This review aims to describe some of the most frequent lymphoproliferative disorders arising from the lung: pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma, lymphomatoid granulomatosis (LG), multicentric Castleman disease (MCD), primary effusion lymphoma (PEL), and nodular lymphoid hyperplasia (NLH). Primary pulmonary lymphoma is defined as a clonal lymphoproliferative disorder affecting one or both lungs, without extrapulmonary involvement 3 months after diagnosis, and includes pulmonary MALT lymphoma and LG. MALT lymphoma is the most common pulmonary lymphoma. The disease is slow growing, most often asymptomatic, and revealed by chronic alveolar opacity on radiography. The diagnosis should involve minimally invasive techniques, and the prognosis is typically excellent. LG is a rare B-cell lymphoma driven by Epstein-Barr virus infection. The disease may mimic pulmonary vasculitis, often revealed by systemic signs. The diagnosis usually requires surgical lung biopsy. Its evolution is unpredictable, but median survival is poor and chemotherapy is usually proposed. MCD and PEL are both driven by Human herpesvirus 8 infection. Patients with MCD present with fever and lymphadenopathy associated with interstitial lung disease. PEL provokes a febrile, lymphocytic-exudative pleural effusion, without any pleural mass on CT. Specific chemotherapy is urgent for both MCD and PEL. NLH is a benign lymphoproliferative disorder of the lung that is usually asymptomatic and revealed by a single nodular opacity. The prognosis is good, without recurrence after surgical resection.

Primary pulmonary lymphoma is defined as a clonal lymphoid proliferation affecting the parenchyma and/or bronchi of one or both lungs, with no detectable extrapulmonary involvement at diagnosis or during the following 3 months [1,2]. The most common primary pulmonary lymphoma types in order of decreasing frequency [1,3] are (1) pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma, (2) diffuse large B-cell lymphoma, and (3) lymphomatoid granulomatosis (LG).

We review the kinds of lymphoproliferative disorder that the pneumologist may encounter and that require specific attention, although they may extend beyond this definition. Indeed, nodular lymphoid hyperplasia (NLH) and multicentric Castleman disease (MCD) are not clonal disorders, and primary effusion lymphoma (PEL) does not affect the lung but will be discussed here - but not diffuse large B-cell lymphoma. Each of these lymphoproliferative disorders clinically presents in different ways and is associated with a distinct histological subtype and a specific therapy (Table 1).

Table 1

Typical presentation of some lymphoproliferative disorders of the lung

Typical presentation of some lymphoproliferative disorders of the lung
Typical presentation of some lymphoproliferative disorders of the lung

Mucosa-Associated Lymphoid Tissue

MALT is a lymphoid tissue that functions to defend the mucosa [1]. Functional B lymphocytes of MALT are memory B cells, involved in immune responses. MALT is physiologically absent from the lung and initially recognized in lungs with infections of an undetermined nature [1]. MALT can also be associated with autoimmune disorders such as Sjögren syndrome.

MALT lymphoma belongs to the group of marginal-zone B-cell lymphomas that also include nodal and splenic marginal-zone lymphomas. However, these three subtypes present distinct clinical, morphological, and molecular features [4,5,6,7,8]. In all, 8% of adults with non- Hodgkin lymphoma have MALT lymphoma [9]. MALT lymphoma usually develops from tissues typically devoid of MALT, such as the stomach, salivary glands, lungs, and thyroid. The stomach is the most commonly affected organ, and several features of stomach MALT lymphoma have been extrapolated to other locations such as the lungs.

Etiology

MALT lymphoma may be considered a model of lymphoma driven by chronic antigen stimulation, whether from autoantigens or a microbial origin [10]. However, an infectious agent does not infect or directly transform the lymphoid cells, unlike in lymphomas associated with Human herpesvirus 8 (HHV8) infection (see below) [11]. In MALT lymphoma, the infectious agent increases the risk of lymphoma by chronically stimulating B lymphocytes.

For instance, MALT develops in the stomach with Helicobacter pylori infection that can later transform to lymphoma. H. pylori was formerly detected in 90% of gastric MALT lymphoma cases, and its eradication was associated with complete remission of the disease in 60-80% of cases of gastric MALT lymphoma [12,13]. The increased use of antibiotics and proton pump inhibitors may have increased the rate of H. pylori-negative gastric MALT lymphoma to 50% [14].

Other infectious agents have been suggested as possible causes of MALT lymphoma at other sites [10,15,16]. A causal relationship has been suggested between Campylobacter jejuni infection and small-intestine MALT lymphoma and between Hepatitis C virus infection and some cases of splenic marginal-zone lymphoma. Several studies have also found associations but no proven causal relationship between Borrelia burgdorferi infection and skin MALT lymphoma and between Chlamydophila psittaci infection and ocular adnexal MALT lymphoma.

A causative antigen associated with MALT lymphoma in the lungs has yet to be found. Several studies of pulmonary MALT lymphoma used PCR to detect DNA from Chlamydiaceae, Mycoplasma, or Mycobacterium infection, or a 16S ribosomal RNA-based approach, but the results remained inconclusive [17,18,19]. In one study, Chlamydiaceae DNA was detected more frequently in MALT than in control tissue, although the difference was not statistically significant. In another study, no mycobacterial DNA was detected. A third study detected DNA from Achromobacter xylosoxidans in 57/124 cases of pulmonary MALT lymphoma versus 15/82 controls (p = 0.004) but with no proven causal relationship. Powerful tools developed for analyzing all DNA and RNA present in a given sample [20] could provide evidence for the presence of an unsuspected pathogen in pulmonary MALT lymphoma [21].

Chronic antigen stimulation may also have an autoimmune origin, particularly in the salivary and thyroid glands. A meta-analysis of 29,423 patients showed patients with Sjögren syndrome or systemic lupus erythematosus with an increased risk of marginal-zone lymphoma [22]. Indeed, patients with Sjögren syndrome showed a 6.5-fold increased risk of any type of lymphoma and a 1,000-fold increased risk of salivary gland MALT lymphoma.

Environmental risk factors have not been evidenced in pulmonary MALT lymphoma, although bakers and oil workers have shown increased risks of ocular adnexal and cutaneous MALT lymphoma, respectively [23].

Epidemiology, Clinical Tests, and Imaging

Pulmonary MALT lymphoma, although rare, represents almost 80% of primary pulmonary lymphoma cases [24,25,26]. The disease usually occurs at an age of 50-60 years, very occasionally affecting those under 30 years old [27]. Smoking rates (approx. 35%) are not higher among people with pulmonary MALT lymphoma than in the general population, and women are affected as often as men [26]. Up to 16% of patients present features of autoimmune disease [26].

In nearly half of MALT lymphoma cases, patients are asymptomatic at diagnosis, and investigations are initiated after abnormal findings on chest X-ray or CT. When present, symptoms are nonspecific, including cough, dyspnea, and chest pain. Crepitant rales are detected by pulmonary auscultation in less than 20% of cases. General symptoms such as fever and weight loss are particularly associated with aggressive disease forms [27].

On radiography, MALT lymphoma typically presents as a chronic alveolar localized opacity less than 5 cm in diameter, and is associated with air bronchograms in nearly 50% of cases [28,29,30,31,32]. CT (Fig. 1) most frequently shows bilateral and multiple lesions (in 60-77% of cases) and an intact bronchial lumen in the lesions [33,34]. Less than 10% of cases show diffuse reticulonodular opacities, atelectasis, pleural effusion, or hilar or mediastinal lymphadenopathy [28,29,30]. The time between the initial abnormal clinical or radiological findings and diagnosis varies from 15 days to 8 years (mean 9 months) [26,28,29,30,31].

Fig. 1

Representative CT scans of pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma with chronic alveolar opacities, all confirmed histologically to be MALT lymphoma. a Right upper lobe consolidation with air bronchogram. b Left lower lobe consolidation with air bronchogram. c Multifocal consolidations from the right lower lobe and the middle lobe with air bronchogram (the bronchi are distended within the lesions); reticulonodular opacities from the left lower lobe and the left upper lobe. d Middle lobe ground-glass opacity with a solid component.

Fig. 1

Representative CT scans of pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma with chronic alveolar opacities, all confirmed histologically to be MALT lymphoma. a Right upper lobe consolidation with air bronchogram. b Left lower lobe consolidation with air bronchogram. c Multifocal consolidations from the right lower lobe and the middle lobe with air bronchogram (the bronchi are distended within the lesions); reticulonodular opacities from the left lower lobe and the left upper lobe. d Middle lobe ground-glass opacity with a solid component.

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Initial staging includes CT scanning of the chest, abdomen, and pelvis, with contrast injection. Bone marrow biopsy is not mandatory but may show MALT lymphoma dissemination in 13-30% of cases [5,26,35,36,37]. Similarly, concomitant disease in other sites, such as the stomach, is present in 25-35% of cases and justifies gastroscopy [36,37,38]. Other mucosal sites that must be assessed in symptomatic patients include the eyes, ears, nose, and throat by MRI or ultrasonography, and the small bowel by camera capsule. The sensitivity and specificity of positron emission tomography (PET) varies depending on the organ involved. The sensitivity in the stomach is 50-89%, versus 80-100% in the lung, and is very weak in bone marrow [26,39,40,41,42].

The lactate dehydrogenase (LDH) level is usually normal. The β2-microglobulin level may be an independent prognostic factor [36]. Monoclonal gammopathy is found in 20-60% of cases, more frequently with plasmacytic differentiation and disseminated disease [26,28,30,31,32].

Diagnostic Strategy

Tissue biopsy, the gold standard for diagnosis, may be achieved with bronchoscopy or CT-guided needle biopsy. Macroscopic findings of bronchoscopy are usually normal, although abnormalities such as inflammatory mucosa and bronchial stenosis may be observed [28]. Polypoid endobronchial lesions are rare and usually evoke small-cell non-Hodgkin lymphoma. Bronchial and transbronchial biopsies are more fruitful when performed on endobronchial lesions or guided by CT [28]. The sensitivity of bronchial and transbronchial biopsies in detecting MALT lymphoma was reported to be 31 and 88%, respectively [26].

Bronchoalveolar lavage (BAL) performed during bronchoscopy may also aid in the differential diagnosis of chronic alveolar opacities. This technique can indicate the absence of the tumor epithelial cells found in other malignancies such as lepidic adenocarcinoma or the presence of pathogens pointing to a chronic infection. The presence of lymphocytic alveolitis in BAL fluid can also indicate MALT lymphoma [43]. A B-lymphocyte level >10% and the demonstration of the clonality of lymphocytes or presence of t(11;18)(q21;q21) translocation in BAL fluid could be a powerful diagnostic tool, currently underemployed in clinical practice [28,43,44,45,46,47,48,49,50]. However, a B-cell clone may be absent in BAL fluid in up to 29% of cases [51].

The sensitivity of CT-guided percutaneous biopsies has been reported to be 80% [26]. MALT lymphoma has anecdotally been diagnosed on endobronchial ultrasonography in experienced hands, with flow cytometry performed on samples [52].

Cryobiopsy could be discussed by experienced teams before diagnostic surgery is performed as a last resort [53]. However, with a localized lesion, surgery provides the opportunity for ultimate treatment performed at the same time as the biopsy.

Diagnosis

MALT lymphoma is characterized by a lymphoid infiltrate composed of small cells with variable cytologic appearance, including small round lymphocytes, centrocyte-like cells, or monocytoid cells. The tumor cells infiltrate the bronchiolar or alveolar epithelium, thereby causing lymphoepithelial lesions [25,29,54,55,56]. Cohesive sheets of large B cells must suggest the diagnosis of diffuse large B-cell lymphoma.

Plasma cells may be numerous with or without light-chain restriction (κ or λ). The density of infiltration often produces a widening of the alveolar walls and a collapse of the residual alveolar lumen. The airways are often left intact, which agrees with air bronchograms seen on CT. Amyloid deposits, granulomatous reactions, vascular invasion, or fibrosis may be evidenced [56,57,58,59,60].

Immunohistochemistry excludes reactive follicular hyperplasia or secondary localization to the lung with other lymphomas. Tumor cells express B-cell antigens (CD20 and CD79a) but not CD5, a marker of mantle cell lymphoma or chronic lymphocytic leukemia (Fig. 2) [25,29,31,32,54,55,56,57,61]. Residual lymphoid follicles (CD21/CD23-positive) and small reactive T lymphocytes (CD3) may be seen [55,57]. The proliferative index is usually low (Ki-67 <10%). Analysis of B-cell clonality is helpful but not sufficient to establish the diagnosis.

Fig. 2

Representative histology of pulmonary mucosa-associated lymphoid tissue lymphoma with positive CD20 staining (a) and cytokeratin staining in epithelial cells to highlight the lymphoepithelial lesions (b). Courtesy of Dr. Claire Danel, Hôpital Bichat, Paris, France.

Fig. 2

Representative histology of pulmonary mucosa-associated lymphoid tissue lymphoma with positive CD20 staining (a) and cytokeratin staining in epithelial cells to highlight the lymphoepithelial lesions (b). Courtesy of Dr. Claire Danel, Hôpital Bichat, Paris, France.

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The main histological differential diagnoses are NLH and lymphocytic interstitial pneumonia, follicular bronchiolitis, chronic aspecific inflammatory reaction, and other low-grade B-cell lymphomas [56,62]. The presence of an intraepithelial CD20/CD43-positive lymphocytic infiltrate is a strong indicator of MALT lymphoma [56]. Molecular analysis is useful to differentiate reactive conditions from lymphoma.

Lymphoid interstitial pneumonia is a benign lymphoproliferative disorder characterized by diffuse infiltration of the alveolar septa by dense collections of lymphocytes mixed with plasma cells and other cellular elements. The most frequent CT pattern is cysts associated with ground-glass infiltrates. Most cases are associated with connective tissue disorders, especially Sjögren syndrome, AIDS, or primary immunodeficiency.

Cytogenetic Abnormalities

Several cytogenetic abnormalities, although neither related to targeted therapy nor sufficient for diagnosis, have been associated with MALT lymphomas. The frequency and type of cytogenetic abnormalities may vary depending on the lymphoma site.

The most common cytogenetic abnormality is t(11;18)(q21;q21) translocation [63]. This translocation results in the production of a chimeric protein, API2-MALT1; it is detected in approximately 40% of pulmonary cases, about 20% of gastric cases, and circa 15% of intestinal cases, but is absent in most cases of thyroid, salivary gland, and liver MALT lymphoma [64,65]. In gastric MALT lymphoma, the presence of t(11;18)(q21;q21) translocation is associated with nodal dissemination and resistance to H. pylori antibiotics.

Other, rarer translocations or cytogenetic abnormalities include t(1;14)(p22;q32) (IGH-BCL10), t(14;18)(q32;q21) (IGH-MALT1), t(3;14)(p14.1;q32) (FOXP1-IGH), and trisomy 3 and 18 [63,64]. Most of these translocations result in the constitutive activation of the NF-κB signaling pathway, which may be specifically targeted. The translocations can be detected by an interphase fluorescence in situ hybridization assay of formalin-fixed paraffin-embedded tissue or RT-PCR of frozen tumor samples [63].

Finally, MALT lymphoma could develop as a result of both cytogenetic abnormalities and antigenic stimulation. Illustrating this point, a mouse genetically modified to overexpress API2-MALT1 showed lymphoma only after antigenic stimulation [66,67,68].

Treatment and Prognosis

Recent recommendations for gastric MALT lymphoma have been reported [69,70]. Because no microorganism is identified in the lung, therapeutic options are surgery, chemotherapy, immunotherapy, radiotherapy, or “watch and wait” [71]. In localized lesions, surgical resection or radiotherapy may be considered; radiotherapy is associated with lower morbidity than is surgery [28,30,72,73,74].

In other cases, chemotherapy is preferred. Treatment with single-agent chemotherapy (chloraminophene or fludarabine) is not less preferred than multiple-agent chemotherapy (cyclophosphamide, adriamycin, vincristine, and prednisone; CHOP) [26,28]. Rituximab alone is effective, with a 70% response rate, but associated with a 36% disease recurrence [75].

The first double-blind, phase III study of MALT lymphoma included 231 patients and compared chlorambucil to rituximab-chlorambucil [76]. The 5-year event-free survival was better with double therapy than with monotherapy (68 vs. 50%, p = 0.02) (Fig. 3). Double therapy increased the complete response rate (78 vs. 65%) [76]. However, the 5-year overall survival (89%) was not improved, and grade 3-4 neutropenia was more common with double therapy than with monotherapy. Rituximab alone was also evaluated and the results are still expected.

Fig. 3

Event free survival (a) and overall survival (b) in the IELSG randomized study: chlorambucil versus chlorambucil + rituximab in extranodal marginal-zone lymphoma [76]. The 5-year event-free survival was better with double therapy; however, the 5-year overall survival was not improved.

Fig. 3

Event free survival (a) and overall survival (b) in the IELSG randomized study: chlorambucil versus chlorambucil + rituximab in extranodal marginal-zone lymphoma [76]. The 5-year event-free survival was better with double therapy; however, the 5-year overall survival was not improved.

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In a retrospective cohort of gastric MALT lymphoma cases, rituximab-chloraminophene was more efficient than rituximab alone in t(11;18)-positive patients, and rituximab alone was as efficient as double therapy in t(11;18)-negative patients [77,78].

Numerous currently available therapies have had antitumoral effects, such as purine analogues (fludarabine and cladribine), pentostatin, NF-κB inhibitors (bortezomib), or a combination of mitoxantrone and bendamustine [70,79,80,81,82,83,84,85]. However, the respective value of each treatment is difficult to estimate [86]. Moreover, numerous phase II/III studies of marginal-zone lymphoma are evaluating compounds currently developed for other lymphomas (anti-btk, anti-CD20 antibody, etc.) [87].

The prognosis with MALT lymphomas is good, with 5-year overall survival >80% and a median survival of >10 years [25,26,28,29,30,31,32,36,37,38,54,59,88]. A long period of monitoring is required, even after surgical resection, because almost 50% of patients show recurrence, either at the same location or outside the thoracic region [28,32,54,59,61].

None of the following factors are associated with prognosis: gender, delay to diagnosis, symptoms, bilateral or unilateral lesions, or extrapulmonary involvement [26]. With a multivariate analysis including all localizations of MALT lymphoma, predictors of prognosis were an elevated β2-microglobulin level and stage IV classification according to the Ann Arbor system [36,89].

Very recently, Thieblemont et al. [90] proposed a simple classification including age >70 years, Ann Arbor stage >2, and elevated LDH level. In a cohort of 393 patients, the addition of these three factors discriminated three risk groups with different 5-year progression-free survival rates (78, 63, and 29%; p < 0.001) and 5-year overall survival rates (99, 92, and 74%; p < 0.001).

Definition

NLH is a rare disease characterized by a nonclonal lymphoproliferation that usually forms a single nodule or, more rarely, multiple pulmonary nodules.

Clinical Presentation and Complementary Examinations

NLH may occur as a solitary lesion in patients without autoimmune disease or immunodeficiency. It may also be associated with combined variable immunodeficiency or, less frequently, with Sjögren syndrome and form a disease called granulomatous-lymphocytic interstitial lung disease that is frequently associated with extrapulmonary localizations [91]. For clarity, only idiopathic NLH is discussed here.

There is no gender predominance, and the mean age at diagnosis is 60 years (range 18-80) [62,92]. Some patients may present with cough or dyspnea, particularly with tracheal involvement, although the most frequent localization is parenchymal. Indeed, most patients are asymptomatic.

CT reveals a unique 2- to 4-cm nodule in 64% of cases (Fig. 4). One-third of the patients present with multiple nodules, and one-third with lymphadenopathy, hilar or mediastinal [62]. NLH usually does not show FDG uptake on PET scans, although a mild increase in uptake may be seen, particularly with cavitary lesions [93]. Blood tests are not helpful.

Fig. 4

a CT scan of nodular lymphoid hyperplasia from the left lower lobe in the context of granulomatous-lymphocytic interstitial lung disease associated with combined variable immunodeficiency. b, c Lymphoid hyperplasia with lymphoid nodules along bronchioles in common variable immunodeficiency.

Fig. 4

a CT scan of nodular lymphoid hyperplasia from the left lower lobe in the context of granulomatous-lymphocytic interstitial lung disease associated with combined variable immunodeficiency. b, c Lymphoid hyperplasia with lymphoid nodules along bronchioles in common variable immunodeficiency.

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Diagnosis

The diagnosis of NLH is established by histology and requires exclusion of the differential diagnoses, particularly MALT lymphoma [94]. Although the diagnosis may be attempted with transbronchial or transthoracic biopsy, NLH features may also be involved in lung cancer or lymphoma, which cannot be excluded without surgical excision.

The typical histology is follicular hyperplasia, interfollicular plasmacytosis, and a variable degree of fibrosis. Immunohistochemical analysis (of CD3, CD20, etc.) is consistent with a reactive process, without an aberrant lymphocyte phenotype (Fig. 4) [62].

Unlike MALT lymphoma, none of the following features is present: lymphoepithelial lesions, amyloid deposits, B-cell clonality, light-chain restriction, or presence of t(11;14) translocation. NLH and hyper-IgG4 syndrome may coexist. However, in a recent series of 26 cases of NLH retrospectively assessed, none fulfilled the diagnosis of hyper-IgG4 syndrome. Moreover, none showed positive Epstein-Barr virus (EBV)-encoded RNA (EBER) staining [95].

Prognosis and Treatment

The only treatment reported is surgical excision, with excellent prognosis without recurrence. However, Kajiwara et al. [96] reported a case of natural regression. A watch-and-wait policy may be also discussed with this nonclonal disease. Because the disease is not fully understood from an etiological or evolutionary viewpoint, and with the risk of transformation to lymphoma, long-term follow-up is required.

Definition

LG is a rare B lymphoma associated with EBV infection [97]. It is frequent with immunodepression: autoimmune disease, AIDS, or solid-organ transplantation [98]. The prevalence is unknown, and about 600 cases have been reported [99,100,101,102].

Clinical Presentation and Complementary Examinations

The median age at diagnosis is 30-50 years, with a male/female ratio of 2/1 [100]. About 90% of patients are symptomatic, and the symptoms are frequently present for several months: general signs (50%) or respiratory signs (75%) [99].

The lung is involved in 80% of cases [99]. Nodules and a mass with poorly defined margins are frequent patterns seen on CT. Nodules are more frequent along the bronchovascular structures or interlobular septa and in the base (Fig. 5). The nodules may grow, form cavities, or spontaneously disappear [97]. Skin manifestations occur in 30-50% of cases: erythematous plaques, and nodules with predominance on the trunk and extremities [99].

Fig. 5

Representative CT scans of lymphomatoid granulomatosis with nodules or a mass. a Spiculated 6-cm mass from the right upper lobe. b 1.5-cm nodule from the middle lobe associated with interstitial lung disease with diffuse ground-glass opacities. c Multiple nodules of different size with lower lobe predominance. All patients required surgical biopsy for the diagnosis.

Fig. 5

Representative CT scans of lymphomatoid granulomatosis with nodules or a mass. a Spiculated 6-cm mass from the right upper lobe. b 1.5-cm nodule from the middle lobe associated with interstitial lung disease with diffuse ground-glass opacities. c Multiple nodules of different size with lower lobe predominance. All patients required surgical biopsy for the diagnosis.

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Neurological manifestations occur in approximately 30% of cases. Symptoms may vary depending on the localization of the disease: the central or peripheral nervous system (confusion, paraplegia, hemiparesis, and ataxia), cranial nerves (hearing loss, diplopia, and dysarthria), or neurovegetative system (atonic bladder) [103]. MRI reveals multiple focal intraparenchymal lesions with increased signals on FLAIR and T2-weighted MRI images. This pattern may also be seen with neurological involvement of sarcoidosis, lymphoma, or vasculitis. Cerebrospinal fluid analysis may show an increased number of lymphocytes or a heightened protein level [103].

Ear, nose, and throat manifestations occur in 10-30% of cases and may mimic granulomatosis with polyangiitis (formerly Wegener granulomatosis) [104]. Renal involvement occurs in 10-40% of cases, mostly presenting as a mass seen on CT without renal insufficiency or proteinuria [105]. Other manifestations such as enlarged lymph nodes are rare.

Clinical staging requires specialized neurological and cutaneous evaluation, and radiological staging requires brain MRI and PET. PET may reveal renal, skin, nodal, and pulmonary involvement and may be used to evaluate response to therapy [106].

The complete blood count is normal in more than 50% of cases, although lymphopenia or hyperleukocytosis may be seen [97,100]. Half of the cases present polyclonal hypergammaglobulinemia. EBV serology is positive, and the EBV viral load is increased without specificity, with a mean of 18 copies/106 genome equivalents [97].

Diagnosis

A diagnosis of LG requires histology, most frequently obtained by surgical lung biopsy for lung involvement, because tissues obtained by bronchoscopy rarely allow for a diagnosis. However, a diagnosis may be obtained by skin biopsy or by ear, nose, and throat biopsy [97]. Sampling from all accessible sites is recommended, because tumoral infiltration and EBV staining vary between sites [97].

The distribution of the lesions is patchy and the surrounding lung is almost normal, although fibroblastic foci may be seen at the periphery, as well as organizing pneumonia or edema. The lesions are angiocentric and associated with various degrees of necrosis [97,107]. Contrary to the name of the disease, there is no granuloma, but a polymorphous infiltrate compound of lymphocytes and histiocytes is seen - and, rarely, plasma cells [100].

Most of the small lymphocytes are T cells (CD3/CD4). Atypical large cells and “ghost cells” are lymphoid (CD45) and are highlighted by CD20 immunostaining within the necrotic area. They may present an aberrant phenotype (CD20/CD43) [108]. They are stained on in situ hybridization for EBER, whereas staining for the latent membrane protein of EBV is positive in only 70% of cases (Fig. 6). The B cells are monoclonal, but clonality analysis is not required for the diagnosis, whereas EBER staining is almost mandatory, even if findings may be negative for up to 50% of cutaneous lesions [97,99].

Fig. 6

Representative histology of lymphomatoid granulomatosis with positive CD20 staining (a) and positive Epstein-Barr virus-encoded RNA (EBER) staining (b). Courtesy of Dr. Claire Danel, Hôpital Bichat, Paris, France.

Fig. 6

Representative histology of lymphomatoid granulomatosis with positive CD20 staining (a) and positive Epstein-Barr virus-encoded RNA (EBER) staining (b). Courtesy of Dr. Claire Danel, Hôpital Bichat, Paris, France.

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Finally, LG is histologically classified from grade 1 to grade 3 depending on the number of tumoral cells: grade 1, no large atypical cells, little necrosis, rare EBV-positive cells; grade 2, occasional large atypical cells, moderate necrosis, 5-20 EBV-positive cells/field; and grade 3, predominant population of large atypical cells that may be confluent and associated with extensive necrosis [109]. Indeed, atypical large lymphoid cells may be difficult to detect in low-grade lesions without specific immunostaining.

An infectious disease must be excluded particularly in localized diseases. Differentiating LG from granulomatosis with polyangiitis and necrotizing sarcoidosis may be difficult. Hodgkin lymphoma and other aggressive lymphomas also must be excluded.

Treatment and Prognosis

The median survival is 4 years. Causes of death in order of frequency are respiratory insufficiency (38-88%), hemoptysis (44-89%), neurological complications (7-31%), and infection (23-38%) [97,100,107].

Factors for good prognosis are older age, no symptoms, and unilateral lung involvement, and those for poor prognosis are age <25 years, neurological involvement, hepatosplenomegaly, leukopenia, persistent fever, and, histologically, the number of tumoral cells and amount of necrosis [97,100,107].

No therapeutic recommendations or clinical trials have been reported. Localized LG has been successfully treated with surgery or radiotherapy [110]. Steroids, rituximab, and polychemotherapy are frequently prescribed, but rituximab is inconsistently effective [111,112]. A striking response to interferon-α was reported [113]. Autologous or allogeneic stem cell transplantation may be considered [114]. Spontaneous regression may be observed, particularly with grade 1 LG. The prognosis for patients not in remission is poor [100].

Human Herpesvirus 8

HHV8 was discovered in 1994 in Kaposi sarcoma lesions and was later associated with MCD and PEL [115,116,117,118]. Pulmonary manifestations of HHV8 infection occur almost exclusively in immunocompromised patients, mostly during HIV infection, and very rarely in older patients or during immunosuppressive therapy [119,120].

HHV8 has two modes of viral replication. During the latent phase, HHV8 persists in infected cells without detectable replication in the blood [121]. During the lytic phase, replication may be detected in the blood, and viral genes such as viral interleukin-6, are expressed. Most of the clinical effects of MCD are secondary to the presence of viral cytokines such as viral interleukin-6 [122,123,124].

The reservoir of HHV8 is strictly human. The prevalence is almost 50% in sub-Saharan Africa, 30% in Sicily, and <1% in Northern Europe and Asia [125]. In low-prevalence countries, HHV8 transmission is mostly sexual, essentially in populations with high-risk sexual behavior, with a high frequency of HIV and HHV8 coinfection [125,126]. In high-prevalence countries, the prevalence increases during childhood, and transmission occurs probably mostly through saliva [127,128]. Primary HHV8 infection is asymptomatic or results in nonspecific signs of infection and is rarely diagnosed [129].

Definition

The definition of MCD is histological: angiofollicular lymph node hyperplasia. The most frequent form is localized, occurs in nonimmunocompromised patients, and is not associated with HHV8 infection [130]. Localized MCD may take the form of a single mediastinal node (Fig. 7). As developed below, HHV8-associated MCD is clinically and histologically different from classic hyaline-vascular or plasma-cell-type MCD [116,131].

Fig. 7

a Chest CT scan of multicentric Castleman disease (MCD) with 3-cm mediastinal (zones 4R and 7) lymphadenopathies. b Positron emission tomography CT scan of MCD with multiple peripheral and mediastinal adenopathies with FDG uptake.

Fig. 7

a Chest CT scan of multicentric Castleman disease (MCD) with 3-cm mediastinal (zones 4R and 7) lymphadenopathies. b Positron emission tomography CT scan of MCD with multiple peripheral and mediastinal adenopathies with FDG uptake.

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MCD is rare. The largest series reported were 173 patients with MCD-associated HIV infection in France, whereas approximately 150,000 patients are living with HIV infection in France [131,132,133].

Clinical Presentation and Complementary Examinations

The initial presentation of MCD may suggest lymphoma with fever, polyadenopathy, and hepatosplenomegaly. Questioning may reveal previous flares that spontaneously resolved and remained without diagnosis.

Cutaneous or mucosal localization of Kaposi sarcoma may be present in up to 75% of cases [134]. Cough, dyspnea, and expectoration are present in 33-75% of cases, but hemoptysis is rare. Nasal obstruction is frequent. Pulmonary auscultation may show crackles [132,134,135].

When respiratory symptoms are present, chest X-ray shows bilateral interstitial and alveolar opacities. A small pleural effusion may be present. Chest CT reveals reticular and micronodular opacities with lymphatic distribution: subpleural, peribronchovascular, or septal. Nodular or ground-glass opacities may be present. CT reveals 1- to 3-cm mediastinal lymphadenopathies. CT findings return to normal with resolution of the flare (Fig. 7) [136].

Almost always, the C-reactive protein level is >200 mg/L and anemia occurs [137]. Liver enzyme and creatinine levels may be increased. Renal insufficiency may be related to autoimmune thrombotic thrombocytopenic purpura [138,139]. In about 50% of cases, protein electrophoresis shows polyclonal hypergammaglobulinemia and hypoalbuminemia. Autoantibodies are present in 30% of cases: antiglobulin or anticardiolipin, antiphospholipid, or anti-ADAMTS13 antibodies [139]. CD4 counts are generally <350/mm3.

The viral HHV8 load as assessed by PCR is usually between 2 and 4 log copies/105 peripheral blood mononuclear cells, and thus HHV8 serology is not helpful [140]. HHV8 PCR has a good negative-predictive value [121,137]. A high HHV8 viral load may predict an MCD flare, whereas PCR results are often negative for patients in remission [121,141,142].

Diagnosis

MCD is usually diagnosed by lymph node biopsy [143]. Histology shows follicular hyperplasia, hyalinization, and involution of germinal centers and hyperplasia of the mantle zone with concentric rings of lymphocytes called “onion skin” layers. Vascularity is increased, with capillary proliferation and endothelial hyperplasia. Sheets of plasma cells are present in interfollicular areas. The results of only one surgical lung biopsy have been reported, and they showed lesions similar to those in lymph nodes [136].

HHV8-infected cells, dispersed in the mantle zone, are detected by immunohistochemistry with latent nuclear antigen antibody [144,145]. HHV8-infected cells are not infected with EBV and are not stained with EBER. Kaposi sarcoma and MCD lesions may coexist in the same lymph node in almost two-thirds of cases [146].

HHV-8 infected cells are polyclonal, although the characterization of surface immunoglobulin shows only IgMλ B cells [147]. B cells may group in a sheet of monoclonal cells called microlymphoma; however, the consequences of this observation remain to be determined [145].

The main differential diagnoses are tuberculosis and lymphomas, which both require a histological diagnosis. With a high HHV8 viral load, HHV8-related disease is likely and non-HHV8-related disease is unlikely. However, an unusual evolution during therapy should suggest reconsidering the diagnosis in the absence of histological proof. During HIV infection, pulmonary manifestations of MCD should exclude infections that justify bronchoscopy with BAL fluid analysis [135]. Pleural effusion may be secondary to MCD-associated hemophagocytosis but also Kaposi sarcoma or PEL, which must be excluded by pleural fluid analysis.

A syndrome called “thrombocytopenia, anasarca including pleural effusion and ascites, fever, renal insufficiency, and organomegaly” (TAFRO) has recently been defined in Japanese patients [148]. This syndrome resembles MCD without HHV8 infection but responds to corticosteroids and tocilizumab.

Prognosis and Treatment

Median survival was reported to be <1 year and mortality 47% [134,149]. The main reported causes of death are infections (24%), multiple organ dysfunctions (15%), non-Hodgkin lymphomas (15%), and MCD (9%). More recent series reported >75% 5-year survival partially due to the introduction of combined active antiretroviral therapy [134,149,150]. Although not demonstrated, delayed MCD diagnosis is probably associated with poor prognosis [134].

The risk of lymphoma, mostly related to HHV8, was previously found to be 10- to 20-fold increased with MCD [150]. This risk has been greatly reduced with the expanded use of rituximab and antiretroviral therapies [151].

MCD flares may spontaneously resolve, but they are likely to recur and be life-threatening without a specific therapy. Therapeutic recommendations rely on only expert opinions that propose treating (1) the HIV infection, (2) the lymphoid proliferation, and (3) the HHV8 infection [143,152].

Although active against HHV8 infection in vitro, cidofovir alone has no effect on MCD. A retrospective series showed transient remission with high-dose zidovudine and valganciclovir, but only 23% long-term responders [153,154].

MCD does not exhibit monoclonal lymphoid proliferation but is aggressive and lethal. The evidence supports the use of chemotherapy. Chemotherapy is urgent and induces rapid remission. Indeed, in a retrospective analysis of patients with hemophagocytosis in an intensive care unit, MCD diagnosis was associated with good prognosis [155]. Remission of MCD symptoms is achieved at about 24-48 h with intravenous etoposide. Etoposide may be given orally and once a week thereafter. Corticosteroids may have a partial effect on MCD flares, but they are associated with worsening of Kaposi sarcoma lesions and are not recommended [143].

However, long-term therapy with etoposide is associated with an increased risk of myelodysplasia, and alternative long-term treatment should be considered [134,156,157]. Although not effective as first-line therapy, rituximab led to prolonged MCD remission in almost 80% of cases [143,149,158,159,160,161]. With rituximab, 5-year overall survival may be >90% [149]. However, Kaposi sarcoma worsens after rituximab injection in almost half of the cases. Prolonged remission has also been reported after polychemotherapy with CHOP or equivalent regimes [134,162,163]. Finally, some MCD experts propose etoposide as first-line therapy to control the disease and a maintenance treatment combining ganciclovir, etoposide, and rituximab, along with optimizing antiretroviral therapy [143,152].

Definition

PEL involves the pleura, pericardium, or peritoneum in immunocompromised patients. PEL is distinguished from solid lymphoma with secondary effusion localization [109,117]. However, PEL has also been described in a solid form - called extracavitary PEL - that may occur as a relapse of classic PEL or as an initial presentation [164,165]. PEL is a rare lymphoma corresponding to 0.5% of all lymphoma cases and 1-8% of HIV-associated non-Hodgkin lymphoma cases [165,166,167].

Clinical Presentation and Complementary Examinations

Patients mostly present with fever, altered performance status, and dyspnea [168]. Pleural effusion is present in 85% of cases and is associated with ascites in 50% of cases [169]. PEL may also provoke a specific pericardial localization with a risk of secondary cardiac tamponade [168]. Hepatomegaly and splenomegaly are present in two-thirds of cases [168]. Cutaneous or mucosal localization of Kaposi sarcoma is present in 25-100% of cases, and 9-50% of patients present with concomitant MCD. However, enlarged peripheral lymph nodes are rare. Neurological deficit or a maxillary lesion should lead to suspicion of the specific localization of extracavitary PEL [169].

Anemia is frequent and is associated in 50% of cases with thrombocytopenia and hypoalbuminemia [169]. LDH levels are frequently elevated [168]. The mean CD4 count is 150-200/mm3[168].

Bone marrow biopsy may show hemophagocytosis, but only rarely tumor cells [168,169]. CT reveals pleural effusion without pulmonary lesions or a detectable mass. A small pleural thickening may be present. Pericardial or peritoneal effusion may occur [170]. Pleural fluid analysis, mandatory for a diagnosis, shows serohematic exudative fluid [168].

Diagnosis

Diagnosis is by cytologic examination of the pleural fluid. Pleural biopsy is generally not required or helpful. Cells are polymorphous and large, sometimes immunoblastic, with some plasma cell differentiation and irregular polylobular nuclei (Fig. 8). Cytoplasm is abundant and hyperbasophilic. Mitoses are numerous. Cells generally do not express B-cell markers (CD19 or CD20) or T-cell markers (CD3) but do express CD45, which confirms the lymphoid origin, and may express aberrant T-cell markers such as intracytoplasmic CD3 or CD4. They may coexpress activation markers (CD30, CD38, CD71, or MUM1) and plasma cell markers (CD138) [171,172]. The B cells are monoclonal, but clonality analysis is not helpful for the diagnosis [173].

Fig. 8

Cytology of a primary effusion lymphoma confirmed by latent nuclear antigen staining and human herpesvirus 8 PCR. Courtesy of Dr. Claire Danel, Hôpital Bichat, Paris, France.

Fig. 8

Cytology of a primary effusion lymphoma confirmed by latent nuclear antigen staining and human herpesvirus 8 PCR. Courtesy of Dr. Claire Danel, Hôpital Bichat, Paris, France.

Close modal

In contrast, HHV8 infection must be confirmed by immunohistochemistry with latent nuclear antigen staining on tumor cells or PCR evaluation of the viral load in pleural fluid. In blood, the HHV8 viral load is generally >4 log copies/105 peripheral blood mononuclear cells, and there is a 3:4 log ratio between pleura and blood [121,140].

In 70% of cases, tumor cells are coinfected with EBV. However, immunostaining with latent membrane protein is negative, whereas EBER staining or PCR analysis of the pleural fluid is positive [169]. Cytogenetic analysis shows a complex karyotype without common or recurrent chromosomal abnormality [174].

Detection of HHV8 is helpful to differentiate PEL from other lymphomas [175,176]. Pleural effusion with fever in an immunocompromised patient is more often secondary to Kaposi sarcoma or an infectious disease such as tuberculosis than due to PEL. In these cases, pleural fluid analysis does not reveal tumor cells, and HHV8 PCR findings in pleural fluid are negative or weak.

Prognosis and Treatment

No recommended therapy for PEL exists. Median survival is <1 year, with a 39% 1-year survival [169]. Absence of antiretroviral therapy at diagnosis is associated with poor prognosis, and optimized antiretroviral therapy alone can have antitumoral activity and may lead to remission [169,177]. The number and type of involved cavities could be associated with median survival [178]. However, a retrospective single-center study did not find any statistical difference between patients with involvement of only one cavity and those with involvement of more than one cavity [165]. LDH level and CD4 positivity may be prognostic factors [179].

Polychemotherapy such as CHOP with or without methotrexate is most often prescribed. Although associated with high morbidity, the treatment may result in complete remission in up to 61% of cases [169,180]. Rituximab should not be prescribed, because tumor cells do not express CD20 and rituximab increases the immunodeficiency. Bortezomib has been investigated, and rapamycin, anti-vascular endothelial growth factor therapy, or interferon has been found to be effective in anecdotal cases [169,181,182]. Pleurodesis with talc or intrapleural cidofovir may be discussed in palliative situations [183,184].

In lymphoproliferative disorders, lung involvement can be widespread, is varied, and may be of concern to lung specialists. Unfortunately, the rarity of these diseases frequently leads to delays in diagnosis or unnecessary examinations. The first step always is to make an assessment of the background: whether or not immunodeficiency is involved, and whether or not it is an autoimmune disease. The second step is to evaluate the presence of general signs that then require a rapid diagnosis. However, minimally invasive procedures (such as pleural fluid analysis and transbronchial biopsy) with specialized and oriented analysis (immunohistochemistry and molecular biological techniques) most frequently allow for a diagnosis. Finally, there are neither clinical trials nor recommendations on pulmonary lymphoproliferative disorders, and treatment is based on expert opinion, which justifies seeking advice from a specialized center.

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