with air trapping have been reported. LDH, soluble interleukin 2 receptor (sIL-2R), and ESR are usually elevated. Hypercalcemia may be observed, though rarely. Pulmonary function tests show a markedly decreased diffusing capacity. Chest X-ray may be normal or show reticulo-nodular infltrates or pleural effusion. CT fndings may include bilateral reticular shadow, ground glass opacity, wedge-shaped subpleural opacities, and pleural effusion. A random skin biopsy of normal-appearing skin or transbronchial (cryo)biopsies are often helpful in making the diagnosis in subjects presenting mainly with thoracic symptoms/signs [34]. Cytological analysis of pulmonary capillary blood cells has been reported as useful for the identifcation of the disorder. Intravascular lymphoma usually shows rapid progression and short survival, with at best transient remissions. Treatment is usually with the R-CHOP regimen. The poor prognosis in these patients re ects, at least in part, frequent delays in diagnosis and initiation of therapy.

Lymphomatoid Granulomatosis

Lymphomatoid granulomatosis (LYG) is an angiocentric and angio-destructive lymphoproliferative disease involving extranodal sites, composed of EBV-positive B cells admixed with reactive T cells, which usually predominate [2, 31]. The lesion has a spectrum of histological grade and clinical aggressiveness, which is related to the proportion of large B cells. Although it may affect virtually any organ, it is most frequently characterized by pulmonary, skin, and central nervous system involvement. This condition usually affects adults (average age 50) with a predilection for males (sex ratio male to female 2:1) and for patients with underlying immunodefciency (HIV + patients, Wiskott-Aldrich syndrome). However, occurrence in childhood has been documented. Few subjects are asymptomatic. Nearly 90% of patients report chronic respiratory symptoms, mainly cough, chest pain, and dyspnea, accompanied by B symptoms such as fever, weight loss, and sweating. Hemoptysis or acute respiratory distress syndrome rarely occur. Laboratory fndings are characterized by increased ESR and, in a minority of cases, lymphopenia, leukocytopenia, and low CD4+ lymphocyte count. Lung nodules are the most common feature in chest radiographs, occurring in perhaps 80% of cases, and cavitation may be noted in 20% of cases [35]. In about 30% of patients, pleural effusion is present at the beginning. Hilar lymphadenopathies are found in less than 25% of cases. Uncommon radiologic features reported in literature include: single nodules, alveolar opacities, small thin-walled cystic lesions, and reticulonodular diffuse lesions. Differential diagnosis in patients with LYG is a real challenge: granulomatosis with polyangiitis, other necrotizing vasculitides, necrotizing nodular sarcoidosis, infections,

bronchogenic carcinoma and metastatic tumors, organizing pneumonia, and IgG4 related fbroin ammatory disease [1, 36]. The clinical course is highly variable [37]. Patients may show waxing and waning of their disease; in grade 1 forms and when the lesions are localized to the lungs, spontaneous resolving may be observed in up to 27% of cases [36, 38]. One-third of patients with grade 1 lesions progress to malignant lymphoma, whereas two-thirds of patients with grade 2 lesions develop lymphoma. The aggressive form of disease is lethal within 2 years, in spite of aggressive therapy. Death is often caused by a progressive pulmonary involvement. However, high-dose therapy (with or without stem cell transplantation) can be effective therapeutic options in some cases and should be considered in all patients with refractory and multiply relapsed LYG [39, 40]. From the pathologic point of view, the term LYG includes a group of related lesions characterized by the infltration of pulmonary parenchyma by an heterogeneous cell population composed of a large number of reactive T-lymphocytes, a variable proportion of large EBV-­infected B cells (as defned by co-expres- sion of B cell related antigens and EBV markers [2, 36]. The lymphoid infltrate often surrounds pulmonary arteries and veins and typically invades the walls of these vessels. Necrosis is a frequent feature of the disease. LYG lesions are heterogeneous, and have been graded depending on the proportion of neoplastic B cells and surrounding reactive T cells, the degree of lymphocytic atypia, and the heterogeneity of the infltrate, distinguishing three grades. Grade 1 lesions contain few or no EBV-infected cells (less than 5 per high-power feld), usually lack necrosis, and are polymorphous. Monoclonality is usually diffcult to demonstrate. Grade 2 lesions have scattered EBV-infected cells (5–20 per high-power feld) and foci of necrosis, but they remain polymorphous. The grade 3 forms can be considered as diffuse large B cell lymphomas; foci of necrosis are evident and sheets of markedly atypical cells (resembling immunoblasts or resembling Reed–Sternberg cells) infltrate the lung parenchyma in an angiocentric fashion. The T cell component is non-neoplastic by defnition, exhibits an activated cytotoxic phenotype, and can be considered as a reactive response to infected/neoplastic B cells. Chemokines such as IP-10 and Mig, elaborated as the result of the EBV infection may be responsible for vascular damage by promoting T cell adhesion to endothelial cells. LYG needs to be distinguished, histologically, from other diseases characterized by polymorphous lymphoid infltration (angioimmunoblastic lymphadenopathy, infection due to Epstein–Barr virus, acute and fbrinous organizing pneumonia, in ammatory sarcomatoid carcinoma), IgG4 related fbroin ammatory disorder, and by lesions characterized by zonal coagulative necrosis and prominent angio-invasion, including extranodal NK/T (nasal-type) T cell lymphoma, and granulomatosis with polyangiitis (Fig. 39.8a, b).

T/Natural Killer-Cell Primary Pulmonary

Lymphomas (T/NK PPL)

Different types of extranodal T/NK cell lymphomas can occur primary in the lungs: nasal-type T/NK lymphoma, peripheral T cell lymphoma not otherwise specifed, anaplastic large T cell lymphoma, mycosis fungoides [2, 41].

Extranodal NK/T cell lymphoma, nasal type is a predominantly extranodal lymphoma of NK cell or T cell lineage, characterized by vascular damage and destruction, prominent necrosis, cytotoxic phenotype, and association with EBV. It is defned as NK/T cell lymphoma because although most cases appear to be genuine NK cell neoplasms, some cases are of cytotoxic T cell lineage [2]. It is not exceptional in Western countries, but predominantly affects middle-aged men in Asia, Mexico, and South America. It presents as tumors or destructive lesions in the nasal cavity, maxillary sinuses, palate, and also the lung.

When occurring in the lung, it can present many clinical and radiological similarities with LYG (Fig. 39.9a–f). Clinically pulmonary (hemoptysis, chest pain) and systemic symptoms (fever, asthenia) are common. Laboratory tests may document an important CD4+ lymphocytopenia in peripheral blood and the disease may manifest with coexisting atypical pulmonary infections and with hemophagocytic syndrome [42]. CT scan documents nodules or masses with an important necrotic component. Diffuse ground glass attenuation is another rarer imaging profle. This lymphoma ranges from monomorphic small−/medium-sized to large cell lymphomas and is characterized by frequent features of angio-invasion/angiocentrism, and common necrosis accounting for frequent diagnostic diffculties on small biopsies. In cases where the neoplastic cells are admixed with an

in ammatory component and/or in small biopsies, the lesions may be mistaken for a reactive process.

The neoplastic cells usually are CD3ε+, CD2+, CD5-, CD7+, CD16+/−, and CD56+/−, and have an activated cytotoxic profle. Most cases are derived from NK cells, but up to 38% of the cases are CD56-negative clonal T cells with a γδ or more rarely αβ TCR confguration at molecular analysis. By defnition, all cases are associated with EBV, which is best demonstrated by in situ hybridization [2]. EBV infection is characterized by a type II latency program with expression of EBERs, LMP1, and EBNA2 [2]. The prognosis of nasal NK/T cell lymphoma is variable, with some patients responding well to chemotherapy and others dying of disseminated disease despite aggressive therapy. Historically, the survival rate has been poor (30—40%), with some improvements in recent years. Regimens incorporating asparaginase are currently the standard. For stage I/II disease, combined chemotherapy and radiotherapy is recommended. Recent studies have documented consistent PD-L1 expression by neoplastic cells in the vast majority of the cases, and recent reports indicate that antagonization of PD1-PD-L1 interactions might represent a therapeutic option for extranodal T/NK cells lymphomas refractory to standard lines of chemotherapy [43].

Peripheral T cell lymphoma not otherwise specifed (NOS) is a heterogeneous category of nodal and extranodal mature T cell lymphomas that do not correspond to any of the specifcally defned entities of mature T cell lymphoma in the current classifcation. The cytological spectrum is extremely broad, from polymorphous to monomorphic. Most cases consist of numerous medium-sized and/or large cells with irregular, pleomorphic, hyperchromatic, or vesicular nuclei, prominent nucleoli, and many mitotic fgures. Clear cells and Reed–

Fig. 39.9  (a) Extranodal NK/T lymphoma, nasal type: the lymphomatous infltrate shows interstitial perivascular infltration of small, medium-sized cells with irregular nuclei (2× EE); (b) Extranodal NK/T lymphoma, nasal type: the lymphomatous infltrate shows interstitial perivascular infltration of small-, medium-sized cells with irregular nuclei (4× EE); (c) Extranodal NK/T lymphoma, nasal type: the lymphomatous infltrate shows interstitial perivascular infltration of small-, medium-sized cells with irregular nuclei (10× EE); (d)

Extranodal NK/T lymphoma, nasal type: the lymphomatous infltrate of small-, medium-sized cells with irregular nuclei and apoptotic bodies shows perivascular infltration of a small artery (20× EE); (e) Extranodal NK/T lymphoma, nasal type: the lymphomatous infltrate has an angiocentric angiodestructive pattern associated with coagulative necrosis and apoptotic bodies (20× EE); (f) Extranodal NK/T lymphoma, nasal type: the lymphomatous cells have T immunophenotype: CD3+ (20× IIC)

Sternberg-like cells can also be seen. Fever, asthenia, and respiratory failure are the main symptoms at onset. Laboratory tests may document lymphopenia and eosinophilia. Serum autoantibodies may be documented. Hemophagocytic syndrome is a rare and ominous complication. CT scan fndings are alveolar consolidations, nodules, ground glass attenuation; part of these features) may be explained by organizing pneumonia around the lymphoid neoplastic infltrates.

Anaplastic large cell lymphoma was previously recognized as Ki-1 lymphoma for the strong expression of the activation antigen CD30/Ki-1 by neoplastic cells. It has rarely been described as primary pulmonary presentation; masses or single nodules are the features observed at CT. The patients present with B symptoms [1, 2].

Mycosis fungoides in its rare granulomatous variant may involve primary the lungs. Patients present with fever, lymphopenia, eosinophilia, and increased ESR and LDH. CT features include nodules with halo-signs, peripheral consolidation, and a crazy paving pattern [44]. Due to its rarity and lack of clinicoradiological specifcity, the diagnosis is always diffcult and requires expert histopathological analysis.

Primary Pulmonary Hodgkin Lymphoma (PPHL)

PPHL is a very rare entity and has to be distinguished from the more common intrathoracic nodal Hodgkin disease secondarily involving the lung [45, 46]. Due to its rarity, epidemiological data are scarce. In a review of 60 cases recorded in the world literature, PPHL is more common than men, shows bimodal age distribution (<35 years and >60 years), without a signifcant correlation with cigarette smoke [47]. Dry hacking cough is the most common presenting symptom. Radiologically, it appears as a solitary mass or multinodular disease. Inhomogeneity or cavitation of these lesions is common [47]. Rarely, it manifests as a diffuse infltrate along the lymphatic routes. Cases of primary diffuse infltrative lung disease due to an Epstein Barr virus associated lymphoproliferative disorder with features simulating Hodgkin lymphoma superimposed on a honeycomb lung background have been reported in patients receiving long-term low-dose methotrexate therapy for rheumatoid arthritis [37]. The differential diagnosis includes tuberculous, fungal infections, metastatic carcinomas, non-Hodgkin lymphomas, granulomatosis with polyangiitis, and Langerhans cell histiocytosis.

Post-Transplantation Lymphoproliferative

Disorders

Post-transplant lymphoproliferative disorders (PTLDs) are lymphoid or plasmacytic proliferations that develop as a consequence of immunosuppression in a recipient of a

solid organ or stem cell allografts. They constitute a spectrum ranging from usually EBV-driven polyclonal proliferations to EBV-positive or EBV-negative proliferations indistinguishable from a subset of B cell or (less often) T/ NK cell lymphomas that occur in immunocompetent individuals [2]. The monomorphic and classic Hodgkin lymphoma types of PTLD are further categorized as in non-immunosuppressed patients, according to the lymphoma they resemble. With the rare exception of EBVpositive MALT lymphomas, indolent B cell lymphomas (e.g., follicular lymphoma and EBV-­negative MALT lymphomas in allograft recipients) are designated as they are in the immunocompetent host and not considered a type of PTLD [2]. The clinicopathological features comprehend “Benign plasmacytic hyperplasia and infectious-mononu- cleosis-like PTLD” which arise in oropharynx or lymph nodes and are polyclonal proliferations with evidence of multiple EBV infectious events but no evidence of oncogene or tumor-suppressor gene alterations; “polymorphic lymphoproliferative disorder” that may be nodal or extranodal and is usually monoclonal; “monomorphic PTL classifed according to lymphoma classifcation (predominantly B cell neoplasms or less often T cell neoplasms) widely disseminated and monoclonal; Hodgkin lymphoma and Hodgkin-like PTLD (Table 39.2). Incidence varies depending on organ recipient (<1% renal recipients; hepatic and cardiac allografts 1–2%; heart-lung or liverbowel allografts 5%). Marrow allograft recipients in general have a low risk of PTLD (1%). Risk factors for this disorder include HLA-mismatched donor, T cell depletion of the

Table 39.2  Post-transplant lymphoproliferative disorders. WHO classifcation [2]

Categories of post-transplant lymphoproliferative disorder (PTLD)

Non-destructive PTLDs

Plasmacytic hyperplasia

Infectious mononucleosis

Florid follicular hyperplasia

Polymorphic PTLD

Monomorphic PTLDs (classify according to lymphoma they resemble)

B-cell neoplasms

 Diffuse large B-cell lymphoma Burkitt lymphoma

Plasma cell myeloma Plasmacytoma Othera

T-cell neoplasms

Peripheral T-cell lymphoma, NOS

Hepatosplenic T-cell lymphoma

Other

Classic Hodgkin lymphoma PTLD

aIndolent small B-cell lymphomas arising in transplant recipients are not included among the PTLDs, with the exception of EBV-positive marginal zone lymphomas

graft, anti–T cell agents, older age of donor, splenectomy, and mismatch in CMV or EBV status between recipient and donor. PTLD frequently present in the frst year after transplantation, especially in EBV-seronegative recipients who acquire early post-transplant EBV infection, often from the donor. This pattern of presentation is particularly common in children. However, the median time to PTLD in some studies, especially those of adult populations, is several years, and as many as 15―25% of cases occur >10 years after the transplant. PTLD had an earlier onset in allo-human stem cell transplants than in solid organ recipients (4 vs. 64 months), and appears to be EBV-positive in almost allo-­transplants, in contrast to solid organ transplants [48]. Lung involvement is seen in 20% of patients. The majority of PTLD are associated with Epstein–Barr virus infection. The majority of patients have a negative serology for Epstein–Barr virus and Cytomegalovirus before transplantation. The clinical manifestations of PTLD commonly include mononucleosis-­type syndrome (fever, fatigue, sore throat), regional lymphoid enlargement, and a disseminated disease [48]. It is very diffcult to diagnose without a history of post-­transplantation and histology confrmation. Because the symptoms of PTLD are often similar to those of other complications of transplantation, particularly infection and organ rejection, a high index of PTLD suspicion is crucial to preventing a delay in diagnosis. Imaging thorax features are characterized by mediastinal/hilar lymph nodes enlargement, parenchymal consolidative masses (with or without necrotic lower attenuation), ill-defned nodules or nodular consolidations. Pleural effusion is not infrequently detected [49]. These lesions are PET positive.

Diagnosis andStaging

Different invasive procedures are used to obtain diagnostic tissue. Endoscopic bronchial or trans-bronchial biopsy is the most frequently used. When the lesion appears in the central airways, a large biopsy obtained by rigid bronchoscopy is rarely required for obtaining tissue samples for a precise diagnosis [50]. Open-lung biopsy or video-assisted thoracoscopic surgery can be chosen if tissue from endoscopy biopsy is not suffcient. BAL does not allow a complete analysis for an accurate diagnosis, but can be highly improved when molecular and immunophenotypic studies are available [50]. The diagnostic yield of transbronchial biopsy is higher when a bronchus sign is present in CT scan or when a transbronchial cryobiopsy is utilized [51]. CT imaging plays an important role in directing to the appropriate biopsy site. Fiberoptic bronchoscope is usually wedged into the most extensively involved pulmonary segments to perform BAL and transbronchial biopsy. Fluoroscopy and endobronchial radial ultrasonography (EBUS) are also

valuable tools to detect pulmonary masses or consolidation, thus increasing the diagnostic yield of transbronchial biopsy [52]. However, the absence of specifc signs in a large quote of those samples necessitates further diagnostic investigations. Almost all patients with suspicious of pulmonary lymphomas undergo a bronchoscopy and transbronchial biopsies, but only in less than half cases (30–50%) it is possible to reach a histological diagnosis without a surgical lung biopsy. BAL is an essential tool for the differential diagnosis of sub-acute or chronic alveolar opacities, and seems to be valuable for the positive diagnosis of PPL. Differential diagnosis of PPL includes viral, bacterial or opportunistic pneumonia, radio-induced and drug induced pneumonitis, tuberculosis, sarcoidosis, cryptogenic organizing pneumonia, alveolar proteinosis, exogenous lipoid pneumonia, alveolar hemorrhage, bronchioloalveolar cell cancer, hypersensitivity pneumonitis, eosinophilic pneumonia, vasculitis, and primary or metastatic lung tumors. Differential diagnosis is primary based on clinicoradiological and histological fndings, however, BAL is particularly valuable to exclude an alternative diagnosis. In about twothird of patients affected by MALT lymphoma, and in particular in those cases in which the CT scan shows alveolar and/or ground glass opacities, BAL shows lymphocytic alveolitis (lymphocytes >20% total cells), a high percentage of cells expressing a B phenotype and in some cases cytological features consistent with low-grade malignant lymphoma (medium sized lymphoid cells with lymphoplasmocytoid differentiation and irregular nuclear borders). Flow cytometry and immunocytochemical analysis of BAL uid represent mandatory procedures to document a monotypic expression of surface light chains (indicating a clonal B cell proliferation) [53]. Recent studies report that genotyping investigation on BAL uid can contribute to the diagnosis of MALT lymphoma with a sensitivity and sensibility higher than ow cytometry or immunocytochemical investigations. In particular immunoglobulin heavy chain gene rearrangement analysis by PCR of alveolar lymphocytes is highly sensitive and specifc (97% specifcity, 95% negative predictive value) to detect clonal alveolar lymphocytes population in patients with B cell pulmonary NHL. Therefore when a dominant B cell clone is not documented on BAL uid more invasive investigation could be dismissed [54]. In other lymphomas BAL is less sensitive and specifc. Rarely Reed-­Sternberg/ Hodgkin’s cells may also be detected. Morphologic andow cytometry analysis of trans-parietal fne needle aspiration/biopsy samples obtained under uoroscopic, CT scan or echographic guide, may be diagnostic in a minority of cases but this procedure is of value in the diagnosis of post-transplant lymphoproliferative disorders.

When a pleural effusion is present medical thoracoscopy may be also diagnostic. When these less invasive procedures fail the defnitive diagnosis rely on histological examination