Castleman’s disease is an uncommon clinicopathological entity first described in 1956 [1]. The incidence is not known and can occur at any age, though it has mostly been reported in adults in the literature. CD is classified according to the clinical and the histopathologic profile, as localized (hyaline- vascular, plasma-cell type) or multicentric with histologic features of one or both of the localized types [2, 3]. The hyaline- vascular type (HV) shows numerous follicles with around a concentric layering of B small lymphocytes (CD20+, IgD+) in an onion-skin apparence, depleted, abnormal, germinal center (CD20+, Bcl6+, Bcl2−) with penetrating hyalinized capillaries in “lollipop” apparence, and large dysplastic cells with vescicular nuclei consistent with follicular dentritic cells (CD21+, CD23+, CD35+). Actually, it has been recognized that CD represent a neoplasm of follicular dentritic cells because have been reported clonal cytogenetic abnormalities in FDC cells [4]. The interfollicular stroma shows marked vascular proliferation, polyclonal plasma cells, immunoblasts, plasmacytoid dentritic cells (CD123+, CD68+,) and myoid cells. Cases of CD in wich the myoid cells are prominent have been referred to as stroma-rich variant of hyaline-vascular CD [5].

The plasma cells type (PC) is characterized by a diffuse polytypic or monotypic (IgA lambda) plasma cells proliferation, often in sheets, in the interfollicular stroma.

The localized form of the disease is mostly asymptomatic with a single site lymph node enlargement. The sites commonly involved are abdomen, peripheral lymph nodes and the mediastinum. It is often discovered incidentally during routine examination, chest X rays. Diagnosis is made by histological analysis of the lymph node biopsy to distinguish it from a thymoma. Multifocal CD, however, presents with systemic symptoms along with multiple lymph node hyperplasia.

Interest in multicentric (M-CD) has grown following the observation that this pathology is often associated with human immunodeficiency virus (HIV) infection and with (HHV8, or Kaposi’s sarcoma herpesvirus KSHV) and Epstein Barr virus (EBV) infections [6]. Pathogenesis remain largely unknown, but HHV8 and Epstein Barr virus may encodes for an homologue of interleukin 6 (vIL 6) which may mediate some systemic features of MCD. Multicentric CD in HIV + patients have a higher prevalence of pulmonary symptoms and usually present with generalized lymphadenopathy characterised by perifollicular vascular proliferation and germinal center angiosclerosis, polyclonal hypergammaglobulinemia, hepatosplenomegaly and constitutional symptoms.

In immunocompetent host the more common pattern is the hyaline-vascular, the associated clinical type is usually the localised one, an asymptomatic mediastinal mass quite benign because in most cases curable by surgery. The plasma-cell variant is more often associated with the multicentric disease characterized by lymphadenopathy, hepatosplenomegaly, skin rashes, sweating, fatigue, anaemia, elevated erythrocyte sedimentation rate (ESR), polyclonal hypergammaglobulinemia and bone-marrow plasmacytosis. It may be associated with the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-proteins and skin changes). The systemic symptoms are thought to be primarily a consequence of elevated Interleukin-6 (IL-6) production [7, 8]. Recently, a unique clinicopathologic variant of multicentric Castleman’s disease (MCD) called TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly) has been identified in Japan. This disease is characterized by a constellation of symptoms, as listed above, and multiple lymphadenopathy of mild degree with a pathologic diagnosis of atypical CD, often posing diagnostic and therapeutic problems for pathologists and hematologists, respectively. These findings suggest that this disease represents a novel clinical entity belonging to systemic inflammatory disorders with a background of immunological abnormality beyond the ordinal spectrum of MCD [9].

Clinical manifestations of lung involvement include dyspnoea, cough, bilateral crackles, or rapidly progressive respiratory failure. Pulmonary symptoms develop always simultaneously with severe systemic manifestations: high grade fever, malaise, generalised lymphadenopathy and hepatosplenomegaly. Hypoxaemia and hypocapnia are often present.

Chest radiographs show reticular and/or nodular interstitial patterns often associated with mediastinal lymphadenopathy and in some cases accompanied by bilateral pleural effusions. Common CT findings are poorly defined centrilobular nodules, thickening of the bronchovascular bundles and interlobular septae, and thin-walled cysts, mostly related to diffuse interstitial, interalveolar, infiltration of small lymphocytes (LIP pattern). Less common findings include subpleural nodules, areas of ground glass attenuation air-space consolidation and bronchiectasis. Bronchoscopy is usually negative, BAL hypercellularity mainly due to an increase of CD8 + lymphocytes is usually present but it is not specific. Microbiological investigations on BAL fluid permit to exclude common infectious aetiologies, and genotyping analysis allows to detect HHV-8 DNA. Definite diagnosis is histological, most cases being diagnosed by peripheral lymph-node biopsy. Specimens of pulmonary lesions may be obtained by trans-bronchial biopsy or by surgical biopsy. Localized CD usually has a good prognosis and requires surgical excision of the enlarged lymph node with no further treatment. M-CD however tends to have a variable prognosis with no documented treatment consensus [2, 3]. Median survival in HIV + patients is 14 months, patients die of infections, transformation to NHL (Large B cell lymphoma associated M-CD or Plasmablastic lymphoma) or chemotherapy toxicity. A variety of combination treatments have been tried with surgical excision, chemotherapy and steroids. In patients with associated Kaposi’s sarcoma polychemotherapy (e.g. cyclophosphamide, vincristine, doxorubicin and prednisone) has been tried with limited success. First line treatment of M-CD in non HIV patients consist of single chemotherapeutic agent, high doses of steroid and/or anti CD-20 monoclonal antibodies. Studies show that humanized anti-human interleukin-6 receptor monoclonal antibody significantly alleviate chronic inflammatory symptoms and wasting [10, 11]. Systemic and pulmonary symptoms improve more rapidly and may disappear. Recently it has been demonstrated that the M-CD symptoms improved by treatment with tocilizumab, which is a humanised antihuman IL-6 receptor monoclonal antibody and corticosteroid [12]. Complete resolution of TAFRO syndrome after immunosuppressive therapies using corticosteroids and cyclosporin A has been reported [13]. However prognosis remain poor, patients die after relapsing of disease, progression to lymphoma or for bacterial sepsis, median survival time being 5 years. Finally treatment with the antiherpesvirus drug, gangciclovir alone or with the antiCD20 B cell monoclonal antibody, rituximab, may markedly improve outcome.

Nodular lymphoid hyperplasia, also known as “pseudolymphoma”, is a localized mass characterized by a lymphoid infiltrate with a lack of evidence of clonality despite immunohistochemical and genetic studies. The most common clinico-radiological feature is a localized and asymptomatic mass, although few patients present fever and elevated ESR. The single lesion is usually curable by surgical excision. Finally it is needed to evaluate the possibility of nodular lymphoid hyperplasia (pseudolymphoma) or clonal lymphoproliferative disorder in the lung as potential manifestations of immunoglobulin(Ig)G4-related disease [14, 15].

Lymphocytic interstitial pneumonia (LIP) [16, 17] is a rare interstitial lung disease characterized by the presence of aggregates of B and T reactive lymphocytes within the lung interstitium.

LIP is associated with serum protein abnormality (monoclonal gammopathy, polyclonal dysproteinemia, hypogammaglobulinemia), immunological disorders, such as Sjogren syndrome (25 % of cases), primary biliary cirrhosis, myasthenia gravis, Hashimoto thyroiditis, pernicious anemia/agammaglobulinemia, autoimmune haemolytic anemia, systemic lupus erythematosus, celiac disease, HIV infection, EBV infection, chronic active hepatitis, other infections (e.g., pneumocystis, tuberculosis), drug injury, allogeneic bone marrow transplantation (GVHD), extrinsic allergic alveolitis. LIP occurs more commonly in women and the mean age is around 55 years.

Presenting symptoms are progressive cough and dyspnoea, weight loss, fever, arthralgias. Common physical findings are bibasilar crackles and finger clubbing (reported in about 50 % of cases). Pulmonary function tests show reduction of lung volume, reduction of DLco, hypoxemia and usually hypocapnia.

The chest radiograph characteristically shows bibasilar reticulonodular infiltrates, a mixed alveolar-interstitial pattern can occur when infiltrates coalesce and cause compression of the alveoli. Typical HRCT abnormalities consist of areas of ground-glass attenuation and poorly defined centrolobular nodules and subpleural small nodules, mostly bilateral (>90 %) and with a diffuse distribution (>60 %). Other common findings are thickening of bronchovascular bundles, interlobular septal thickening (82 %), cystic lesions (68 %) (Fig. 31.3), and lymph node enlargement (68 %). Less common findings include nodules 1–2 cm in diameter (41 %), airspace consolidation (41 %), emphysema (23 %), bronchiectasis (18 %), pleural thickening (18 %), and honeycombing (5 %). Honeycombing and pulmonary hypertension appears in advanced disease. Pleural effusion are infrequent, except in HIV related LIP. Usually the presence of pleurisy, large nodules and mediastinal adenopathy is suggestive for pulmonary lymphoma. Histologically, LIP is characterized by a heavy interstitial lymphoid infiltrate with minor peribronchiolar involvement. Granuloma formation is sometimes noted. Intraalveolar accumulation of small lymphocytes, scanty granulation tissue tufts, and proteinaceous material along with type II cell hyperplasia are ancillary findings. Immunohistochemestry using CD20 shows that B cells are mainly limited to germinal centres (CD10+, Bcl6+, Bcl2−). The interstitial, interalveolar, lymphocytes are prominently T-cells, while the follicles are mainly constituited by B lymphocytes. The immunoglobulin heavy chain gene or the T cell receptor gene using the polymerase chain reaction show no rearrangement. Epstein–Barr virus has been identified in lung biopsy specimens from both HIV infected and non-infected patients [18, 19].

Treatment with corticosteroid and immunosuppressive drugs may lead to resolution. Median survival is 11,5 years. The outcome is unpredictable and may vary from resolution to death due to progression to fibrosis, cor pulmonale and respiratory failure, to superimposed infection, or to development of a complicating lymphoma.

Follicular bronchitis/bronchiolitis is a term introduced to describe the predominant peribronchial lymphocytic infiltrate with abundant germinal centres, often associated with various allergic diathesis, immunodeficiency disorders (HIV infection, common immunodeficiency syndromes), and collagen vascular diseases.

Patients usually present dyspnoea, occasionally fever and cough, hypoxemia, hypocapnia; either obstructive or restrictive spirometric patterns have been reported. The chest film shows bilateral reticular or nodular opacity. Common high-resolution CT findings are centrolobular nodules, bronchiolar dilatation, tree in bud and mosaic perfusion patterns. Expiratory dynamic HRCT scans are important to assess air trapping. Flow-cytometry of BAL usually document a slight increase of polyclonal B lymphocytes. Surgical lung biopsy is often performed to obtain a definite histological diagnosis. Therapy with steroids and also with macrolides at low dose may have some benefit.

The most common histotype is mucosa-associated lymphoid tissue type (MALT) B cell lymphoma, which represents 70–90 % of all primary pulmonary NHL [16–21]. Diffuse large B cell lymphoma (DLBCL) occurs only in 10 % cases of primary pulmonary NHL [21]. In some cases, transformation from MALT lymphoma to DLBCL may occur. Clinically, these present with non-specific symptoms. Radiologically, these can present as consolidation, well-defined mass or nodules. So, PPL can easily be confused radiologically with primary lung carcinoma or metastases when presenting as multiple masses or/and nodules but they have different treatment and prognosis. The main diagnostic criterion for PLL is the absence of extra-pulmonary involvement. Therefore, in patients with biopsy-proven lymphoma of the lung, PLL is diagnosed if extra-pulmonary involvement is ruled out. B-cell primary pulmonary NHL are subdivided into low-grade B-cell PPLs (58–87 %), high-grade B-cell PPLs (11–19 %). The high-grade B-cell PPLs spread rapidly into mediastinal and extra-thoracic locations. This may lead to underestimation of true incidence.

As in other extranodal-MALT lymphomas, an heterogeneous pattern of cytogenetic abnormalities has been demonstrated in pulmonary lymphomas, including aneuploidy (observed in nearly 40 % of cases, with trisomy 3 and 18 being the most common), and specific chromosomal translocations. Translocation t(11;18)(q21;q21) which characterizes about one third of extranodal marginal MALT lymphomas is the most frequent chromosome translocation occurring in pulmonary MALT lymphomas (38.3–41 % in different series). This translocation involves the API2 and MALT1 genes, and can be then directly correlated to the pathogenesis of this lymphoma [29]. Accordingly, API2 is a member of the IAP (inhibitor of apoptosis) gene family, whereas MALT1, a paracaspase of unknown functions, is able to interact with bcl-10 inducing NF-kbeta (nuclear factor K beta) activation. The abnormal fusion of MALT1 with API2 produces chimeric transcripts involved in inhibition of apoptosis, thus contributing to lymphoma development. 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 defines a distinctive clinicopathologic subtype of pulmonary MALT-lymphomas characterised by the absence of any underlying autoimmune disease and lack of plasmacytic differentiation.

Information regarding the occurrence and frequency of other genetic abnormality involved in the pathogenesis of MALT lymphomas such as t(1;14)(p22;q32) are scanty.

Pulmonary plasmacytoma is a plasma cell malignancy that most commonly occurs in the upper respiratory tract. Plasmacytoma located in the lung is an unusual finding, and in such cases the disease may be confined to the lung and regional lymph nodes or may be disseminated. The most common location for plasmacytoma is the submucosa of the upper airways [32, 33]. It is an extremely rare tumour, 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 confined into the lungs. When only located in the lower respiratory tract (primary pulmonary plasmacytoma), diagnosis is difficult and is usually based on the excised tissue

The less differentiated plasmablastic pulmonary plasmacytoma occurs mainly in patients with advanced HIV infection. Phenotypically similar to mature plasma-cells, the malignant cells appear most like plasmablasts. Prognosis in HIV + patients is poor (5.5 months) even if recent small reports suggest it may have improved after HAART advent. The relationship between plasma cell myeloma, solitary plasmacytoma of bone, and extraosseous plasmacytoma is not well understood. For some authors these 3 entities represent different aspects of the same disease spectrum. 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 infiltrate nearby lymph nodes or cause distant metastasis. In immunocompetent patients pulmonary plasmacytoma is more frequently observed in the upper respiratory tract. Common clinical findings are cough, dyspnoea and haemoptysis. Laboratory features include paraproteinemia and urinary Bence Jones. When involving lung the most frequent radiologic finding is a pulmonary nodule or mass near the hilum. Lobar consolidation and bilateral diffuse infiltrates have also been described, but this manifestation is very rare [34]. Little is known about endoscopic findings, but as occurred in our third patient, infiltration of the mucosa has been observed, along with polypoid tumors, all lesions which are comparable to those seen in bronchogenic carcinoma [35].

Follicular lymphoma is generally an indolent B-cell lymphoproliferative disorder of transformed follicular center B cells. Follicular lymphoma is characterized by diffuse lymphoadenopathy, bone marrow involvement, splenomegaly, and less commonly other extranodal sites of involvement such as gastrointestinal tract, lung, skin and other sites [36].

It affects adults (median age 59 years) and it is more frequent in females (male/female ratio 1/1.7). In general, cytopenias can occur but constitutional symptoms of fever, nightsweats, 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 of preferably biopsy. Immunohistochemical staining is positive in virtually all cases for cell surface CD20, CD10, nuclear for Bcl6 and monoclonal immunoglobulin, as well as membrane expression of bcl-2 protein. The overwhelming majority of cases have 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 five independent predictors of inferior survival: age >60 years, hemoglobin <12 g/dL, serum LDH > normal, Ann Arbor stage III/IV, number of involved nodal areas >4. The presence of 0–1, 2, and ≥3 adverse factors defines low, intermediate, and high-risk disease with median 10 year survivals in the pre-rituximab era of approximately 71, 51, and 36 months, respectively.