging features include bilateral ground-glass opacities and/or sometimes migratory atelectatic shadows ( eFig. 54-5 ). Treatment with conventional combination chemotherapy with or without rituximab leads to remission and prolonged survival.
Primary pulmonary Hodgkin lymphoma has been reported exclusively in old studies, and might actually correspond to nodal Hodgkin disease with secondary pulmonary involvement. On chest radiography, it is described as a solitary mass ( eFig. 54-6 ) with cystic and heterogeneous features, typically involving the upper lobes, or as a multinodular disease. Diagnosis is based on the recognition of characteristic Reed-Sternberg cells at pathologic examination. The overall outcome is poorer than in nodal Hodgkin lymphoma.
Primary pulmonary plasmacytoma is a solitary lesion exclusively composed of atypical monoclonal plasmocytes, possibly associated with amyloid deposition, without evidence of extrapulmonary myelomatous disease. Again, the apparent decrease of the incidence of primary pulmonary plasmacytoma may be related to the increased sensitivity of biologic and imaging studies for the detection of primary extrapulmonary disease. Moreover, about one third of patients operated on for pulmonary plasmacytoma were reported to present with multiple myeloma in following years. Surgical resection is, however, recommended for solitary tumors, with a 5-year survival of 60%.
Carcinoids and Other Neuroendocrine Tumors
Primary lung neuroendocrine tumors share common histopathologic features and correspond to four different clinical and prognostic entities: (1) low-grade typical carcinoids, (2) intermediate-grade atypical carcinoids, and (3) high-grade large and (4) small cell neuroendocrine carcinomas. The small cell lung carcinomas are common, accounting for 15% to 20% of all primary lung malignancies. On the contrary, carcinoids and large cell neuroendocrine carcinomas account for 0.5% to 2% of lung tumors and are thus considered the most frequent lesions among the rare lung tumors.
Pathologic Classification
Neuroendocrine tumors share varying degrees of neuroendocrine morphologic features, including organoid nesting, the palisading and trabecular pattern, and “rosette-like” structures. Classification is mainly based on the mitotic index and the amount of necrosis. Typical carcinoids exhibit neuroendocrine features, with a mitotic index less than 2 mitoses per 10 high-power fields (2 mm 2 ), and the absence of necrosis in a tumor that is more than 5 mm in diameter. Atypical carcinoids exhibit a mitotic index ranging from 2 to 10, or areas of focal necrosis. Peripheral carcinoids often may also be associated with small (<5 mm) neuroendocrine “tumorlets” and/or with diffuse hyperplasia of pulmonary neuroendocrine cells. These lesions may correspond to early-stage in situ carcinoid proliferation.
Large cell neuroendocrine carcinomas exhibit a mitotic index higher than 10 (ranging from 70 to 80 in most cases) and extensive necrosis. Unlike small cell carcinoma, large cell carcinomas have large tumor cells, with moderate to abundant cytoplasm and, frequently, prominent nucleoli. Immunohistochemically, the expression of at least one neuroendocrine marker, including chromogranin, synaptophysin, or N-CAM (CD56), confirms the diagnosis. The pathologic classification also distinguishes large cell neuroendocrine carcinoma from non–small cell lung cancer (NSCLC) “with neuroendocrine differentiation,” a pattern without specific prognostic or therapeutic implications.
Carcinoid Tumors
Excluding small cell lung cancer, more than 80% of lung neuroendocrine tumors are carcinoids. Carcinoids arise mostly in never-smokers (60% to 80% of cases). Carcinoids develop in the proximal airways in 60% to 70% of cases and may produce chronic cough, hemoptysis, and signs of bronchial obstruction. Peripheral carcinoids are asymptomatic, unless they are associated with diffuse hyperplasia of pulmonary neuroendocrine cells that produces bronchiolar obstruction in 50% of cases and possible airflow obstruction. Unlike carcinoids in extrathoracic locations, lung carcinoids are small size lesions only rarely associated with liver metastases and do not generally produce the carcinoid syndrome (<2% of cases). CT shows a peripheral or proximal circumscribed solitary nodular lesion in 90% of cases, often manifesting as a hilar or perihilar mass ( eFig. 54-7 ). Carcinoid tumors may present as “iceberg-like” lesions, with a small amount of endobronchial growth and a prominent parenchymal mass ( Fig. 54-2 ). In some cases, carcinoid tumors may present as endobronchial lesions, with or without ( eFig. 54-8 ) lobar or segmental atelectasis. Calcification (see eFig. 54-7C ) may be observed in up to 30% of cases. Their hypervascularity (see eFig. 54-7B and C ) can distinguish carcinoids from mucous plugging. Regional lymph node invasion is more frequent in atypical carcinoids (40% to 50% of cases vs. 10% to 15% of typical carcinoids) ( eFig. 54-9 ), and the tumor-node-metastasis classification, although designed for carcinomas, has been used to stage carcinoids. Although hypervascularized, carcinoids generally exhibit a low to moderate activity on PET scanning. Imaging for somatostatin receptors using Indium-labeled octreotide ( eFig. 54-10 ) has shown great promise and may increase the sensitivity for diagnosis, staging, and follow-up for recurrence. The risk of hemorrhage following endobronchial biopsy is less than 1%.
Surgery is the standard treatment for stage I-II and most stage III carcinoids, which account for 75% and 15% of cases, respectively. Typical carcinoids, with a low local recurrence rate, can be treated with limited resection with segmentectomy and regional lymph node dissection; this local approach is associated with local control and survival rates identical to that following extensive procedures. Endobronchial techniques, such as cryotherapy, have also been reported as an alternative approach for typical carcinoid but fail to ensure accurate counting of the mitotic index and, therefore, the confirmation of the subtype. Atypical carcinoids, which have a higher local recurrence rate, require lobectomy and mediastinal lymph node dissection. Lung carcinoids metastasize in less than 10% of cases. In those cases, cisplatin-based chemotherapy is ineffective, whereas local treatment of metastases may lead to prolonged remission. Combination of everolimus plus octreotide may represent the best option. In sum, the most significant prognostic factor is the histopathologic subtype, because 5-year survival rates of typical and atypical carcinoids are 87% to 98% and 56% to 73%, respectively.
Large Cell Neuroendocrine Carcinoma
The incidence of large cell neuroendocrine carcinoma has long been underestimated, probably because these tumors are often misdiagnosed as large cell undifferentiated carcinoma either on cytology or on tissue sections in the absence of immunostaining for neuroendocrine markers. Large cell neuroendocrine carcinomas are strongly associated with tobacco smoking (90% of cases). Clinical and radiologic ( eFig. 54-11 ) features are similar to those of other bronchogenic carcinomas and, in most reported series, treatment follows recommendations for NSCLC, including resection in stage I-II tumors. Epidermal growth factor receptor (EGFR) mutations may be present. Efficacy of chemotherapy is significantly better, with up to 75% of response to the cisplatin-etoposide combination in a neoadjuvant (presurgical) setting. Several studies, including one prospective trial, showed a reduced metastatic recurrence rate and increased survival in patients receiving adjuvant chemotherapy even in early-stage tumors. Overall survival is better than in small cell carcinoma, with stage being the most significant prognostic factor. Five-year survival is 52% to 88%, 20% to 45%, and 0% to 15% in stages I-II, III, and IV, respectively.
Rare Malignant Primary Pulmonary Epithelial Tumors
Mucoepidermoid Carcinoma
Mucoepidermoid carcinoma is the most frequent salivary gland-type tumor arising in the lung; other subtypes include adenoid cystic carcinoma and epithelial-myoepithelial carcinoma. Mucoepidermoid carcinoma is a mixed malignant tumor characterized by the presence of squamous cells, goblet mucin-secreting cells, and cells of intermediate type ( Fig. 54-3C and D ). Identification of these three cellular subtypes in cytologic examination is pathognomonic. Tumors are classified as low-, intermediate-, and high-grade lesions, depending on the mitotic index, the degree of cellular atypia, and the degree of necrosis. High-grade tumors contain predominantly squamous and intermediate cells and tend to infiltrate the lung parenchyma.
Mucoepidermoid carcinoma in adults mostly develops between the third and fourth decades, with an equal sex distribution. High-grade tumors (30% of cases) are usually diagnosed in older patients. Mucoepidermoid carcinoma is often associated with tobacco smoking. Symptoms, including dyspnea, cough, and hemoptysis, are related to the level of bronchial obstruction ( eFig. 54-12 ). Metastases are found at time of diagnosis in 20% of cases, mainly in the liver, the bone, and the subcutaneous tissues (see Fig. 54-3B ). In the lung, mucoepidermoid carcinoma often presents as a well-circumscribed homogeneous, lobulated homogenous mass, often with cystic features and/or calcification (see Fig. 54-3A ). The lesion is solitary in 40% to 70% of cases. Hilar involvement is found only for high-grade lesions. There is increased uptake on PET scanning. Proximal mucoepidermoid tumors can be diagnosed using endobronchial biopsy.
Treatment is the same as for NSCLC with, when feasible, extensive surgical resection including mediastinal lymph node dissection. High-grade lesions have often been reported to receive postoperative radiotherapy and chemotherapy, without clear benefit. Chemotherapy of metastatic tumors in most cases is based on cisplatin and/or 5-fluorouracil. As in NSCLC, a small number of patients with mucoepidermoid carcinoma may benefit from EGFR tyrosine kinase inhibitors. Prognosis is correlated with the grade of the lesion, the existence of nodal involvement, and the success of the initial surgical resection. Low-grade mucoepidermoid tumors mostly present in children and young adults, usually without hilar involvement, and have a 5-year survival ranging from 70% to 80%. High-grade tumors have a substantially worse prognosis, with a 5-year survival of only 30% to 45%.
Pneumoblastoma
Pulmonary blastoma is a biphasic tumor that is classified among the sarcomatoid carcinomas in the current World Health Organization classification. This tumor contains both an epithelial well-differentiated component, showing tubular architecture resembling the normal fetal lung, and a mesenchymal undifferentiated stroma, defining the “blastema-like” configuration. Pulmonary pneumoblastoma arises in adults and must be distinguished from “pleuropulmonary blastoma,” a tumor of early childhood related to other embryonic neoplasms, such as nephroblastoma and neuroblastoma.
Pulmonary pneumoblastoma arises in patients aged 30 to 45 years, with a marked female predominance (70% of cases) and frequent association with tobacco smoking. CT shows a solitary circumscribed homogeneous mass, often with cystic and necrotic features. PET scans show increased uptake. In many cases, the tumor is initially thought to be a bronchogenic carcinoma, and complete surgical resection with mediastinal lymph node dissection ensures both the initial diagnosis and the therapy. Adjuvant treatment, mostly consisting of radiotherapy, has been reported in a few cases following incomplete resection or in patients with N2 mediastinal involvement. In unresectable tumors, chemotherapy is based on protocols used for sarcomas, including doxorubicin and ifosfamide. In most recent reports, survival is better than in NSCLC, especially in completely resected cases.
Sarcomatoid Carcinomas (Other Than Pneumoblastoma)
Sarcomatoid carcinomas are a group of poorly differentiated non–small cell carcinomas that contain a sarcomatous component. In addition to pneumoblastoma, four subtypes are recognized:
- 1.
Pleomorphic carcinoma, which corresponds the combination of adenocarcinoma, squamous cell carcinoma, or large cell carcinoma with spindle or giant cells.
- 2.
Spindle cell carcinoma, which consists exclusively of fascicular cells.
- 3.
Giant cell carcinoma, composed of highly pleomorphic mononucleated or multinucleated cells.
- 4.
Carcinosarcoma, containing a mixture of carcinoma (frequently of epidermoid subtype) and poorly differentiated fibromatous sarcoma.
Sarcomatoid carcinoma has been defined in the 1999 World Health Organization classification. These tumors represent from 0.3% to 1.3% of lung tumors, and their specific clinical and radiologic features are rarely reported. Moreover, small biopsies usually do not disclose both the epithelial and the sarcomatous components of the tumor, which is then misdiagnosed as NSCLC in more than 60% of cases. Clinical features are similar to other non–small cell carcinomas. Sarcomatoid carcinomas develop mostly in men, at a mean age of 65 years at diagnosis. Tobacco smoking is described in more than 80% of cases. Radiologic studies usually show a solitary voluminous peripheral heterogenous mass invading the chest wall in 60% of cases. Vascular invasion is observed in 20% of cases. PET scans show increased uptake.
Sarcomatoid carcinomas are often treated as other non–small cell carcinomas. Alternatively, chemotherapy has been reported to follow soft tissue sarcoma regimens. Response to EGFR-targeted therapies is infrequent, which may be related to frequent KRAS mutations in the epithelial component.
Contrary to pneumoblastomas, the other sarcomatoid carcinomas have been considered as highly aggressive tumors with early metastatic spread, especially in unusual sites such as the esophagus, the peritoneum, the kidney, and the subcutaneous tissues. Chemoresistance is frequent. Median overall survival ranges from 6 to 20 months. The main favorable prognostic factors include tumor size, stage, and the absence of mediastinal involvement.
Primary Pulmonary Sarcomas
Primary pulmonary sarcomas account for 20% of all primary rare lung malignancies and comprise (1) parenchymal lung sarcomas, which usually present as a lung mass, and (2) pulmonary vascular sarcomas, which include pulmonary artery sarcomas, which may mimic chronic pulmonary embolism, and small vessel sarcomas, which may produce interstitial lung disease.
Parenchymal Sarcomas
Primary lung parenchymal sarcomas show identical pathologic subtypes to those of their soft tissue counterparts, with a wide spectrum of differentiation from low to high grade. Leiomyosarcoma is the most frequent primary lung sarcoma and presents with fascicles of spindle cells at right angles and/or an epithelioid growth pattern with marked hypercellularity and polymorphism. Tumor cells have irregular nuclear chromatin and prominent nucleoli. Immunohistochemistry shows a high level of muscular actin, vimentin, and h-caldesmon, an actin-binding protein. Synovial sarcoma is the second most frequent subtype and presents with a prevalent monophasic growth pattern consisting of interweaving fascicles of densely packed spindle cells. As in their soft tissue location, the chromosomal translocation t(X;18) (p11.2;q11.2) is pathognomonic of the diagnosis and results in the fusion of two genes, SYT-SSX1 and SYT-SSX2. Other subtypes include pleomorphic sarcoma, made of atypical spindle cells showing a “cartwheel” or so-called storiform or radiating pattern, with elongated nuclei and giant cells with multiple and bizarre nuclei and prominent nucleoli, as well as osteosarcoma and chondrosarcoma. Because most mesenchymal malignant tumors have a benign counterpart, pathologic examination must first evaluate the grade of the lesion, according to the three-grade system of the French Federation of Cancer Centers Sarcoma Group, and second rule out other epithelial tumors with sarcomatoid differentiation, such as pneumoblastoma or myofibroblastic tumors. Differential diagnosis also includes “benign” metastases from uterus (metastasizing leiomyoma) or bone (giant cell tumor).
Compared with their soft tissue counterparts, primary pulmonary sarcomas present in older patients, mainly in the sixth to eighth decade. Clinical symptoms are nonspecific and usually consist of cough, dyspnea, and hemoptysis, depending on the size and the location of the lesions. The incidence of radiation-induced sarcomas has decreased because cobalt-based radiotherapy has been abandoned. Unlike metastatic sarcoma, primary pulmonary sarcoma presents as a solitary lesion ( eFigs. 54-13 and 54-14 ), with heterogeneous cystic, necrotic, or hemorrhagic features but well-defined circumference. Size ranges from 4 to 25 cm ( Fig. 54-4A ). PET scanning shows increased uptake (see Fig. 54-4B and eFig. 54-14D ). Tumor progression is mainly local, and mediastinal lymph node invasion and systemic metastases are rare at the time of diagnosis (<2%).
Surgery is then the most effective initial treatment, and complete resection is obtained in 80% of cases. Strategies developed in soft tissue sarcoma may not be applicable to primary lung sarcomas: for example, neoadjuvant chemotherapy, based on anthracycline and ifosfamide, is commonly used in soft tissue locations but has been disappointing in primary lung tumors. In case of unresectable lesions, chemoradiation may be the best therapeutic strategy. As in soft tissue sarcoma, the chemotherapeutic drug trabectedin may be an option for second-line treatment. Prognosis mainly depends on the completeness of initial surgical resection, which, when combined with the grade of the lesion, is the best predictive factor of recurrence-free and overall survival. Overall 5-year survival varies from 30% to 50% and may be better for leiomyosarcomas.
Vascular Sarcomas
Primary pulmonary vascular sarcomas include pulmonary artery sarcomas and small vessel sarcomas, corresponding to epithelioid hemangioendothelioma and its high-grade counterpart, angiosarcoma.
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). Pulmonary artery sarcomas mainly develop in patients in their fifth to sixth decade. Symptoms may mimic pulmonary embolism, with dyspnea, chest pain, cough, and hemoptysis. Failure of anticoagulants in this setting, as well as the presence of symptoms of weight loss and fever (arising in 40% of cases), may also suggest the diagnosis. Imaging findings also help differentiate between pulmonary artery sarcoma and pulmonary embolism: CT scanning may show a polypoid filling defect in the pulmonary artery but, contrary to thromboembolic disease, sarcoma forms a contiguously soft, smooth, tapering tissue, with possible extravascular nodular spread in the parenchyma (40% of cases) ( eFig. 54-15 and 
) and localized ground-glass opacities ( Fig. 54-5A and B ). Sarcoma also presents with a heterogeneous appearance including areas of necrosis and hemorrhage, and with intense hyperactivity on PET scanning (see eFig. 54-15F and G ). Magnetic resonance imaging (MRI) shows intermediate to mildly increased signal on T1-weighted images, often with heterogenous enhancement ( eFig. 54-16 ), and T2-weighted images show intermediate to diminished signal relative to skeletal muscle; furthermore, the intravascular mass may enhance, a feature not typically encountered with uncomplicated thromboembolic disease. Surgery is the only potentially curative treatment and, even if performed in an emergency setting in case of acute right-sided heart failure, allows resectability in 60% to 75% of cases (see Fig. 54-5C ). Alternatively, heart and lung transplantation may be an alternative option for unresectable tumors. 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. Reoperation is feasible in 30% of cases. However, in recent series, overall median survival is as low as 6 to 12 months ( eFig. 54-17 ).
Epithelioid hemangioendothelioma (EHE), a small vessel sarcoma, is a low- to intermediate-grade mixed epithelioid, endothelial, and vascular tumor. Lung is the most frequent extrahepatic location (10% of cases), because EHE can also arise from the liver (63% of cases), the bone (8% of cases), and the skin (6% of cases). EHE was initially considered an intravascular and intra-alveolar extension of bronchoalveolar carcinoma and thus was called “intravascular bronchoalveolar tumor.” Now, however, it is clearly identified as a mesenchymal tumor corresponding to low-grade angiosarcoma. 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. A recently identified translocation t(1;3)(p36.3;q25) involving the PAX7 gene, which encodes a transcription factor involved in regulation of development, may be helpful in making the diagnosis. EBV RNA sequences are detected in 90% of cases. Overlapping entities with IgG4-related disease have been described (see later).
Clinically, 80% of cases of EHE are seen in white females. The tumor is asymptomatic in 50% of cases; when present, symptoms are nonspecific and include pleuritic chest pain, nonproductive cough, dyspnea, and rarely hemoptysis. Physical examination may reveal inspiratory crackles in 30% of cases. By CT imaging, EHE appears either with bilateral slow-growing perivascular multiple nodules, usually located adjacent to small vessels or bronchi, or with predominant infiltrative ground-glass opacities ( eFig. 54-18 ) with a micronodular pattern, mimicking carcinomatous lymphangitis. EHE nodules usually range from 3 to 50 mm, and their number varies from 10 to 20 lesions. Nodules in patients with EHE may show increased uptake on PET scans.
Although there are a few reports of spontaneous remission, the complete resection of all pulmonary nodules is the only curative treatment of EHE. Surgery remains effective even in cases of localized recurrence. In contrast, EHE is generally insensitive to chemotherapy (cisplatin-based) or radiotherapy. Treatments with rituximab or antiangiogenic kinase inhibitors, such as sorafenib or bevacizumab, have been reported to be effective in isolated case reports. In most cases, EHE is a slow-growing tumor that rarely metastasizes and is associated with a median survival of 5 to 6 years. Endobronchial spread, pleural effusion, and extended endovascular disease have been identified as unfavorable prognostic factors.
Angiosarcoma is a high-grade primary pulmonary vascular sarcoma considered a counterpart of EHE. However, no direct transformation from EHE to angiosarcoma has been reported yet. 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, with a specific “cauliflower-like” appearance on T2-weighted MRI. This aspect may be shared by other disorders, including malignancies (e.g., adenocarcinoma with lepidic pattern, metastatic sarcomas, choriocarcinoma, melanoma, lymphoma), infectious diseases (e.g., mycobacteriosis, aspergillosis, cytomegalovirus infection), granulomatosis with polyangiitis, and eosinophilic conditions. Management of angiosarcoma is not established: surgical resection is rarely possible owing to local and regional invasion; radiotherapy and chemotherapy are poorly effective as seen in other locations of angiosarcoma.
Intrathoracic Pseudotumors
Pseudotumors represent a wide range of etiologic, pathologic, and clinical-radiologic disorders that all share some degree of reactive inflammation and may present with some cancer-related biologic hallmarks. Pseudotumors may mimic the clinical and radiologic features of various intrathoracic diseases.
Inflammatory Myofibroblastic Tumor
Inflammatory myofibroblastic tumor (IMT) is the most representative entity of the pulmonary pseudotumors and encompasses a wide spectrum of lesions previously called “inflammatory pseudotumor,” “fibroma,” “fibroxanthoma,” “fibrous 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 the surgical series of the Mayo Clinic. IMT, which includes both benign and malignant features, represents an archetype of borderline neoplastic/non-neoplastic disorders.
IMT appears as an intraparenchymatous well-circumscribed mass of variable size. Histologically, the tumor is made of irregular proliferation of fibroblasts and myofibroblasts intermixed with an infiltrate of inflammatory 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 inflammatory myxoid proliferation with fascicles of spindled fibroblasts or myofibroblasts, abundant lymphocytes and plasma cells, and minimal fibrous connective tissue.
- 2.
Fibrohistiocytic type, which appears as a compact spindle-cell pattern simulating fibrous histiocytoma that is characterized by a myxoid proliferation of fibroblasts and myofibroblasts 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 myofibroblastic cells show no cellular atypia, no necrosis, and only rare mitotic figures. The myofibroblastic cells usually stain for vimentin and smooth muscle actin. Differential pathologic diagnosis includes all the diseases composed of fibroblasts and myofibroblasts, some of which may overlap with IMT: benign and malignant fibrous histiocytoma, myofibroblastoma, inflammatory fibrosarcoma, spindle cell carcinomas, plasmacytoma, and organizing pneumonia.
The concept of IMT as a proliferating neoplasm has been questioned. Historically, IMT, which was then called “inflammatory pseudotumor,” was thought to originate from organizing pneumonia through an exaggerated inflammatory response to injury. Older case reports emphasized that, in as many as 30% of cases, chronic or repeated infections could be a potential cause, but this concept was reconsidered with more recent reports that included chest CT studies, suggesting that recurrent pulmonary infections were rather a consequence of bronchial obstruction by the tumor. The concept of IMT as an immunologic disorder was raised after the detection of EBV and human herpesvirus 8 sequences in myofibroblastic cells, with associated expression of cytokines such as interleukin-6 and -8, and cyclin D1. The recent identification of IgG4 expression in polyclonal plasma cells extracted from intrathoracic IMTs suggested that an immunopathologic process may participate in the development of these tumors, especially the plasma cell variants. Such proliferation of IgG4-positive cells has also been associated with autoimmune disorders, including sclerosing pancreatitis and retroperitoneal and mediastinal fibrosis. IMTs may then be part of IgG4-related disease, a newly recognized fibroinflammatory condition characterized by tumefactive lesions, a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis, and often, but not always, elevated serum IgG4 concentrations. Based on molecular data, myofibroblasts are considered to be pivotal in the development of IMT. Clonal gene rearrangements may be observed, especially involving the anaplastic lymphoma kinase (ALK) gene located in region 2p23. ALK overexpression is observed in 40% to 70% of IMTs at immunohistochemistry, but may also be at low levels in a wide variety of non-IMT soft tissue tumors. ALK rearrangement is identified in 40% to 50% of IMT cases, especially in younger patients, and most frequently consists of t(1;2)(q21;p23) translocation implicating the tropomyosin 3 gene. Other translocations have been reported. Given the oncogenic nature of ALK activation, these data lead some authors to consider IMT as a true neoplasm. Other elements further reinforce this concept, including the presence of vascular invasion, the local recurrence rate as high as 25%, the existence of multifocal lesions in 5% of cases, reports about malignant transformation, and genomic and expression profiling data, showing DNA aneuploidy, abnormal p53 expression, and up-regulation of other known cancer-related genes such as glutathione-S-transferase. Overlap exists between IMT, IgG4-related disorders, and inflammatory fibrosarcoma that exhibits prominent cellular atypias and necrosis.
Pulmonary IMTs usually appear before the fourth decade, accounting for more than 50% of pulmonary tumors in children. Patients are asymptomatic in about 60% of cases, or may present with nonspecific symptoms, including chronic cough, dyspnea, or rarely hemoptysis. At imaging, IMT appears as a solitary well-circumscribed peripheral mass, ranging from 2 to 15 cm in size ( Fig. 54-6 ; eFig. 54-19 ). Contrary to its presentation at extrathoracic locations, pulmonary IMT is usually solitary. Calcifications are observed in 15% of cases. The usual stability in size over time is an important imaging feature. Multifocal and bilateral IMTs are exceptional ( eFig. 54-20 ) and are considered as overlapping forms of low-grade fibrosarcoma or malignant fibrous histiocytoma. IMTs are usually hypermetabolic on PET scanning. Extrapulmonary involvement is seen in 10% to 20% of cases and is mostly observed in the mediastinum and pleura. Conversely, extrapulmonary IMTs may metastasize to the lung, especially in younger patients. Preoperative diagnosis with endoscopic or percutaneous biopsies remains difficult due to the heterogeneous morphology of IMTs. Cytologic fine-needle aspiration accuracy was as low as 42% in a recent study.
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 with local, pleural, parietal, or mediastinal invasiveness (15% to 25% of cases and 3% to 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 corticosteroid challenge 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 IgG4-positive tumors. In recurrent or multifocal lesions, chemotherapy may use the same regimens as for soft tissue sarcomas. Crizotinib, a small pharmaceutical tyrosine kinase inhibitor of ALK, was recently reported to produce tumor responses in two patients with ALK -rearranged extrathoracic IMTs.
Patients with a resected IMT have a 5-year overall survival ranging from 75% to 100%. Transformation to low- and/or high-grade fibrosarcoma has exceptionally been reported and may correspond to initially misdiagnosed high-grade tumors. ALK-positive tumors are considered to be more aggressive but can recur locally regardless of ALK expression level. The most consistent prognostic factor is the initial invasiveness of the tumor.
Mediastinal Fibrosis and Hyalinizing Granuloma (see Chapter 84 )
Similar to IMT, mediastinal fibrosis and hyalinizing granuloma both consist of tissue infiltration by dense collagen fibrosis forming lamellar bands, interspersed with lymphocytes and plasma cells. These two entities differ by the primary anatomic location: mediastinal fibrosis, also known as sclerosing mediastinitis, predominantly involves the mediastinum, with possible extension to the lung parenchyma; hyalinizing granuloma involves the lung parenchyma without contiguous involvement of the mediastinum. Overlap exists between these entities and other fibrosing disorders such as IMT, retroperitoneal fibrosis, and other IgG4-related disorders.
A hallmark of mediastinal fibrosis is the obstruction of major mediastinal veins with multifocal venous infarcts observed in the tumor leading to cellular fibrosis, hemorrhage, and necrosis. Mediastinal fibrosis has mostly been described in North America, where it is thought to result in most cases from exacerbated responses to Histoplasma. Because the fungus is not typically cultured, it is thought that the fibrosis is a response to fungal antigens leaking from mediastinal nodes. Mediastinal fibrosis may be idiopathic, familial, or associated with various disorders, including infections with other fungi, such as Aspergillus or Cryptococcus , and tuberculosis or sarcoidosis. It has also been described following therapy with radiation, ergot derivatives, and beta-blockers. Autoimmune reactions may also participate, because an association with elevated serum IgG4 syndrome has been reported. Clinically, mediastinal fibrosis is observed in the fourth decade, with a slight male predominance. Patients may be asymptomatic or develop chest pain, fever, hemoptysis, and dyspnea, as well as signs related to invasion of mediastinal structures. Pulmonary venous infarction can be the first manifestation of the disease. The severity of symptoms is related to the extension of the fibrosis. At imaging, mediastinal fibrosis presents either as a localized mass ( eFig. 54-21 ), possibly calcified, in the paratracheal, hilar, or subcarinal areas, or as diffuse infiltration throughout the mediastinum, without calcification ( Fig. 54-7 and eFig. 54-22 ). The lung may be marginally affected, with consolidated areas resulting from venous infarction (see eFig. 54-22A and B ), and possible pleural effusion. Surgical biopsy is often necessary to obtain a definite diagnosis. Prognosis depends on the structures involved. Treatment of mediastinal fibrosis may involve surgical resection, which often may be only palliative given the extent of the fibrosis, or the use of stents to restore patency of critical vessels. There is little evidence to support use of antifungal agents or corticosteroids, but trials of these are sometimes attempted.
Hyalinizing granuloma is seen in young to middle-aged adults with a slight predominance in men. Patients usually have symptoms (80% of reported cases), consisting of cough, dyspnea, and pleuritic chest pain. Association with other fibrosing diseases has been reported, including mediastinal fibrosis (15% of cases) and retroperitoneal fibrosis (10% of cases). The radiologic presentation is that of solitary or multiple well-circumscribed lung nodules, usually 2-4 cm in size, which may grow over time and thus mimic cancer. The lesion may be found in the context of sarcoidosis and IgG4-related disease ( Fig. 54-8 ). The main differential diagnosis is nodular amyloidosis, because hyalinizing granuloma may demonstrate factitious Congo red positivity. The clinical course is benign.
Other Pseudotumors
The most common mechanism causing the development of a pseudotumor is thought to be an exaggerated host response to injury. Developmental pseudotumors include benign lesions such as hamartomas ( eFigs. 54-23 through 54-27 ), leiomyomas, and choristomas. Tissue remnants or heterotopias related to embryologic variation is another etiologic group, the most frequent entity being minute meningioma-like nodules ( eFig. 54-28 ) that correspond to glial heterotopias. Similarly, clear cell tumors, also called “sugar tumors,” are derived from perivascular epithelioid cells of the lung epithelium; these cells are of neuroectodermal origin and are also implicated in the development of perivascular epithelioid cell tumor and lymphangioleiomyomatosis.
Functional pseudotumors are related to dysfunctional pathophysiologic states, often of an endocrine nature, and are rare in the lung parenchyma. Iatrogenic pseudotumors are due to several medical procedures that can produce tissue reactions, most of which are reparative in nature. Infectious pseudotumors may be produced by mycobacteria (tuberculoma), fungi (aspergilloma), or even viruses (EBV, HIV, cytomegalovirus). The pathogenesis of these tumors may be complex, possibly implicating multiple mechanisms. The clinical and radiologic features of these tumors may be similar to that of IMT.
Borderline Entities
Benign tumors and preneoplastic conditions of the lung are considered elsewhere in Chapter 56 . Borderline neoplastic and non-neoplastic disorders include entities that are generally considered to have benign behavior despite being associated with true neoplasm or presenting with some pathologic or molecular characteristic of neoplasia, including clonal proliferation. Borderline lesions may also have features of malignant behavior, such as invasion and recurrence following resection. These disorders may also present as pulmonary nodules or infiltrative disease, mimicking bronchogenic carcinoma or interstitial pneumonias, respectively.
Mesenchymal Borderline Disorders
Some benign lesions, presenting as slow-growing intraparenchymal masses with homogeneous attenuation and regular contours, may present with clonal chromosomal aberrations. For example, hamartomas may exhibit gene rearrangements in regions 12q15 and 6p21. These regions contain the high mobility group AT-hook genes, respectively, encoding nonhistone nuclear proteins that participate in the regulation of gene expression via alteration of chromatin structure. Interestingly, similar alterations have been described in other mesenchymal tumors. Similarly, multiple minute pulmonary meningothelial-like nodules (see eFig. 54-28 ), which are millimeter-sized nodular proliferations of oval to spindle-shaped cells resembling meningioma and arranged in a nested pattern, exhibit loss of heterozygosity in multiple genomic loci in 33% of cases. Relationship of minute meningothelial-like nodules with primary pulmonary meningioma is not certain, given the contrast between the relatively high prevalence of meningothelial-like nodules and the low frequency of meningioma as a primary lung tumor.
Respiratory Tract 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). Histologically, squamous papillomas are usually exophytic with an epithelial layer covering a central fibrovascular core that forms a frondlike architecture protruding into the lumen of the airway. Squamous papillomas are lined by stratified squamous epithelium, sometimes keratinized. Distal papillomas exhibit a more inverted growth pattern. Papillomas may exhibit imaging features similar to those of lung cancer, including heterogeneous, cavitating, or poorly defined masses.
Pulmonary papillomas may be solitary or multiple ( eFigs. 54-29, 54-30, and 54-31 ); 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. Specifically, HPV type 11 infection has been reported to bear a high-risk of transformation of papilloma to squamous cell carcinoma ( eFig. 54-32 ). 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. PET scanning may not be useful given the mild hypermetabolism of high-grade papillomas. Pathologically, the distinction with invasive squamous cell carcinoma can be difficult in some exophytic cases or when there is atypical cytology. Given this uncertain malignant potential and the difficult differential diagnosis with lung cancer, complete resection of papillomas is recommended if possible; complete resection may not be possible in the setting of multiple and bilateral lesions ( Fig. 54-9 ).
Nodular Lymphoid Hyperplasia
Pulmonary nodular lymphoid hyperplasia (NLH), historically called “pseudolymphoma,” is a nodular reactive polyclonal lymphoid proliferation infiltrating the lung, characterized by low-grade histology, presence of lymphoid follicles, and a benign clinical course. Histologically, NLH corresponds to lymphoid follicles with intercalated prominent plasma cells and usually mild interstitial fibrosis. Lymphocytes and plasma cells may distribute along lymphatics in the bronchovascular bundles and interlobular septa. Immunohistochemistry shows a mixture of polytypic B and T cells. No immunoglobulin heavy chain gene rearrangement has been identified. Differential diagnoses are MALT lymphoma, lymphocytic interstitial pneumonia, lymphomatoid granulomatosis; overlap entities, such as “atypical lymphoid proliferation,” have also been described. Sjögren syndrome may also have peribronchial lymphocytic infiltrates and may be associated with true lymphoma. In several cases of pulmonary NLH compared to other lymphoid proliferations of the lung, NLH was found to overexpress IgG4, suggesting that NLH may lie within the family of IgG4-related sclerosing diseases.
In a series of 14 well-characterized NLHs published in 2000, most patients (81%) were asymptomatic. Radiologic presentation was that of a solitary peripheral nodule in nine patients, median size was 3 cm, and multifocal nodules were seen in five patients. Five patients (36%) also had concomitant hilar, mediastinal, or paraesophageal lymphadenopathy. In most cases, given the initial consideration of lung cancer, treatment consisted of surgical resection. Interestingly, no recurrence or progression to more aggressive lymphoproliferative disease was documented, stressing the usually benign behavior of NLH.
Amyloidosis
Amyloidosis is characterized histopathologically by tissue infiltration with fibrillar protein with a β-sheet structural conformation, specifically stained by Congo red dye with a yellow-green birefringence under polarized light. Amyloidosis has a highly variable presentation and may manifest in the lung as either parenchymal nodules ( eFigs. 54-33 through 54-36 ) or masses. Pulmonary amyloidosis may be localized to the lung or be associated with systemic amyloidosis.
Pulmonary nodules usually consist of AL (“amyloid light chain”) amyloid, which is the most common subtype of amyloidosis deposition. AL amyloidosis is primary in more than 80% of cases and associated with inflammatory or lymphoproliferative disease in 20% of cases. AL amyloidosis develops as a result of the abnormal production of light immunoglobulin chains, often of lambda isotype. AL amyloidosis may be either systemic (e.g., in myeloma) or localized (e.g., in primary pulmonary lymphoma), with mild pulmonary interstitial (especially vascular) involvement that is usually asymptomatic. Serum and/or urinary monoclonal gammopathy is frequent.
Pulmonary nodular amyloidosis has been observed in patients in their seventh decade, without gender predominance. Patients are usually asymptomatic. Association with Sjögren’s syndrome has been reported. Radiologically, pulmonary nodules are rounded and sharply delimited (see eFig. 54-34 ). Most nodules are peripheral. The nodules may range from 5 mm to more than 15 cm, may be solitary or multiple, and may be calcified. Nodules have shown increased activity on PET scans and may thus mimic bronchogenic carcinoma, although lack of FDG avidity is also seen (see eFig. 54-35F and G ). Other unusual imaging patterns may rarely be encountered (see eFigs. 54-35A-D and 54-36 ). Fine-needle biopsy may provide a pathologic diagnosis. Pulmonary amyloid nodules may remain stable for years, and surgical resection is proposed only in case of threatening symptoms. Recurrence is frequent after surgery.
Nonamyloidotic Monoclonal Immunoglobulin Deposition Disease
Nonamyloidotic monoclonal immunoglobulin deposition disease is more rare than amyloidosis and presents with deposits that are not stained by Congo red dye and do not demonstrate birefringence under polarized light. These deposits most often consist of light chains, frequently kappa, or more rarely of single heavy chains or of mixed light and heavy chains. The lung is a very unusual location. Pulmonary nonamyloidotic monoclonal immunoglobulin deposition disease most frequently presents as multiple parenchymal nodules or, less frequently, as multiple cysts; deposition is usually limited to the lung without systemic involvement. Approximately half of the cases are associated with hematologic malignancies. Treatment of any underlying hematologic disease usually leads to regression of the monoclonal peak but has little effect on existing deposits. Pulmonary nonamyloidotic monoclonal immunoglobulin deposition disease may benefit from lung transplantation in cases of severe respiratory failure and in the absence of an underlying hematologic disorder.
Pulmonary Langerhans Cell Histiocytosis
Langerhans cell histiocytosis (LCH) is a heterogeneous disease defined by the proliferation of Langerhans cells, corresponding to CD1a-positive histiocytes exhibiting Birbeck granules on electron microscopy. 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 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 and is thought to stimulate this process in the bronchiolar epithelium. 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. An activating BRAF mutation, similar to that observed in melanoma, may be identified in LCH pulmonary nodules. 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 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 fibrosis, and cavitation of the nodules leading to cyst formation.
Clinically, pulmonary LCH develops in young smokers who present with nonspecific respiratory symptoms, including dyspnea, cough, and chest pain. Pneumothorax may herald the disease in 15% of patients; 10% to 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 ( eFig. 54-37A and B ) with smooth or irregular margins. LCH is an active process, with predominant nodular aspect at early stages of the disease (see eFig. 54-37A and B ), evolving to cavitated nodules, cysts of variable wall thickness (see eFig. 54-37C ), and confluent cystic lesions over time (see eFig. 54-37D ). Lesions of different age are usually observed. Rarely, pulmonary LCH presents as a single nodule, localized consolidation, or mediastinal disease.
Whereas the typical clinical-radiologic presentation may be virtually diagnostic for pulmonary LCH, pulmonary biopsy may be required in case of a tumor-like nodular or atypical ( eFig. 54-38 ) presentation. Open lung biopsy is usually performed in patients with pneumothorax who require surgical intervention. Increased uptake on PET may suggest lung cancer; in a recent study of 11 patients, nodular lesions exhibited hyperavidity, with maximum standardized uptake values ranging from 2 to 18. PET might be useful in the follow-up of the activity of the disease and is the subject of current research. Smoking cessation may lead to regression in as many as 25% of patients. No other treatment has been confirmed to be useful in pulmonary LCH, which may also regress spontaneously. Patients with progressive or multiorgan disease may benefit from chemotherapy with cladribine, which produced a 75% objective response rate in a landmark study of 13 patients. Supporting the neoplastic hypothesis, pulmonary LCH can recur following lung transplantation.
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