Pulmonary lymphomatoid granulomatosis

INTRODUCTION — Pulmonary lymphomatoid granulomatosis (PLG) is an uncommon Epstein-Barr virus-associated lymphoproliferative disorder characterized by multiple pulmonary nodular lesions with lymphocytic invasion of vascular walls on biopsy [1-6]. The clinical implications of this lesion have been controversial, as evidenced by a long list of competing synonyms including angiocentric immunoproliferative lesion and angiocentric lymphoma [7-9].

Pulmonary lymphomatoid granulomatosis will be reviewed here. Clinical aspects of other pulmonary lymphocytic and lymphoproliferative disorders are discussed separately. (See "Lymphoid interstitial pneumonia" and "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)" and "Clinical manifestations, pathologic features, and diagnosis of peripheral T cell lymphoma, not otherwise specified" and "HHV-8/KSHV-associated multicentric Castleman disease".)

EPIDEMIOLOGY — PLG generally presents between the ages of 30 and 50, although patients can be affected at any age [9-16]. It is predominantly seen in men, with an estimated male to female ratio of at least 2:1 [2,17]. The effects of race and geography on disease incidence are not known, although a higher diagnosis rate is reported in Western countries [2].

PATHOGENESIS AND RISK FACTORS — PLG is associated with Epstein-Barr virus (EBV) infection in most if not all cases [2,3], in that “negative” cases may reflect grade 1 disease with infrequent EBV-positive cells that were not detected [18-20]. (See 'EBV in situ hybridization and grading' below and "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Lymphomatoid granulomatosis'.)

Patients with an underlying immunodeficiency (eg, Wiskott-Aldrich, X-linked severe combined immunodeficiency [SCID], immunosuppression post allogeneic organ transplantation, dedicator of cytokinesis 8 [DOCK8] deficiency, HIV infection) or a lymphoproliferative disorder are at increased risk of developing PLG [2,10,11,21-25]. These immune defects may lead to an abnormal host response to EBV infection, resulting in lymphomatoid granulomatosis rather than clearance of the viral infection [2,7].

PLG may develop as a consequence of the immunosuppression induced by certain medications. Rare cases of PLG have been reported in patients being treated with azathioprine, methotrexate, and imatinib with resolution sometimes following cessation of the medication [26-34].

CLINICAL PRESENTATION — The lung is the most commonly involved organ (>90 percent) [2]. The skin (20 to 50 percent), kidney (15 to 32 percent), neurologic system (20 to 38 percent), and liver (12 to 19 percent) may be affected concurrently or independently [2,10,23]. Less commonly, patients have involvement of other organ systems, such as the eyes, hard palate, gastrointestinal tract, and genitourinary tract [2,7,10,35-38]. Involvement of the spleen and lymph nodes is rare [2,23]. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Lymphomatoid granulomatosis'.)

●Symptoms – The most common presenting symptoms are cough (60 percent of patients), fever (60 percent), rash/nodules (40 percent), malaise (35 percent), weight loss (35 percent), neurologic abnormalities (30 percent), dyspnea (30 percent), and chest pain (15 percent) [10]. Rarely, patients are asymptomatic.

●Physical examination – Physical examination of the lungs is generally normal, although basilar crackles have been reported [39].

Extrapulmonary involvement may be more readily apparent, as examination of the skin can reveal single or multiple, pink-to-purple, dermal or subcutaneous nodules with or without ulceration [40]. Plaque-like skin changes are also described. The skin lesions are generally painless, but can occasionally be tender and pruritic.

Neurologic involvement is often manifested by ataxia, cranial nerve abnormalities (eg, hearing loss, diplopia, dysarthria), peripheral neuropathy, and altered mental status [2,41].

EVALUATION — PLG should be suspected in patients presenting with cough, dyspnea, constitutional symptoms and nodular pulmonary opacities on chest imaging, or, rarely, with asymptomatic pulmonary opacities [2]. Careful skin examination is helpful to identify potential lesions for biopsy. Lymph nodes and spleen are generally not involved.

The general evaluation of a patient with multiple pulmonary nodules is described separately. (See "Diagnostic evaluation of the incidental pulmonary nodule".)

Laboratory studies — Laboratory studies are generally nondiagnostic. Laboratory tests including a complete blood count with white blood cell differential, renal and liver function tests, lactate dehydrogenase (LDH), and urinalysis, should be obtained. Depending on the patient, testing for HIV infection and serum immunoglobulin levels may be appropriate.

In PLG, the complete blood cell count is generally normal with occasional mild leukocytosis or leukopenia [1]. Nonspecific abnormalities in immunoglobulins (usually increases in immunoglobulin G [IgG] and immunoglobulin M [IgM]) are seen in the majority of patients [10,11].

Serologic evidence of previous Epstein-Barr virus (EBV) infection is generally present, although the heterophile test may be negative [10,14]. The serologic evaluation of EBV infection is discussed separately. While not necessary to obtain, the EBV viral load is usually minimally elevated [23]. (See "Infectious mononucleosis", section on 'Diagnosis'.)

In patients with neurologic involvement, lumbar puncture commonly reveals pleocytosis with an elevated protein level [7,42]. (See "Clinical manifestations and treatment of Epstein-Barr virus infection".)

Lung function testing — Pulmonary function tests (PFTs) may be helpful to determine the severity of respiratory impairment, but no characteristic PFT abnormalities have been reported [9]. Hypoxemia and chronic respiratory alkalosis are reported in association with advanced disease [9]. (See "Overview of pulmonary function testing in adults" and "Measures of oxygenation and mechanisms of hypoxemia".)

Imaging studies — Chest radiography typically reveals multiple poorly defined nodules and/or masses in the mid- and lower-lung zones; diffuse reticular abnormalities may also be present [7,9,17,39].

Chest computed tomography (CT) usually shows both well and poorly-defined bilateral lung nodules that are predominantly in the lower lung zones and may wax and wane over time [23,39]. Most lesions are less than 1 cm in diameter, but larger cavitary masses have been reported [2,17,43]. Nodules are preferentially located along the bronchovascular structures or interlobular septa (image 1A-B) [2]. Thin walled cystic lesions may also be present (image 2) [17]. (See "High resolution computed tomography of the lungs" and "Diagnostic evaluation of the incidental pulmonary nodule".)

A few case reports have reported variable uptake of 18F-fluorodeoxyglucose (18F-FDG) on positron emission tomographic (PET) scanning [44-46].

Tissue biopsy — Histopathologic examination of involved tissue is necessary to make a diagnosis. When the lung is the primary site of involvement, lung tissue is usually obtained by video-assisted thoracoscopic surgery or thoracotomy, as transthoracic needle aspirate and transbronchial biopsy samples are often too small for adequate evaluation.

In a large series, the diagnostic biopsy usually came from the lung (73 percent) or skin (17 percent); additional sites included the liver, kidney, nasal cavity, adrenal gland, gastrointestinal tract, and eyelid/conjunctiva [23]. It is important to perform multiple lung biopsies if the patient has multiple lesions and to include sampling of dominant lesions in order to properly ascertain the grade [23].

When present, skin lesions should undergo biopsy for histopathologic and microbiologic studies.

Pathology — An accurate morphologic, immunophenotypic, and genetic analysis of involved tissue is essential for the diagnosis of PLG [6,23].

Morphology — The histopathologic diagnosis of PLG typically manifests as a triad of polymorphic lymphoid infiltrates, transmural infiltration of arteries and veins by lymphoid cells ("angiitis"), and focal areas of necrosis within the lymphoid infiltrates (picture 1A-B) [1,2,23]. These areas of necrosis gave rise to the term "granulomatosis;" however, well-formed granulomas are typically absent in PLG [2]. Skin lesions may have a more prominent granulomatous reaction in subcutaneous tissue.

In the lung, lesions are generally well-circumscribed and composed of small lymphocytes, plasma cells, and a variable number of large atypical mononuclear cells. The majority of the small lymphocytes are T cells, while large atypical cells are usually B cells [47,48]. T cells are polyclonal and represent a "reactive," non-neoplastic population [49]. Variably atypical B cells represent the neoplastic component and show evidence of EBV infection with in situ hybridization [2,5]. Reed-Sternberg cells are not present. (See "Clinical manifestations and treatment of Epstein-Barr virus infection".)

EBV-positive large B-cell lymphoma is differentiated on the basis of a uniform population of large atypical EBV-positive B cells without a polymorphous background. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma".)

Immunophenotype — The EBV positive B cells typically express CD20 and may express CD30 [2]. They are negative for CD15. Larger, atypical, pleomorphic cells may be latent membrane protein 1 (LMP1) positive. Epstein Barr virus nuclear antigen-2 (EBNA2) is frequently positive, consistent with latency type III [23]. The background lymphocytes are CD3 positive T cells with a preponderance expressing CD4 rather than CD8, although the proportions can vary [2,18,23].

EBV in situ hybridization and grading — Three histopathologic grades have been proposed, based upon the proportion of EBV-positive large B lymphocytes, as determined by in situ hybridization for EBV-encoded small RNA (EBER) [2,7,50]. It is important to differentiate between low grade (grades 1 and 2) and high grade (grade 3) disease, as high grade disease has a less favorable prognosis and is treated like diffuse large B cell lymphoma (DLBCL) with immunochemotherapy [40]. (See 'Management' below.)

●Grade 1 lesions are either devoid of or contain only scattered EBV-positive cells. It is unclear whether lesions devoid of EBV-positive B cells represent a distinct primary T cell disorder, or an exuberant response to rare (but not visualized) EBV-positive cells [2,4,7].

●Grade 2 lesions contain occasional large lymphoid cells or immunoblasts in a polymorphous background. Clusters of cells positive for CD20 are present, as well as areas of necrosis. In situ hybridization demonstrates approximately 5 to 20 EBV-positive cells per high power field, but in some areas up to 50 EBV-positive cells may be seen.

●Grade 3 lesions have an inflammatory background, but large atypical B cells are easily identified by CD20 staining. Necrosis is typically extensive. In situ hybridization typically demonstrates numerous EBV positive cells (>50 per high power field), although EBV identification by EBER can be less reliable in large areas of necrosis as RNA is poorly preserved. Other methods of identification of EBV may be helpful (eg, EBV nuclear antigen [EBNA2] polymerase chain reaction) [23]. Grade 3 lesions must be differentiated from more conventional forms of DLBCL. Features such as a uniform population of large atypical EBV-positive cells and absence of a polymorphous background are not typical of PLG and favor a diagnosis of EBV-positive DLBCL not otherwise specified [2]. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma".)

Genetic features — There is no single cytogenetic change that is characteristic of PLG. Generally, in grades 2 and 3 disease, B cell monoclonality can be demonstrated with testing of the immunoglobulin genes or Southern blot, whereas B cell clonality is inconsistent in grade 1 disease (possibly due to the relative rarity of EBV-positive cells) [2]. Analysis of the T cell receptor gene shows polyclonality. Oncogene alterations have not been reported [2].

DIAGNOSIS — Since the clinical presentation of PLG is nonspecific, the diagnosis hinges on lung histopathology showing the classic triad (ie, polymorphic lymphoid infiltrates, transmural infiltration of arteries and veins by lymphoid cells, and focal areas of necrosis) and demonstration of Epstein-Barr virus (EBV) positive B cells by in situ hybridization.(See 'Pathology' above.)  

Immunohistochemical analysis that uses antibodies directed against B and T cell-associated antigens is used to determine the proportion and clonality of these cells. In situ hybridization is used to establish the presence and proportion of EBV-positive B cells. The presence of large B cells demonstrating EBV-positive cells by in situ hybridization with the EBV-encoded small RNA (EBER) probe is definitional for PLG [50]. (See 'Pathology' above.)

DIFFERENTIAL DIAGNOSIS — PLG should be distinguished from other lung diseases that present with nodular opacities and lymphocytic infiltration.

●Sarcoidosis – Sarcoidosis is distinguished from PLG by the presence of well-formed granulomas on biopsy. Mediastinal and hilar adenopathy are more common in sarcoidosis than PLG [51]. (See "Clinical manifestations and diagnosis of sarcoidosis".)

●Fungal infection – Coccidioidomycosis and histoplasmosis can present with nodular lung lesions and central nervous system involvement, as can some other fungal infections. Travel history is helpful in identifying patients at risk for coccidioidal and histoplasma infections. Further evaluation with stains, culture, and laboratory tests is discussed separately. (See "Primary pulmonary coccidioidal infection" and "Pathogenesis and clinical features of pulmonary histoplasmosis" and "Diagnosis and treatment of pulmonary histoplasmosis".)

●Lymphoid interstitial pneumonia – Lymphoid interstitial pneumonia (LIP) is a benign polyclonal proliferation, usually of mature B or T lymphocytes, that can either involve the lung diffusely or be a focal process, often associated with a rheumatic disease. Since LIP is a benign disorder, the lymphocytic infiltrate, usually B cells, must be polyclonal. (See "Lymphoid interstitial pneumonia".)

●Immunoglobulin G4 related disease (IgG4-RD) – IgG4-RD can affect multiple organs including the lung. The presenting symptoms overlap with PLG (dyspnea, cough, chest pain). IgG4-RLD often resembles lung cancer in chest images, with imaging findings of nodular solid or ground-glass opacities [52]. While associated lymphadenopathy is common in IgG4-RD, it is uncommon in PLG. Histopathologic features of IgG4-RD include a dense lymphoplasmacytic infiltrate enriched for IgG4-positive plasma cells. (See "Clinical manifestations and diagnosis of IgG4-related disease".)

●Granulomatosis with polyangiitis (GPA) – While prominent vascular infiltration with inflammatory cells and arterial narrowing are noted in PLG, vessel wall necrosis, a feature of GPA, is generally minimal to absent. In addition, multinucleated giant cells are not seen in lymphomatoid granulomatosis, but are often seen in PGA [2]. A positive test for antineutrophil cytoplasmic antibody further supports a diagnosis of GPA. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis".)

●Multicentric Castleman disease (MCD) – MCD is a lymphoproliferative disorder that typically presents with lymphadenopathy in multiple lymph node regions. A spectrum of lung parenchymal findings may be present, including subpleural nodules, interlobular septal thickening, peribronchovascular thickening, ground glass opacities, and patchy, rounded areas of consolidation. In approximately half the patients, MCD is associated with human herpes virus-8 (HHV-8) infection. (See "HHV-8/KSHV-associated multicentric Castleman disease" and "HHV-8-negative/idiopathic multicentric Castleman disease".)

●Epstein Barr virus (EBV)-positive diffuse large B cell lymphoma (DLBCL) – EBV-positive DLBCL, not otherwise specified (NOS), is a clonal B cell lymphoproliferative disorder seen in patients without known immunodeficiency and typically presents with extranodal disease. The diagnosis of EBV-positive DLBCL is made when a uniform population of large, atypical EBV-positive B cells is noted without the polymorphous background population of cells that characterizes PLG [2]. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'EBV-positive DLBCL, NOS'.)

●Extranodal natural killer (NK)/T cell lymphoma – NK/T cell lymphoma, nasal type, is also associated with EBV infection [2]. However, the EBV positive tumor cells in PLG are of B cell origin and thus positive for pan-B cell markers such as CD20; whereas the EBV positive cells in NK/T cell lymphoma are T cells. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal NK/T cell lymphoma, nasal type".)

STAGING — A formal staging system for PLG has not been reported, other than that used for non-Hodgkin lymphomas. However, it is reasonable to assess the extent of disease in the lungs and other organ systems, using careful skin and neurologic examinations, and also thoracic and abdominal computed tomography (CT) scanning. The role of positron emission tomographic (PET) scanning using 18F-fluorodeoxyglucose (18F-FDG) for staging PLG is unclear, and PLG lesions do not always have increased uptake of 18F-FDG [44-46,53,54]. The clinical relevance of such a staging approach is unknown. (See "Pretreatment evaluation and staging of non-Hodgkin lymphomas".)

MANAGEMENT — The choice of a treatment strategy should be based upon the type of underlying immunosuppression (eg, iatrogenic, genetic, acquired), the presence and severity of symptoms, the extent of extrapulmonary involvement, and the histopathologic grade of the lesion [2,6,7,16,23,40,50].

Disease associated with immunosuppressive medication — Patients who have been taking an immunosuppressive medication that is associated with PLG should stop the suspect medication, if at all possible (see 'Pathogenesis and risk factors' above). For those with low grade (grade 1 or 2) disease, observation off therapy with serial (eg, over several weeks to months) clinical examinations and chest computed tomography (CT) is reasonable. [2].

Patients with high grade (grade 3) disease will likely need active therapy for PLG, although resolution of grade 3 disease after methotrexate withdrawal has been described [32].

Among patients with PLG associated with methotrexate therapy, several patients had remission or stabilization of disease with methotrexate discontinuation [32,55-58]. However, disease progression can occur despite cessation of methotrexate and prednisone, as described in a patient with grade 3 PLG and extensive lung disease [59].

In a patient who developed PLG while taking azathioprine and intravenous immune globulin (IVIG), these agents were discontinued and rituximab added for grade 3 PLG with resolution of the lung lesions [60].

Associated with HIV infection — In the setting of HIV infection, resolution of lymphomatoid granulomatosis has been reported after initiation of antiretroviral therapy [61] and after addition of rituximab [62].

Asymptomatic low-grade pulmonary disease — Occasional patients are asymptomatic and have histopathologically low grade (eg, grades 1 and 2) disease confined to the lungs [2]. These patients should be followed with serial clinical and radiologic evaluations, as this group of patients can experience a waxing and waning course, sometimes with spontaneous remission [2,40]. If symptoms develop or radiographic disease shows progression, active therapy is usually indicated. (See 'Symptomatic, extensive, or high-grade disease' below.)

Symptomatic, extensive, or high-grade disease — For patients with symptomatic or extensive disease, grade 3 histology, progressive disease (especially with neurologic involvement), and/or recurrent disease, we recommend treatment with interferon alfa (IFNa) or systemic chemoimmunotherapy, rather than expectant management.

We encourage referral to a hematology-oncology specialist for consultation and enrollment in a clinical trial. Treatment should be individualized, with consideration of disease grade, comorbidities, prior treatment, and patient preference.

No prospective studies have directly compared treatments and there is no consensus. The choice of therapy should be individualized with consideration of the stage and grade of disease, comorbid conditions, and patient preference.

A case series of 67 patients described treatment of low-grade disease with IFNa and high-grade disease with chemoimmunotherapy [63]. Patients with residual or progressive disease after initial therapy crossed over to alternative therapy.

●IFNa was associated with 64 percent overall response rate (ORR; including 61 percent complete response [CR]) and 49 percent five-year progression-free survival (PFS) among 45 patients with low-grade lesions [63]. For eight patients who were treated with IFNa after initial chemoimmunotherapy, ORR was 63 percent (including 50 percent CR). One-half of patients treated with IFNa had grade ≥3 adverse events (primarily neutropenia/leukopenia).

●Treatment of 18 patients with high-grade lesions using R-EPOCH (rituximab, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) was associated with 76 percent ORR (including 47 percent CR) and 63 percent five-year PFS [63]. For patients who crossed over to DA-EPOCH-R, ORR was 67 percent (including 47 percent CR). Among patients treated with R-EPOCH, 88 percent had grade ≥3 neutropenia, and 55 percent had infections.

Treatment with IFNa and R-EPOCH are discussed separately. (See "Essential thrombocythemia: Treatment and prognosis", section on 'Interferon alfa' and "Initial treatment of advanced stage diffuse large B cell lymphoma".)

Clinical trials — Information about clinical trials for PLG is available at clinicaltrials.gov.

PROGNOSIS — The clinical course of lymphomatoid granulomatosis is variable [10,12]. Approximately 20 percent of patients achieve remission without treatment, but the majority of patients experience progressive disease without treatment [7,10,64]. The presence of histopathologic grade 2 or 3 disease and the presence of neurologic disease appear to predict a worse outcome [7,10].

In one study, treatment of grade 1 and 2 disease with interferon (IF) alpha was associated with progression-free survival (PFS) of 56 percent (median follow-up 5.1 years), while treatment of grade 3 disease with immunochemotherapy (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab, DA-EPOCH-R) resulted in PFS of 44 percent (median follow-up 32 months) [23]. In another study of 67 patients who received interferon alfa2b for low-grade disease and DA-EPOCH-R for high-grade disease (median follow-up of 15 years), the median overall survival was 20 years (95% CI 9.8–not estimable), and the 10-year overall survival was 61 percent (95% CI 47–73 percent) [63].

SUMMARY AND RECOMMENDATIONS

●Pathologic description – Pulmonary lymphomatoid granulomatosis (PLG) is an uncommon Epstein-Barr virus-associated B-cell lymphoproliferative disorder characterized by multiple pulmonary nodular lesions with lymphocytic invasion of vascular walls on biopsy. (See 'Introduction' above.)

●Epidemiology – PLG presents between the ages of 30 and 50, although patients can be affected at any age. Men are more commonly affected than women, with an estimated male to female ratio of 2:1. (See 'Epidemiology' above.)

●Clinical presentation

•The lung is the most commonly involved organ; the skin and neurologic system may be affected separately or concurrently. Involvement of other organs occurs, but is less common. (See 'Clinical presentation' above.)

•The most common presenting symptoms and signs include cough, fever, rash/nodules, malaise, weight loss, neurologic abnormalities, dyspnea, and chest pain. Lung examination is typically normal. (See 'Clinical presentation' above.)

•Chest imaging studies typically show multiple ill-defined nodular opacities, predominantly in the lung bases. Lymphadenopathy is typically absent. (See 'Clinical presentation' above.)

●Pathology – The histopathologic diagnosis of PLG typically manifests as a triad of polymorphic lymphoid infiltrates, transmural infiltration of arteries and veins by lymphoid cells ("angiitis"), and focal areas of necrosis within the lymphoid infiltrates (well-formed granulomas are not present) (picture 1A-B). Additional features are the presence of EBV-positive B cells on in situ hybridization studies, polyclonality of T cells, and usually monoclonality of B cells. (See 'Pathology' above.)

●Treatment – The choice of a treatment strategy should be based upon the presence of symptoms, history of using an inciting medication, extent of extrapulmonary involvement, and careful assessment of the histopathologic grade of the lesion. (See 'Management' above.)

•When a medication (eg, azathioprine, methotrexate) is implicated, it should be stopped, if possible, and the patient observed for changes in the extent of disease.

•For asymptomatic patients with low-grade (grades 1 and 2) disease that is confined to the lungs, disease may wax and wane or spontaneously remit, and therefore treatment is not warranted unless the disease progresses. Serial clinical and radiologic evaluations are required during observation.

•For patients with extensive, symptomatic, progressive (especially with neurologic involvement), and/or recurrent disease, we recommend treatment with interferon alfa (IFNa) or systemic chemoimmunotherapy rather than expectant management (Grade 1B). There is no consensus on optimal regimens; we encourage enrollment in a clinical trial. Treatment should be individualized, with consideration of comorbidities, disease grade, and patient preference. (See 'Symptomatic, extensive, or high-grade disease' above.)

●Prognosis – The clinical course of PLG is variable, ranging from indolent to progression to large B cell lymphoma. Improved outcomes have been associated with immunochemotherapy selected based on the histologic grade. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Dr. Harold Collard, who contributed to an earlier version of this topic review.