Follicular Bronchitis/Bronchiolitis

Follicular bronchitis/bronchiolitis is a term introduced to describe the predominant peribronchial lymphocytic infltrate with abundant germinal centers, often associated with various allergic diathesis, immunodefciency disorders (HIV infection, common immunodefciency syndromes), and collagen vascular diseases [7]. Patients usually present dyspnea, occasionally fever and cough, hypoxemia, hypocapnia; either obstructive or restrictive spirometric patterns have

been reported. The chest radiograph shows bilateral reticular or nodular opacity. Common HRCT fndings are centrilobular nodules, bronchiolar dilatation, tree in bud and mosaic perfusion patterns. Expiratory dynamic HRCT scans are important to assess air trapping. Flow cytometry of bronchoalveolar lavage (BAL) usually document a slight increase of polyclonal B lymphocytes. Surgical lung biopsy is often performed to obtain a defnite histological diagnosis. Therapy with corticosteroids and also with macrolides at low dose may have some beneft.

Castleman Disease

Castleman disease is an uncommon clinicopathological entity frst described in 1956 [8]. Nowadays Castleman disease is a term used to identify a heterogeneous group of hematological disorders that mainly affect the lymph nodes [9–12]. The spectrum of histopathology changes ranges from atrophic germinal centers with hypervascularization to hyperplastic germinal centers with polytypic plasmacytosis.

Unicentric Castleman disease involves a single region and generally has hyaline vascular/ hypervascular histopathological features. When the thorax is involved, unicentric Castleman disease appears with mediastinal or hilar giant lymph nodes; symptoms are usually absent or when present they are related to the mass effect of the lesion (superior vena cava syndrome, obstruction of large airways). Very rarely it manifests as a pulmonary mass. Surgical excision is curative in the large majority of cases.

Multicentric Castleman disease (MCD) involves different lymph node stations and manifests with laboratory markers of systemic in ammation. The histopathological background can be classifed into three groups: plasmacytic, mixed, and hypervascular [38]. MCD is an aggressive disorder that potentially leads to fatal multiple organ dysfunction caused by a cytokine storm, often including IL-6. 50% of MCD cases are related to an uncontrolled HHV-8 infection. In such cases, HIV infection or, more rarely, another cause of immune-suppression enables HHV-8 to escape host immune control and signal for excessive cytokine production and polyclonal lymphoproliferation. In half of the HIVnegative and HHV-8-negative MCD cases, the etiology is still unclear. In HHV-8- negative MCD cases, two clinical phenotypes have been identifed. Patients present with either heterogenous clinical symptoms—which can include intense episodes of thrombocytopenia, anasarca, fever/elevated C-reactive protein, renal dysfunction/reticulin myelofbrosis, organomegaly, megakaryocytic hyperplasia, and normal gamma globulin level (MCD-TAFRO)—or a less intense in ammatory syndrome, normal/elevated platelet counts, and polyclonal hyper-gammaglobulinemia. Lung involvement in MCD is characterized by lymphoplasmacytic (with lymphoid follicles) and fbroin ammatory lesions with a lymphatic distribution (visceral pleura, interlobular septa, and bronchovascular bundles). Obstructive phlebitis and eosinophilic infltration are typically absent. Plasma cells are usually clustered in sheets. In HHV-8-related MCD, interstitial lymphocyte infltrates mimicking LIP are more frequently observed. Immunohistochemistry analysis documents the presence of HHV-8 [13]. HRCT scan features include areas of ground glass attenuation, peri-lymphatic nodules, reticular changes associated to enlarged mediastinal/hilar lymph nodes and very rarely cysts. The evolution towards HHV-8-positive large B cell lymphoma may be

observed in HHV-8-related MCD. Patients often present with low-grade fever, cough and dyspnea. HRCT of the lung may show hilar and mediastinal lymphadenopathies, multiple­ nodules of different sizes, cysts, patches of ground glass opacities and LIP-like images. The main therapeutic options include corticosteroids, immunosuppressive therapy (cyclosporin A, cyclophosphamide, etc.), rituximab or rituximab-­ based therapy, and anti-IL-6 therapies (e.g. tocilizumab and siltuximab) [14, 15].

Primary Pulmonary Lymphomas

Primary Pulmonary Lymphomas (PPL) is defned as a clonal lymphoid proliferation affecting one or both lungs (parenchyma and/or bronchi) in a patient with no detectable extrapulmonary involvement at diagnosis or during the subsequent 3 months.

The World Health Organization Classifcation of tumors of lung (WHO 2017) [2] include three forms of PPL: B cell primary pulmonary NHL, Marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT) type, primary pulmonary diffuse large B cell lymphoma (DLBCL), and Lymphomatoid granulomatosis (LYG). Nevertheless, the lung may rarely be the primary site of presentation of most types of lymphomas such as Follicular lymphoma (FL), Mantle cell lymphoma (MCL), extraosseous plasmacytoma (EP), Large B cell lymphoma arising in HHV8-associated multicentric Castleman disease, plasmablastic lymphoma (PBL), different subtypes of T/NK lymphomas, Hodgkin Lymphoma, and others.

Primary pulmonary non-Hodgkin lymphoma (NHL) is very rare and accounts for 0.4% of all lymphomas and 3.6% of extranodal lymphomas. Mature B cell neoplasms are the prevalent phenotype.

Primary Pulmonary B Cell Non-Hodgkin

Lymphomas (PPBL)

The most common histological type is mucosa-associated lymphoid tissue type (MALT) B cell lymphoma, which represents 70–90% of all primary pulmonary NHL [1, 2]. Diffuse large B cell lymphoma (DLBCL) occurs only in 10% of PPBL cases. In some cases, transformation from MALT lymphoma to DLBCL may occur. Clinically, PPBLs present with non-specifc symptoms. Radiologically, they can present as consolidation, well-defned masses or nodules. Therefore, PPBLs can easily be radiologically confused with primary lung carcinoma or metastases when presenting as multiple masses or/and nodules but, obviously, they have different treatments and prognosis. The main diagnostic criterion for PPBL is the absence of extrapulmonary involvement.

Therefore, in patients with biopsy-proven lymphoma of the lung, PPBL is diagnosed if extrapulmonary involvement is ruled out. B cell primary pulmonary NHL are subdivided into lowgrade B cell PPLs (58–87%) and high-grade B cell PPLs (11–19%). The high-grade B cell PPBLs spread rapidly into mediastinal and extra-thoracic locations. This may lead to underestimation of true incidence.

Primary Pulmonary MALT B Cell Lymphoma

Primary pulmonary MALT lymphoma is a rare extranodal lymphoma that is usually of the low-grade B cell type and is considered to arise from the mucosa-associated lymphoid tissue (MALT) of the bronchus (histologically distinct from true intrapulmonary lymph nodes). Low-grade B cell lymphomas represent 50–90% of all primary lung lymphomas. MALT-associated malignant lymphomas develop most frequently in the stomach and, more rarely, in the bowel, salivary glands, larynx, and thyroid gland [16]. Unlike the model of gastric MALT lymphoma and Helicobacter pylori, no triggering of antigens has been identifed in the primary pulmonary MALT lymphoma. Nevertheless, recent studies have detected the microorganism Achromobacter xylosoxidans with signifcant frequency [17]. Among the non-­ gastrointestinal MALT lymphomas,the pulmonary lymphoma is the most frequent (up to 19% among MALT lymphomas).

Pulmonary MALT-lymphomas seem to arise on pre-­ existing in ammatory accumulations of organized lymphoid tissue (lymphoid follicles of the bronchus-associated lymphoid tissue – BALT). BALT is inconspicuous in adults, but it undergoes hyperplasia in patients with chronic immune­ -­mediated diseases such as chronic infections, connective tissue diseases, rheumatoid arthritis, and Sjögren syndrome [18, 19]. These in ammatory processes are likely related to chronic antigen stimulation, as in other extranodal lymphomas, where this correlation (and especially that with infections) is now well established and also relevant for specifc therapy. Accordingly, the occurrence of intra-clonal sequence variations (ongoing mutations) is a common fnding in both gastric and pulmonary lymphomas, indicating the role of antigen stimulation in their pathogenesis [20, 21]. In a proportion of pulmonary lymphomas, correlations have been clearly established with conditions where the immune system is abnormally stimulated/ deregulated, such as in autoimmune diseases (Sjögren syndrome, Hashimoto thyroiditis, systemic lupus erythematosus-SLE, rheumatoid arthritis), or immunodefciency (either primary or acquired). Very rarely, an association between yellow nail syndrome and MALT lymphoma in the lung has been observed.

About half of the patients with primary pulmonary MALT lymphoma are asymptomatic at presentation, and nearly half

of these cases are identifed on the basis of abnormal radiological fndings [19, 22]. The pulmonary symptoms are ­non-­specifc like cough, dyspnea, chest pain, and occasional hemoptysis, but are more common than constitutional symptoms like body weight loss, fever, night sweats, or fatigue. These symptoms may present for several weeks to months before diagnosis. This indolent behavior explain why many cases of pulmonary MALT-lymphoma have been previously defned as “pseudo-lymphoma” [23]. Laboratory fndings are non-specifc and usually normal: only few patients have increased levels of lactate dehydrogenase (LDH) and/or Beta2-microglobulin in the serum and also less frequently a monoclonal band in serum immunoelectrophoresis is found. Radiologic feature of MALT lymphoma are solitary, welldelineated masses with air bronchogram. Although hilar and mediastinal lymphadenopathy is not a prominent radiologic fnding, nodal involvement is documented at pathologic analysis in about 30% of cases. HRCT fndings include: areas of alveolar consolidation more frequently centered on dilated bronchi, ground glass attenuation, the presence of “halo sign,” peribronchovascular nodules, “tree in bud pattern,” peribronchovascular thickening and septal lines [24]. The lesions are multiple in more than 70% of cases. The so-called angiogram sign previously considered typical of low-grade lymphoma in the lung has been observed in other numerous alveolar flling disorders. Radiographic fndings may remain unvaried for several years. Cases of endo-­tracheobronchial polypoid MALT lymphoma have been reported, often causing unilateral lung hyper-transparency. MALT lymphomas have generally been reported without increased uorine 18uorodeoxyglucose (18-FDG) accumulation on positron emission tomography (PET). The outcome of MALT-type PPL is generally favorable. More than 80% of the cases have a 5-year survival rate, and the median survival is more than 10 years. The overall survival is better than other types of non-Hodgkin lymphoma [18, 19]. Clinical features associated with poor prognosis in a series of PPL included patients over 60 years of age, elevated serum lactate dehydrogenase and elevated serum beta2 microglobulin levels [19].

As with other types of extranodal MALT lymphomas, a variety of cytogenetic abnormalities have been demonstrated in P-MALTL, including translocations and/or trisomies, which can provide very useful diagnostic information [1, 2]. The most frequent cytogenetic abnormalities in P-MALTL are the t(11;18)[q21;q21], observed in ≤50% [3, 8]. In this translocation, the N-terminus of the API2 gene is fused with the C-terminus of the MALT lymphoma translocation gene 1 (MALT1), forming the protein API2-MALT1, an oncogenic fusion protein that is able to generate a stable, non-canonical nuclear factor-κB-activating fragment. API2-MALT1 translocation is specifc to MALT lymphoma and frequently occurs in the absence of in ammation. t(14;18)(q32;q21) and t(1;14)(p22;q32) are observed in a proportion of

P-MALTL. These chromosomal abnormalities are able to bring either the BCL10 or the MALT1 gene to the IGH locus, thus deregulating their expression. Interestingly, as previously observed in gastric lymphomas where t(11;18) can serve as a molecular marker for cases not responding to H. pylori eradication, this translocation defnes a distinctive clinicopathologic subtype of pulmonary MALT-lymphomas characterized by the absence of any underlying autoimmune disease and lack of plasmacytic differentiation [2].

At histological analysis the pulmonary structure is effaced by abnormal lymphocyte infltration, predominantly localized along bronchovascular bundles, interlobular septa and visceral pleura, in a lymphangitic pattern [25]. As MALT lymphomas arising at other sites, pulmonary MALTlym- phoma is formed by the accumulation of clonal lymphoid cells characterized by the morphological and biological ­features of marginal-zone B cells. Marginal-zone cells, that are particularly abundant in the spleen, are post-germinal center lymphocytes with memory functions that migrate from lymphoid tissues to extranodal sites where they can rapidly become antibody producing plasma cells upon stimulation. Morphologically, lymphoma cells are similar to normal marginal-­zone cells, exhibiting a spectrum of cytological features (small-round cells, centrocyte-like cells, monocytoid B cells), characterized by small and irregular nuclei, inconspicuous nucleoli, and abundant clear cytoplasm. Neoplastic lymphocytes typically accumulate around non-­ neoplastic lymphoid follicles, forming poorly defned sheets of cells at the periphery of the mantle zones, extending into the lung parenchyma. The presence of reactive follicles, that can be particularly abundant and are presumably pre-existing the lymphoma development, can pose diagnostic problems at morphological and also immunophenotypical analysis. The presence of lympho-epithelial lesions (neoplastic lymphoid cells infltrating bronchiolar epithelium) is frequent and involve bronchiolar and bronchial epithelial structures. Histologically the differential diagnosis includes all pulmonary diseases characterized by accumulation of lymphoid follicles, and in particular the spectrum of follicular hyperplasia, follicular bronchiolitis, and LIP, as well as, more rarely, hypersensitivity pneumonitis, in ammatory pseudo-­ tumor, intraparenchymal thymoma, and Castleman disease. For these reasons, the use of immunophenotypical and molecular techniques is recommended to substantiate the histological diagnosis of pulmonary MALT lymphoma, especially when the tissue samples are scanty [26]. In a consistent proportion of cases it is possible to demonstrate lymphoplasmacytic differentiation, with a signifcant plasma cell component exhibiting immunoglobulin light chain restriction. It is possible that at least some cases of primary plasmacytoma of the lung (a rare low-grade tumor of unclear etiopathogenesis presenting as isolated nodules or diffuse) can in fact be included in the clinicopathologic spectrum of

MALT lymphomas, together with localized pulmonary amyloidosis (another lesion that has been described in association with pulmonary marginal lymphoma).

Pulmonary Plasmacytoma

Pulmonary plasmacytoma is a plasma cell malignancy that most commonly occurs in the upper respiratory tract. Plasmacytoma located in the lung is an unusual fnding, and in such cases the disease may be confned to the lung and regional lymph nodes or may be disseminated. The most common location for plasmacytoma is the submucosa of the upper airways [27, 28]. It is an extremely rare tumor, less than 50 cases are reported in literature and in fact represent only the 6% of all extraosseous plasmacytomas. About the 7% of patients affected by plasma cell myeloma have intrathoracic disease, and it is rarely confned into the lungs. When only located in the lower respiratory tract (primary pulmonary plasmacytoma), diagnosis can be particularly diffcult. The less differentiated plasmablastic pulmonary plasmacytoma occurs mainly in patients with advanced HIV infection. Phenotypically similar to mature plasma cells, the malignant cells appear immature, most like plasmablasts. Prognosis in HIV+ patients is poor (5.5 months) even if recent small reports suggest it may have improved after highly active anti-retroviral therapy (HAART) advent. The relationship between plasma cell myeloma, solitary plasmacytoma of bone, and extraosseous plasmacytoma is not well understood. For some authors, these three entities represent different aspects of the same disease spectrum, whereas others regard solitary plasmacytoma of bone as a rare manifestation of plasma cell myeloma. Extraosseous plasmacytoma should, however, be regarded differently, and the diagnosis restricted to tumors that occur outside the bone marrow, may infltrate nearby lymph nodes or cause distant metastasis. In immunocompetent patients pulmonary plasmacytoma is more frequently observed in the upper respiratory tract. Common clinical fndings are cough, dyspnea, and hemoptysis. Laboratory features include paraproteinemia and urinary Bence Jones. When involving the lung, plasmacytomas might be considered within the spectrum of MALTL, as previously described. The most frequent radiologic fnding is a pulmonary nodule or mass near the hilum. Lobar consolidation and bilateral diffuse infltrates have also been described, but this manifestation is very rare [29].

Follicular Lymphoma

Follicular lymphoma is generally an indolent B cell lymphoproliferative disorder of transformed follicular center B cells. Follicular lymphoma is characterized by diffuse lymphade-

nopathy, bone marrow involvement, splenomegaly, and less commonly other extranodal sites of involvement such as gastrointestinal tract, lung, skin, and other sites [2]. It affects adults (median age 59 years) and it is more frequent in females (male/female ratio 1/1.7). In general, cytopenia can occur but constitutional symptoms of fever, night sweats, and weight loss are uncommon. Primary lung involvement is usually asymptomatic. HRTC scan shows ground glass opacities sometimes with a “crazy paving” pattern or nodules. Diagnosis is based on histology. Immunohistochemical staining is positive in virtually all cases for cell surface CD20, CD10, and nuclear Bcl6. Monoclonal light chain restriction can be demonstrated on cryostat sections (when available). Membrane expression of bcl-2 protein can be demonstrated in the majority of cases, corresponding to the characteristic translocation t(14;18)(q32;q21) involving the IgH/bcl-2 genes. The Follicular Lymphoma International Prognostic Index (FLIPI) prognostic model for FL uses fve independent predictors of inferior survival: age > 60 years, hemoglobin <120 g/L, serum LDH > normal, Ann Arbor stage III/IV, number of involved nodal areas >4. The presence of 0–1, 2, and ≥3 adverse factors defnes low, intermediate, and high-risk disease with median 10-year survivals in the pre-rituximab era of approximately 71, 51, and 36 months, respectively. Chemotherapy plus rituximab (anti-CD20), has improved response rates [30].

Difuse Large B Cell Lymphoma

Diffuse large B Cell lymphoma (DLBCL) as a group is the second most common type of primary pulmonary lymphoma and most usually affects adults in the sixth and seventh decades [2, 31, 32] Morphological, biological and clinical studies have subdivided DLBCL into morphological variants, molecular subtypes and distinct disease entities [2]. The main morphological variants are centroblastic, immunoblastic, and anaplastic. The molecular subtypes are the germinal center B cell and the activated B cell. However, many cases remain that may be biologically heterogeneous, and have no clear and accepted criteria for subdivision. The centroblastic variant is characterized by cells with oval to round vesicular nuclei, multiple nuclear membrane-bound nucleoli, and scanty pale cytoplasm. The immunoblastic variant contains large lymphoid cells with round to oval vesicular nuclei and a single centrally located prominent nucleolus with scant to moderate basophilic cytoplasm. In some cases, plasmacytic differentiation may be seen, with eccentrically located nuclei. The anaplastic variant is characterized by large pleomorphic cells with bizarre irregular nuclei, often with multinucleated forms, and variable amounts of cytoplasm.

Lymphoma cells are positive for mature B cell related antigens (CD20, CD79a, PAX5), and variably express dif-

ferentiation markers than can be used to further defne the subtypes: CD10 (30–50%), BCL6 (60–90%), MUM1 (35– 65%), BCL2 (47–84%), and CD5 (5–10%), etc. Some DLBCL cases, especially the anaplastic variant, are positive for CD30. Ki67 staining is usually >40%; in some cases, it may be >90. BCL6(3q27) rearrangement is seen in ≤30% of DLBCL. 20–30% of DLBCL cases have t(14;18) involving the BCL2 gene. MYC (8q24) rearrangement occurs in8–14% of DLBCL cases. Cases with MYC and BCL2 and/ or BCL6 rearrangement are called “double/triple-hit lymphomas” and are classifed in a separate category of “High-­ grade B cell lymphoma with MYC and BCL2 and/ or BCL6 rearrangement” [3]. In a minority of cases, markers for Epstein–Barr virus (EBV) infection may be detected (EBV-­ positive diffuse large B cell lymphoma not otherwise specifed).

Diffuse large B cell lymphomas often occur in patients with underlying immunological disorders such as immunosuppression in solid organ transplantation, HIV infection, and Sjögren syndrome [33]. Patients are usually symptomatic with respiratory symptoms (cough, dyspnea, hemoptysis), fever, and weight loss.

Common radiological and CT fndings include single pulmonary mass, and atelectasis; pleural effusion may be present. In HIV patients or in other immunosuppressed hosts, multiple excavated opacities are more frequently found. Survival is poor in patients with underlying immunologic disorders such as AIDS and transplantation. R-CHOP (rituximab, cyclophosphamide, doxorubicine, vincristine, and steroids) is the treatment of choice; the 5-year progression-free and overall survival rates were found to be 60% and 65%, respectively [2].

Intravascular large B cell lymphoma is a rare subtype of large B cell lymphoma with an estimated frequency of <1% of all lymphomas. This rare entity is characterized by an intravascular proliferation of clonal B cells with little to no parenchymal involvement and usually without involvement of lymphoid tissues and occasionally peripheral blood [1, 2, 31]. Proliferation of CD20 positive neoplastic cells in blood vessels of parenchymal organs results in vessel obliteration and ischemia. The clinical presentation is highly variable, ranging from no or limited organ involvement to multiple organ failure. Two major patterns of clinical presentation have been recognized: the so-called classic form (mostly present in Western countries), which is characterized by symptoms related to the mainly involved organs (predominantly central nervous system, skin and lungs) and a hemophagocytic syndrome-associated form, originally documented as an Asian variant, in which patients present with multiorgan failure, hepatosplenomegaly and pancytopenia, B symptoms, particularly fever. The diagnosis of intravascular lymphoma is often diffcult. Rare presentations with pulmonary arterial hypertension or respiratory insuffciency