What every physician needs to know:

Malignant lymphoproliferative disorders encompass a spectrum of disorders with varied clinical, radiographic and pathologic features. Recognition of the distinct diseases is important, as appropriate therapy is dependent upon accurate classification. While usually presenting as a mass or nodule(s), some diseases may mimic interstitial lung disease. Low-grade lymphoma of the bronchus-associated lymphoid tissue (BALT), the most common primary pulmonary lymphoma, follows an indolent course. Exogenous immunosuppression, human immunodeficiency virus (HIV), human herpes virus-8 (HHV-8), and Epstein-Barr virus (EBV) infection are important risk factors for development of pulmonary lymphoma. While many hematologic malignancies may originate in the lung, secondary involvement of the lung is far more common for most leukemias and lymphomas.

Classification:

There are nine primary malignant lymphoproliferative disorders:

Low-grade B-cell lymphoma of BALT

Low-grade B-cell lymphomas of the bronchus-associated lymphoid tissue (BALT) are the pulmonary form of extranodal marginal zone B-cell lymphoma. Primary pulmonary lymphomas, representing less than 1 percent of all non-Hodgkins lymphomas, are uncommon. Among pulmonary lymphomas, low-grade B-cell lymphoma of BALT accounts for two-thirds of primary pulmonary lymphomas. Low-grade lymphomas of BALT, which tend to remain localized for long periods of time, are associated with a good prognosis.

Diffuse large B-cell lymphoma of the lung

Diffuse large B-cell lymphoma (DLBCL) is the most common systemic histologic subtype of non-Hodgkins lymphoma, but it very rarely originates in the lung. Primary lung lymphomas account for less than 1 percent of non-Hodgkins lymphoma, and diffuse large B-cell lymphoma accounts for only 10-20 percent of primary pulmonary lymphomas. In approximately 50 percent of cases, areas of co-existing low-grade B-cell lymphoma of BALT are found. DLBCL is an aggressive disease with survival measured in months without treatment.

Lymphomatoid granulomatosis

Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr-virus-associated lymphoproliferative disease characterized by multiple pulmonary nodules, a high mortality rate, and frequent extrapulmonary manifestations, especially in the skin and the nervous system.

Post-transplant lymphoproliferative disorder

Post-transplant lymphoproliferative disorders (PTLD) encompass a spectrum of lymphoproliferative disease that occurs in the setting of exogenous immunosuppression following solid organ or allogeneic bone marrow transplantation. The clinical spectrum varies from polyclonal lymphoproliferations that are mononucleosis-like to aggressive DLBCL that proceeds rapidly to death without treatment. Most cases are associated with Epstein-Barr virus (EBV) and are B-cell based, though EBV-negative and T-cell disease is well documented. Thoracic presentations most often include one or more pulmonary nodules and/or mediastinal and hilar lymphadenopathy. Decreases in immunosuppression have resulted in remission in some cases, with chemotherapy and/or rituximab used in more aggressive disease.

Primary effusion lymphoma

Primary effusion lymphoma (PEL) is defined as a human herpes virus-8- (HHV-8) associated lymphoma that originates in the pleural, peritoneal, or pericardial space and that has a distinct immunophenotype. PEL accounts for less than 5 percent of HIV-associated lymphomas. Aside from patients with HIV, PEL has also been reported, although rarely, in HIV-negative hosts, typically following organ transplantation. PEL, which is considered an AIDS-defining illness in HIV-infected individuals, has a poor prognosis.

Pyothorax-associated lymphoma

Pyothorax-associated lymphoma is a rare lymphoma that occurs in HIV-negative individuals in the setting of longstanding pleural inflammation. Most cases develop after decades of pleural inflammation, such as after therapeutic pneumothorax for tuberculosis.

Pulmonary involvement by leukemia or lymphoma

Pulmonary involvement by leukemia or lymphoma is comparatively common, ranging from 20-60 percent on autopsy series. The incidence of clinically significant involvement is much lower, occurring in less than 10 percent of patients.

Rare hematologic malignancies presenting in the lung

Rare hematologic malignancies may present in the lung including intravascular lymphoma, primary pulmonary Hodgkin’s disease, anaplastic large-cell lymphoma, extramedullary plasmacytoma, and peripheral T-cell lymphoma. Except for their presentation in the lung, these disorders behave similarly to their counterparts in extrathoracic locations.

Primary pulmonary AIDS-related lymphoma

Non-Hodgkins lymphoma, which is the second most common malignancy, affecting 5-10 percent of HIV-infected patients, is an AIDS-defining illness. The frequency of AIDS-related lymphoma has decreased with the advent of highly active antiretroviral therapy. AIDS-related lymphomas rarely originate in the lung but commonly involve the lung and pleural space secondarily. A primary pulmonary AIDS-related lymphoma is most often a high-grade diffuse large B-cell lymphoma. The risk of AIDS-related lymphoma increases with decreasing CD4 count. Low-grade B-cell lymphoma of BALT, primary effusion lymphoma, and lymphomatoid granulomatosis also occur with increased frequency in patients with HIV infection.

Are you sure your patient has a malignant lymphoproliferative disorder of the lung? What should you expect to find?

Low-grade B-cell lymphoma of BALT

Affected patients are usually 50-70 years old, with disease rarely occurring before age 30. Patients are most often asymptomatic, but they may have non-specific symptoms of cough and dyspnea, and a minority have fever and weight loss. Chest imaging shows one or more areas of air space consolidation or nodules. About a fifth of patients have an associated autoimmune disorder (Sjögren’s syndrome, rheumatoid arthritis, Hashimoto’s thyroiditis).

Diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma occurs in adults with a median age of 61. Symptoms include cough, chest pain, dyspnea, fever, and weight loss. Imaging shows one or more nodules or masses within the lung parenchyma, with or without intrathoracic lymphadenopathy. Diffuse large B-cell lymphoma is associated with HIV infection and autoimmune diseases, but it occurs sporadically and in immunocompetent individuals as well.

Lymphomatoid granulomatosis

Lymphomatoid granulomatosis usually occurs in adults (median age 48), and males are affected more often than females by a ratio of 2:1. Respiratory symptoms include cough, dyspnea, and chest pain. Extrapulmonary symptoms often occur (>40%) because of involvement of the peripheral and central nervous system (30%), the kidney (30%), the skin, and other organs, such as the liver, the adrenals, and the heart. Lymphomatoid granulomatosis is associated with immunodeficiency states, including HIV infection, common variable immune deficiency, hypogammaglobulinemia, and immunosuppressive medications, such as methotrexate. Previous cases reported in transplant patients would now be considered as variants of post-transplant lymphoproliferative disorders.

Post-transplant lymphoproliferative disorder (PTLD)

The diagnosis of PTLD requires histologic evidence of a lymphoproliferative disorder in the post-transplant setting. The clinical presentation of thoracic PTLD is non-specific: patients may have cough, dyspnea, chest pain, or hemoptysis, or they may be asymptomatic. Patients may have disseminated disease at diagnosis, with extranodal involvement of the transplanted organ. The liver, the spleen, and the intestinal tract are the most common sites of involvement. Lung transplant patients are more likely to present with PTLD involving the lung than are other organ transplants.

PTLD is diagnosed a median of 10 months and 50 months post-transplant in EBV-positive and EBV-negative cases, respectively. The incidence varies according to the type of transplant (5-10% in lung transplants to 1% in kidney transplants), the intensity of immunosuppression, the frequency of acute rejections episodes, and pre-transplant EBV status. Lung transplant patients also develop PTLD earlier (median time to onset = 5-7 months).

Primary effusion lymphoma (PEL)

Patients typically present with a pleural, pericardial, or peritoneal effusion without a mass lesion in the setting of AIDS. Lymphadenopathy or organomegaly is usually absent, but spread to distant sites may develop over time. PEL often affects young to middle aged severely immunocompromised patients with HIV infection. There is a strong male predominance. Rarely, PEL occurs in the post-transplant setting without HIV infection.

Pyothorax-associated lymphoma

This disorder develops in patients who have severe, longstanding pleural inflammation. The majority of reported cases occur in patients who are undergoing artificial pneumothorax for pulmonary or pleural tuberculosis. However, pyothorax-associated lymphoma has been reported with other causes of pleural inflammation, such as asbestos-related pleural effusion. Symptoms include chest or back pain (50%), fever (40%), chest wall swelling (40%), cough, dypsnea, and hemoptysis. The disorder predominantly affects males, with a 12:1 male-to-female ratio.

Pulmonary involvement by leukemia/lymphoma

Diagnosis of secondary involvement of the lung by lymphoma or leukemia should be accompanied by careful evaluation for infection and non-infectious immunologic processes, such as drug toxicity and radiation pneumonitis. Clinical symptoms are nonspecific and consist of cough, dyspnea, chest pain, and hemoptysis. The diagnosis of hematologic malignancy usually predates the onset of pulmonary symptoms. Chronic lymphocytic leukemia (CLL) is the most common hematologic malignancy to involve the lung secondarily.

Pulmonary involvement by acute myeloid leukemia leads to several unique clinicopathologic syndromes, including pulmonary leukostasis, tumor lysis pneumonopathy, and hyperleukocytic reaction. Pulmonary leukostasis develops in the setting of acute myelogenous leukemia (AML) when the blast count exceeds 100,000/mm3. Tumor lysis pneumonopathy is characterized by an acute respiratory distress (ARDS)-like syndrome that develops within 48 hours of treatment onset from lysis of blasts within the lung. Hyperleukocytic reaction is characterized by the development of ARDS in association with a rapid increase in the peripheral blast count (greater than 245,000/ul).

Hematologic malignancies rarely presenting in the lung

Hematologic malignancies rarely presenting in the lung include intravascular lymphoma, Hodgkin’s disease, anaplastic large-cell lymphoma, extramedullary plasmacytoma, and peripheral T-cell lymphoma. Primary presentation in the lung, occurring before detectable nodal involvement or involvement at other extranodal sites, is far more unusual than is secondary lung involvement. Symptoms are non-specific and include cough, dyspnea, chest pain, and constitutional symptoms.

Anaplastic large-cell lymphoma, extramedullary plasmacytoma, Hodgkin’s disease, and peripheral T-cell lymphomas typically present with one or more parenchymal nodules or masses. Pulmonary involvement by intravascular lymphoma is unique in that it may mimic interstitial lung disease or present with pulmonary hypertension because of small-vessel occlusive disease.

Primary pulmonary AIDS-related lymphoma

Clinical presentation is as described in the sections for diffuse large B-cell lymphoma. Patients with HIV infection tend to be young to middle-aged. The CD4 count is typically less than 50-100/uL, and most have had previous AIDS-defining illnesses.

What imaging studies will be helpful in making or excluding the diagnosis of a malignant lymphoproliferative disorder of the lung?

Low-grade B-cell lymphoma

Chest X-ray and computed tomography (CT) scan show one or more lung nodules or masses or areas of air space consolidation. Air bronchograms are frequently present. Sixty to seventy percent present with multifocal disease (Figure 1). Rare cases may present with endobronchial or endotracheal nodules or only parenchymal ground glass opacities.

Figure 1.

Low-grade lymphoma of BALT. Chest CT scan shows a nodular density in the right lung (arrow). Air bronchograms are present.

Diffuse large B-cell lymphoma

Chest X-ray and CT scans usually show one or more lung nodules or masses. Diffuse ground-glass opacities have been reported. Pleural effusion and endobronchial disease rarely occur. Endobronchial disease may present as a solitary lesion or as diffuse submucosal disease associated with clinically apparent disease elsewhere (Figure 2).

Figure 2.

Diffuse, large B-cell lymphoma. On CT scan a large, irregular mass-like area of consolidation is present in the posterior portion of the left upper lobe.

Lymphomatoid granulomatosis

Chest CT typically shows a diffuse bilateral nodular infiltrate, but occasional cases consist of a solitary mass. Hilar adenopathy and pleural effusion may occur but are uncommon (Figure 3).

Figure 3.

Lymphomatoid granulomatosis. Chest CT scan showing multiple nodules in the left lung.

Post-transplant lymphoproliferative disorder

When the lung is involved, chest X-ray or CT scan shows one or more nodules with or without hilar and mediastinal adenopathy. Patchy air space disease and pleural effusion have also been reported.

Primary effusion lymphoma

PEL develops in body cavities that include the pleura (60-90% of the time), the peritoneum (30-60%), and the pericardial space (0-30%), as well as, rarely, within the joints and the central nervous system. Consequently, chest imaging may demonstrate pleural effusion(s), pericardial effusion, or ascites. In some cases, the effusion may be accompanied by mild thickening of the serosal lining. Most cases lack an associated mass lesion or adenopathy (Figure 4). However, a small subset of cases may develop associated adjacent solid components.

Figure 4.

Effusion lymphoma. CT scan shows a large pleural effusion in the right lower lobe.

Pyothorax-associated lymphoma

A pleural-based mass may be seen on chest x-ray. Chest CT typically shows a crescentic or lenticular-shaped mass at the margin of the empyema cavity. Extension into the chest wall, ribs, lung parenchyma, or abdomen may occur (Figure 5).

Figure 5.

This patient had longstanding pleural inflammation related to asbestos exposure. Note the loculated pleural effusion with empyema-like pleural thickening.

Pulmonary involvement by leukemia/lymphoma

Pulmonary involvement usually presents as a diffuse or nodular infiltrate on chest X-ray. Bronchovascular-lymphangitic, alveolar, interstitial, and nodular patterns have been described on chest CT. Diffuse infiltrates may develop in the setting of acute respiratory failure that is due to tumor lysis pneumonopathy or to the hyperleukocytic reaction when peripheral blast counts rise rapidly above 245,000/ul. Occasional cases may present with endobronchial or endotracheal involvement.

Rare presentations of hematologic malignancies

Primary pulmonary Hodgkin’s disease, anaplastic large cell lymphoma, extramedullary plasmacytoma, and peripheral T-cell lymphoma typically present as one or more parenchymal nodules or masses on chest X-ray or CT scan. Pulmonary involvement by intravascular lymphoma often mimics interstitial lung disease with bilateral reticular or reticulonodular infiltrates, variably accompanied by centrilobular nodules and ground-glass infiltrates.

Primary pulmonary AIDS-related lymphoma

Chest CT typically shows one or more lung nodules or masses. Diffuse ground-glass opacities have been reported, as have cavitary nodules. Pleural effusion and endobronchial disease rarely occur. The vast majority of AIDS-related lymphomas involve the lung secondarily, so CT imaging typically reveals disease outside the lung parenchyma.

Beware: there are other diseases that can mimic malignant lymphoproliferative disorders of the lung:

Low-grade lymphoma of BALT – differential diagnosis
  • Nodular lymphoid hyperplasia

  • Follicular bronchiolitis

  • Secondary pulmonary involvement by low-grade lymphomas

Histologic distinction of low-grade BALT lymphoma from benign lymphoproliferative lesions, such as nodular lymphoid hyperplasia and follicular bronchiolitis, may be difficult and may depend upon immunohistochemical and molecular genetic studies. Pulmonary involvement by chronic lymphocytic leukemia may mimic low-grade lymphoma of BALT, but it can usually be distinguished by considering clinical history and pathologically by appropriate immunohistochemical studies.

Diffuse large B-cell lymphoma (DLBCL) – differential diagnosis
  • Secondary pulmonary involvement by DLBCL

  • Lymphomatoid granulomatosis

  • Carcinoma

  • Melanoma

  • Anaplastic large-cell lymphoma

  • Burkitt lymphoma

These disorders can usually be distinguished by consideration of clinical and pathologic features.

Lymphomatoid granulomatosis – differential diagnosis
  • Wegener’s granulomatosis

  • Post-transplant lymphoproliferative disorder

  • Pulmonary involvement by peripheral T-cell lymphoma

  • Nasal type extranodal T / natural killer (NK)-cell lymphoma.

  • IgG4-related sclerosing disease

  • Bronchogenic Carcinoma

  • Necrotizing Pneumonia

Some cases of grade I lymphomatoid granulomatosis may actually represent IgG4-related sclerosing disease. Lymphomatoid granulomatosis may be histologically indistinguishable from PTLD and should not be diagnosed in the post-transplant setting. Cases that occur in patients who are receiving methotrexate may also be considered part of the spectrum of iatrogenic immunodeficiency-associated lymphoproliferative syndrome. Distinction between lymphomatoid granulomatosis and the other disorders requires pathologic assessment of B-cell and T-cell markers, combined with immunohistochemical staining for EBV.

The clinical differential for cases of lymphomatoid granulomatosis includes bronchogenic carcinoma and necrotizing pneumonia. Recognition of the scattered atypical cells and the absence of staining for epithelial markers histologically aids in the distinction from these disorders.

Post-transplant lymphoproliferative disorder (PTLD) – differential diagnosis

The diagnosis of PTLD requires histologic evidence of a lymphoproliferative disorder in the post-transplant setting. Prior to tissue biopsy, presentation with one or more pulmonary nodules raises concern for fungal, bacterial, and mycobacterial infection.

Primary effusion lymphoma – differential diagnosis

The clinical differential diagnosis for pleural or pericardial effusion is broad, and it includes a number of infectious and non-infectious entities. The histologic differential diagnosis of a lymphomatous effusion includes:

  • Secondary involvement of the pleura by lymphomas

  • Pyothorax-associated lymphoma

  • Extranodal Burkitt lymphoma

  • HHV-8-negative “PEL-like” lymphoma

Pleural involvement by lymphomas that began elsewhere is usually evident from the clinical history. These lymphomas typically have distinct immunophenotypic signatures, including lack of association with HHV-8. Burkitt lymphoma is HHV-8-negative and is associated with c-myc deregulation. Chronic pyothorax-associated lymphoma is HHV-8-negative, and it usually occurs in HIV-negative individuals in the setting of pleural inflammation that has been present for decades. Rare cases of lymphoma that originate in a body cavity and that are HHV-8-negative but are immunophenotypically similar to PEL have been reported (HHV-8-negative “PEL-like” lymphoma).

Chronic pyothorax-associated lymphoma – differential diagnosis
  • Primary effusion lymphoma

  • Secondary involvement by large B-cell lymphomas with other sites of origin

The clinical differential diagnosis includes causes of chronic pleural inflammation, such as bacterial infection and asbestos-related pleural effusion, as well as intrapleural malignancies, such as mesothelioma and metastatic carcinoma.

Pulmonary involvement by leukemia/lymphoma – differential diagnosis
  • Low-grade lymphoma of BALT

  • Other primary pulmonary hematopoetic malignancies

  • Concurrent infection or treatment-related toxicity

Rare presentations of hematologic malignancies – differential diagnosis
  • Interstitial lung disease (in the case of intravascular lymphoma)

  • Secondary involvement of the lung with disease originating elsewhere

The rarity of these diseases may lead to erroneous histologic diagnoses of more common lung entities, such as carcinoma.

Primary pulmonary AIDS-related lymphoma – differential diagnosis
  • Diffuse large B-cell lymphoma without HIV infection

  • Lymphomatoid granulomatosis

  • Low-grade B-cell lymphoma of BALT

  • Fungal, mycobacterial, and bacterial infection

Distinction between a diffuse large B-cell lymphoma and primary pulmonary AIDS-related lymphoma is somewhat artificially based on HIV status since these two entities are histologically identical. Lymphomatoid granulomatosis and low-grade B-cell lymphoma of BALT can be distinguished from primary pulmonary AIDS-related lymphomas based on their histologic, immunohistochemical and genotypic features. However, both lymphomatoid granulomatosis and low-grade B-cell lymphoma of BALT occur at increased frequency in patients with HIV and AIDS.

How and/or why did the patient develop a malignant lymphoproliferative disorder of the lung?

Low-grade lymphoma of BALT

Lymphomas that arise in mucosal-associated lymphoid tissue (MALT) in other organs are associated with chronic antigen stimulation. For example, gastric MALT lymphoma is associated with H. pylori infection, and 70-80 percent of cases will remit with H. pylori treatment. Like MALT lymphomas elsewhere, BALT lymphomas are presumed to be driven by chronic inflammation. In keeping with this hypothesis, BALT lymphoma has been associated with inflammatory disorders like rheumatoid arthritis, Sjögren’s syndrome and rarely hepatitis C infection. Some cases are reported to have evolved from lymphocytic interstitial pneumonitis. Moreover, regression of BALT lymphoma with chronic macrolide therapy has been described. However, a specific agent responsible for antigenic stimulation in the lung has not been identified.

Diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma is associated with HIV infection and autoimmune disease, but it occurs sporadically and in immunocompetent individuals as well.

Lymphomatoid granulomatosis (LYG)

LYG was initially thought to represent a post-thymic T-cell lymphoproliferative disorder. Along with extranodal T-NK cell lymphoma, it was considered part of a spectrum of diseases termed “angiocentric immunoproliferative lesions.” More recently, numerous studies have shown that lymphomatoid granulomatosis is actually an EBV-associated B-cell lymphoproliferative disorder with a prominent T-cell background. In this way, it is similar to PTLD.

Post-transplant lymphoproliferative disorder (PTLD)

Immunosuppression plays a central role in development of this disorder. Factors that influence the strength of immunosuppression, such as transplant type and episodes of acute rejection, increase the risk for PTLD. Similarly, EBV plays an important role in pathogenesis, with conversion to EBV positivity in the post-transplant setting conferring increased risk.

Primary effusion lymphoma

HHV-8 plays a central role in oncogenesis, although the exact mechanisms are unknown.

Pyothorax-associated lymphoma

Pyothorax-associated lymphoma is rare. Most reported cases have been reported in patients 20-64 years after therapeutic pneumothorax as treatment for tuberculosis. In the largest series from Japan, where artificial pneumothorax for tuberculosis was performed more frequently, 20 percent of patients had a different reason for chronic pyothorax. Males are affected more often than females by a ratio of 12:1.

Pulmonary involvement by leukemia/lymphoma

Pulmonary involvement by lymphoma/leukemia is comparatively common, ranging from 20-60 percent on postmortem series. Clinically significant involvement, however, is less frequent, occurring in less than 10 percent of patients.

Rare presentations of hematologic malignancies

Primary pulmonary presentations of Hodgkin’s lymphoma, anaplastic large cell lymphoma, extramedullary plasmacytoma, intravascular lymphoma, and peripheral T-cell lymphoma are extremely rare and are described only in isolated case reports or small series.

Primary pulmonary AIDS-related lymphoma

Primary pulmonary AIDS-related lymphomas are rare, with an estimated incidence rate of 0-0.3 per 100 person-years. As a result of AIDS, patients have severe underlying immune deficiency and very low peripheral blood CD-4 counts. Most patients have also had other AIDS-defining illnesses. Low-grade B-cell lymphoma of BALT, lymphomatoid granulomatosis, and primary effusion lymphoma all occur at increased frequency because of the immunosuppression caused by HIV infection. The incidence of primary pulmonary AIDS related lymphomas has decreased with anti retroviral therapy treatment.

Which individuals are at greatest risk of developing a malignant lymphoproliferative disorder of the lung?

Low-grade B-cell lymphoma of BALT

The majority of patients with BALT lymphoma do not have a specific risk factor, other than age, beyond the third to fourth decade. The incidence of low-grade B-cell lymphoma of BALT is increased in patients with HIV infection. A minority of patients may have an associated autoimmune disorder (e.g., Sjögren’s syndrome, Hashimoto’s thyroiditis). Rare cases have been reported in association with Hepatitis C infection.

Diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma occurs in adults with a median age of 61. Diffuse large B-cell lymphoma is associated with HIV infection and autoimmune diseases, but it occurs sporadically and in immunocompetent individuals as well.

Lymphomatoid granulomatosis

Immune deficiency increases the risk of developing LYG. HIV infection, common variable immune deficiency, hypogammaglobulinemia, x-linked agammaglobulinemia, and dedicator of cytokinesis 8 (DOCK8) deficiency are associated with LYG. Immunosuppression that is due to solid or allogenic stem cell transplant leads to histology that is sometimes indistinguishable from LYG and is better classified as PTLD. Immunosuppression that is due to cytotoxic medications like methotrexate also predisposes one to LYG.

Post-transplant lymphoproliferative disorder (PTLD)

By definition, PTLD occurs in patients with a prior solid organ or hematopoetic transplant. The incidence of PTLD is highest in lung and heart-lung transplants (5-10%) and lowest in renal transplantation (l%). The incidence may be as high as 20 percent with very aggressive immunosuppression for HLA-mismatched T-cell depleted hematopoetic transplants or with aggressive treatment for graft versus host disease. Primary EBV infection (i.e., conversion of EBV serology) in the post-transplant setting also confers an increased risk for PTLD.

Primary effusion lymphoma

Most cases of PEL have been reported in patients with advanced AIDS, but more recent series suggest the diagnosis occurs in the setting of HIV infection with preserved CD4 count. Patients with HHV-8-associated primary effusion lymphoma are more likely to be males than females and to develop Kaposi’s sarcoma than not. Rarely, PEL occurs following solid organ transplant without HIV infection. PEL has also been reported to occur in the elderly and patients with cirrhosis and chronic viral hepatitis.

Pyothorax-associated lymphoma

Affected patients have a longstanding history of chronic pleural inflammation. Most reported cases are from Japan and occur in patients 20-64 years after therapeutic pneumothorax for tuberculosis. Those with asbestos exposure or longstanding exudative pleural effusions are at risk for pyothorax-associated lymphoma.

Pulmonary involvement by leukemia/lymphoma

Affected patients usually have a prior history of extrapulmonary lymphoma or leukemia.

Rare presentations of hematologic malignancies

Primary pulmonary presentations of Hodgkin’s lymphoma, anaplastic large-cell lymphoma, extramedullary plasmacytoma, intravascular lymphoma, and peripheral T-cell lymphoma are all extremely rare. Sites of extrapulmonary involvement and alternate diagnoses should be considered prior to accepting a primary pulmonary presentation. While rarely presenting in the lung, intravascular lymphoma secondarily involves the lung more than half the time. Analysis of peripheral blood is typically non-diagnostic. Skin and central nervous system involvement typically precede lung involvement.

Primary pulmonary AIDS-related lymphoma

Most patients have advanced AIDS, although rare cases have been reported in HIV-seronegative patients. These cases have usually occurred in individuals who are immunocompromised in other ways or who live in HHV-8-endemic areas.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Low-grade B-cell lymphoma of BALT
  • Serum protein electrophoresis (SPEP)

  • Bone marrow biopsy and aspirate

  • Esophagogastroduodenoscopy should be considered, given that concurrent involvement at other mucosal sites, especially the gastric mucosa, occurs.

  • SPEP shows a monoclonal spike in about a third of patients. The monoclonal fraction is usually low (<3g/dL) and is usually unassociated with clinical disease.

Staging is as for extrapulmonary non-Hodgkins lymphoma. Bone marrow involvement may be present in 5-10 percent of patients. Lymph nodes may be involved in a similar fraction.

Diffuse large B-cell lymphoma
  • HIV testing

Staging is as for extrapulmonary non-Hodgkins lymphoma.

Lymphomatoid Granulomatosis
  • HIV testing

Aside from imaging and biopsy, additional laboratory studies are not usually helpful in the diagnosis of lymphomatoid granulomatosis. Serologic assessment of HIV status and gammaglobulins is indicated in those in whom LYG is being considered.

Post-transplant lymphoproliferative disorder (PTLD)

Microbiologic studies, such as stains and cultures of body fluids and assessment of circulating fungal antigens, may be helpful in excluding infection, but definitive diagnosis requires tissue biopsy.

Primary effusion lymphoma
  • Serologic assessment of HIV infection

  • Microbiologic studies on body cavity fluid to exclude infection

Pyothorax-associated lymphoma
  • HIV testing

  • Examination of peripheral blood and bone marrow, as well as staging studies for lymphoma, such as CT

Spread to distant sites including peripheral blood and bone marrow is not common.

Pulmonary involvement by leukemia/lymphoma
  • Peripheral blood

  • Bone marrow aspirate and biopsy

Examination of peripheral blood, bone marrow, and CT or PET imaging may reveal distant sites of disease if the current stage is unknown or the diagnosis has just been made. Artefactual hypoxia occurs because of the rapid metabolism of oxygen by leukocytes in blood gas samples.

Rare presentations of hematologic malignancies
  • CBC / differential

  • SPEP (Extramedullary plasmacytoma is occasionally associated with a serum monoclonal gammopathy.)

Primary pulmonary presentation of AIDS-related lymphoma
  • CBC / differential

  • CD4 count and HIV viral load

  • Bone marrow examination

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of a malignant lymphoproliferative disorder of the lung?

Pulmonary function studies and other noninvasive pulmonary diagnostic studies have little utility in the diagnosis of malignant lymphoproliferative disorders. Staging studies, including bone marrow aspirate and biopsy, chest-abdomen-pelvis CT, and consideration of esophagogastroduodenoscopy, are appropriate once the diagnosis is established.

What diagnostic procedures will be helpful in making or excluding the diagnosis of a malignant lymphoproliferative disorder of the lung?

Low-grade B-cell lymphoma of BALT
  • BAL with flow cytometry

  • Transbronchial biopsy

  • Transthoracic needle biopsy

  • Surgical lung biopsy

Low-grade B-cell lymphoma may occasionally be diagnosed on transbronchial biopsy if the lesion is adequately represented and enough tissue is available for additional immunohistochemical studies. The diagnostic yield may be improved by flow cytometric analysis of lymphoid markers and clonal analysis for immunoglobulin gene rearrangements on BAL fluid. Identification of a low-grade B-cell lymphoma on transbronchial biopsy/BAL or transthoracic needle biopsy does not exclude higher-grade component areas of diffuse large B-cell lymphoma, which may occur with low-grade B-cell lymphoma and may not be present in a smaller biopsy sample. In cases in which transbronchial biopsy with BAL or transthoracic needle biopsy are not diagnostic, wedge biopsy or lobectomy should allow diagnosis.

Diffuse large B-cell lymphoma
  • BAL with flow cytometry

  • Transbronchial biopsy

  • Transthoracic needle biopsy

  • Surgical lung biopsy

Procedures to diagnose diffuse large B-cell lymphoma are similar to those for low-grade B-cell lymphoma. Approximately half of cases of large B-cell lymphoma have associated areas of low-grade B-cell lymphoma of BALT. Accordingly, diagnosis of low-grade B-cell lymphoma on a limited sample, such as transbronchial biopsy or transthoracic needle biopsy, does not exclude a component of large B-cell lymphoma.

Lymphomatoid granulomatosis
  • Transbronchial biopsy

  • Transthoracic needle biopsy

  • Surgical lung biopsy

In some cases, the diagnosis of lymphomatoid granulomatosis may be suspected based on transbronchial or transthoracic needle biopsy. Surgical lung biopsy is typically required for definitive diagnosis. Diagnosis on fine needle aspirate cytology is not possible.

Post-transplant lymphoproliferative disorder
  • Transbronchial biopsy

  • Transthoracic needle biopsy

  • Surgical lung biopsy

A diagnosis of PTLD is often established with transbronchial or transthoracic needle biopsy. Surgical lung biopsy may be required to obtain sufficient tissue.

Primary effusion lymphoma
  • Thoracentesis with cytologic examination of pleural fluid

The diagnosis of PEL is made with pleural fluid obtained by thoracentesis, which almost always demonstrates malignant cells. Immunophenotyping using flow cytometry and assessment for HHV-8 should be performed. Needle biopsy or thoracoscopy are not helpful in most cases since a tissue mass or solid lesion is usually not present, and pleural fluid analysis is almost always diagnostic.

Pyothorax-associated lymphoma
  • Percutaneous CT, ultrasound or MRI guided biopsy may allow diagnosis

  • Thoracoscopic pleural biopsy is often required.

Pulmonary involvement by leukemia/lymphoma
  • CBC / differential to quantify circulating blasts

  • BAL with flow cytometry

  • Transbronchial biopsy

  • Transthoracic needle biopsy

  • Surgical lung biopsy may be necessary to provide adequate tissue sampling to exclude infection or for expediency.

Rare presentations of hematologic malignancies
  • Cytology on blood from a wedged pulmonary artery catheter (for intravascular lymphoma)

  • Transbronchial biopsy

  • Transthoracic needle biopsy

  • Surgical lung biopsy may be necessary to provide adequate tissue sampling for a confident diagnosis, given the rarity of these diseases.

Primary pulmonary AIDS-related lymphoma
  • BAL with flow cytometry

  • Transbronchial biopsy

  • Transthoracic needle biopsy

  • Surgical lung biopsy may be necessary to provide adequate tissue sampling to exclude infection or for expediency.

The diagnosis of primary pulmonary AIDS-related lymphoma may occasionally be made on BAL, transbronchial biopsy, or transthoracic needle biopsy. However, surgical lung biopsy is often necessary.

What pathologic features/genetic studies help in making the diagnosis of a malignant lymphoproliferative disorder of the lung?

Low-grade B-cell lymphoma of BALT

Biopsy of low-grade B-cell lymphoma of BALT typically shows one or more tan to white, well-demarcated masses. Some cases have a more infiltrative margin with pulmonary consolidation. Histologically, low-grade B-cell lymphoma of BALT consists of a confluent proliferation of monomorphous small lymphocytes, monocytoid lymphocytes, plasmacytoid lymphocytes, and plasma cells, which efface the underlying pulmonary parenchyma.

Occasionally, the infiltrate is diffuse rather than confluent and spreads along existing lymphatic tracts. Dutcher bodies are present in about half of cases. The pleura and bronchial cartilage are often involved. In approximately 90 percent of cases, lymphoepithelial islands, consisting of permeation of bronchial and bronchiolar epithelium, may be identified by aggregates of lymphocytes. There is often a component of admixed non-neoplastic lymphocytes present as reactive germinal centers.

Germinal centers may show follicular colonization by the neoplastic centrocyte-like cells. Other variable but nonspecific findings include small foci of amyloid, small, ill-defined granulomas, and dense bands of hyalinized connective tissue. Areas of diffuse large B-cell lymphoma may be identified in approximately 18 percent of patients. These areas coexist with more typical low-grade lymphoma of BALT, and they may occur within the same lung, in a different part of the lung, or in associated mediastinal nodes.

On immunohistochemistry, the neoplastic cells stain positively for pan B-cell markers, including CD-20 and CD-79a. Stains for CD-10, cyclin D1 and CD-5 are usually absent. Co-expression of CD-20 and CD-43 may be found in a majority of cases. BCL-2 is typically positive. Light chain restriction can be demonstrated in most cases on staining for kappa and lambda by immunohistochemistry or in situ hybridization. PCR analysis for IgH chain gene rearrangements may show a clonal immunoglobuline gene rearrangement in cases that do not show light chain restriction on immunohistochemistry. Analysis of translocations commonly found in BALT lymphoma, such as t(11;18)(q21:q21) or the less common t(1;14)(p22;q32), t(14;18)(q32,q21), or t(3;14)(p13;q32) may be assessed by FISH and, if detected, may help to confirm the diagnosis (See Figure 6, Figure 7 and Figure 8).

Figure 6.

Low-grade lymphoma of BALT. The nodule histologically consists of a confluent proliferation of small lymphocytes.

Figure 7.

Low-grade lymphoma of BALT. At slightly high power, the lymphocytes efface and variably extend into the adjacent pulmonary parenchyma. Spread of low-grade BALT lymphomas away from the mass is often in a lymphantic distribution along bronchovascular bundles and the pleura.

Figure 8.

Low-grade lymphoma of BALT. High power shows that lymphocytes are monotonous, small, and round. There is permeation of adjacent bronchiolar epithelium by small collections of lymphocytes (arrow–so-called “lymphoepithelial islands.”

Recent studies have suggested that most cases of nodular pulmonary amyloidosis and/ or pulmonary nodular light chain deposition disease represent uncommon pathologic manifestations of an associated low grade BALT lymphoma. This conclusion is supported by studies of the amyloid or nodular material by liquid chromatography and tandem mass spectrometry. These studies show that most cases have a peptide profile consistent with immunoglobulins of either kappa or lambda type. Monotypic expression of kappa or lambda may also be identified in the associated lymphoplasmacytic inflammation in many cases.

Diffuse large B-cell lymphoma

Gross features of diffuse large B-cell lymphoma consist of a white to tan mass that may contain areas of necrosis. Biopsies usually show sheets of large lymphoid cells with irregularly shaped, vesicular nuclei and medium to large nucleoli. Scattered mitoses are present, and there may be variable necrosis. Areas of coexisting low-grade B-cell lymphoma are present in approximately half of cases.

On immunohistochemistry, the neoplastic cells, which are of B-cell differentiation, stain positively for pan B-cell markers (CD-20 and CD-79a). Light chain restriction may be identified on immunohistochemical stains or in situ hybridization for kappa and lambda. A clonal rearrangement of the IgH chain gene may be identified on PCR. EBV may be present by in situ hybridization for EBER or immunohistochemical staining for EBV-encoded latent membrane protein-1, particularly those associated with HIV infection (See Figure 9, Figure 10 and Figure 11).

Figure 9.

Diffuse, large B-cell lymphoma. A diffuse proliferation of large lymphocytes effaces the underlying pulmonary parenchyma and focally involves the overlying bronchial epithelium.

Figure 10.

Diffuse, large B-cell lymphoma. At higher power, the lymphoid cells are cytologically atypical and monotonous. An occasional mitotic figure and apoptotic bodies are present.

Figure 11.

Diffuse, large B-cell lymphoma. The cells stain uniformly positive for CD-20, a pan B-cell marker.

Lymphomatoid granulomatosis (LYG)

On gross examination, biopsies or resections show single or multiple nodules or masses with variable central necrosis. Histologically, nodules of lymphomatoid granulomatosis are characterized by a polymorphous lymphoid infiltrate with an angiocentric distribution and variable degrees of central necrosis. Two key histologic features distinguish lymphomatoid granulomatosis from other lymphoproliferative disorders. The infiltrate is strikingly angiocentric with transmural involvement of small and medium sized arteries, and variable numbers of scattered cytologically atypical cells are present.

Lymphomatoid granulomatosis has been graded from I-III, based on the degree of cytologic atypia and the number of cytologically atypical cells present. Grade III lesions fulfill histologic requirements for malignant lymphoma.

Immunohistochemical stains show that the small lymphocytes comprise the majority of cells that stain positively for pan T-cell markers (CD-3). However, the scattered large, cytologically atypical cells stain positively for pan B-cell markers (CD-20 and CD-79a). On in situ hybridization, the large atypical cells also stain positively for EBV. The number of EBV-positive cells varies with the number of cytologically atypical cells and may be difficult to demonstrate in grade I lesions. PCR analysis of IgH chain gene may show clonal or oligoclonal gene rearrangements in approximately half of cases. PCR analysis for T-cell receptor gene rearrangements is typically negative (See Figure 12, Figure 13, Figure 14, Figure 15, Figure 16).

Figure 12.

Lymphomatoid granulomatosis. Low-power view shows a large area of necrosis with a surrounding polymorphous lymphoid infiltrate.

Figure 13.

Lymphomatoid granulomatosis. The infiltrate is strikingly angiocentric, permeating the wall of this small artery. The area around the artery is necrotic.

Figure 14.

Lymphomatoid granulomatosis. Rare, atypical lymphoid cells (arrow) are present within the polymorphous infiltrate. Epstein Barr virus was identified in these cells by in situ hybridization.

Figure 15.

Lymphomatoid granulomatosis. The atypical cells lack staining for CD-3, a pan T-cell marker (arrow).

Figure 16.

Lymphomatoid granulomatosis. The atypical cells stain positively for CD-20, a pan B-cell marker (arrow).

Post-transplant lymphoproliferative disorder (PTLD)

In general, pulmonary PTLD consists of white to tan nodule(s) with variable amounts of central necrosis. Histologic features of PTLD vary. Polymorphic infiltrates consist of a mixture of small lymphocytes, immunoblasts, plasma cells, and small cleaved and large non-cleaved lymphocytes. High-grade monomorphic infiltrates most commonly consist of large B-lymphoid cells similar to diffuse large B-cell lymphoma. Monomorphic PTLD may also demonstrate Burkitt/Burkitt-like lymphoma, plasma cell myeloma, or plasmacytoma-like lesions. Rare cases resemble Hodgkin’s disease or consist of peripheral T-cell lymphoma or NK-cell type lymphomas. In some cases, the histologic features of PTLD are similar to lymphomatoid granulomatosis and should be interpreted as PTLD in the post-transplant setting.

In polymorphic PTLD, immunohistochemical stains for pan B-cell (CD-20) and pan T-cell (CD-3) markers show a mixture of B and T-lymphocytes. In situ hybridization for EBV is positive in immunoblasts. Immunohistochemical stains often detect EBV-LMP1 and EBNA2. Either a polyclonal or a monoclonal pattern of lambda and kappa light chain expression may be detected. However, PCR for IgH chain gene rearrangements typically show a monoclonal pattern.

In monomorphic PTLD, there is uniform expression of the sheets of large, atypical lymphocytes for pan B-cell markers (CD-20 and CD-79a). EBV can be demonstrated by in situ hybridization or detected by immunohistochemical stains for EBV-LMP1 or EBNA2. Immunohistochemical stains for kappa and lambda typically show a monoclonal pattern. PCR analysis usually shows a monoclonal IgH chain gene rearrangement (See Figure 17, Figure 18, Figure 19.)

Figure 17.

Post-transplant lymphoproliferative disorder (PTLD). At low power, a nodular infiltrate effaces the underlying pulmonary parenchyma.

Figure 18.

Post-transplant lymphoproliferative disorder (PTLD). At medium power, an infiltrate of dyscohesive lymphocytes fills alveoli.

Figure 19.

Post-transplant lymphoproliferative disorder (PTLD). At high power, the infiltrate is composed of monomorphous, cytologically atypical lymphocytes.

Primary effusion lymphoma

Cytologic examination of pleural fluid shows large, pleomorphic malignant cells. The cells are occasionally multinucleated with irregular nuclei and prominent nucleoli. Frequent mitotic figures may be identified.

Immunohistochemical analysis and flow cytometry show that the cells express CD-45 but lack expression of either pan B-cell (CD-19,CD-20 or CD-79a) or pan T-cell (CD-3) markers. Markers of activation (CD-30, CD-38, and CD-138) are often present. Detection of HHV8 within nuclei of malignant cells by immunohistochemistry or in situ hybridization is key to the diagnosis. Co-infection by EBV is usual but not always present, and it can be detected by in situ hybridization. PCR shows clonal rearrangement of the IgH chain gene. Occasional cases may also show aberrant rearrangement of T-cell receptor genes (See Figure 20).

Figure 20.

Primary effusion lymphoma. Wright Giemsa stain shows scattered, cytologically atypical mononuclear cells.

Pyothorax-associated lymphoma

In general, multiple pleural-based masses are present. Contiguous invasion of adjacent structures, such as the liver, the lung, and the diaphragm, is often present. Histologically, the pleural-based masses consist of diffuse large B-cell lymphoma with sheets of medium to large atypical lymphocytes. Necrosis is often present, and mitotic figures are frequent. In most cases (90%), the neoplastic cells are B-cells (CD-20+, CD-79a+). Occasional cases may have aberrant expression of T-cell markers (CD-3+). EBV can be demonstrated in the majority (80%) of cases by either in situ hybridization or on immunohistochemical staining for EBV-LMP1 or EBV-EBNA-2. PCR analysis for IgH chain gene rearrangements usually identifies a clonal rearrangement (See Figure 21, Figure 22, and Figure 23).

Figure 21.

Chronic pyothorax lymphoma. Nests of cytologically atypical lymphoid cells are present within a background of marked necrosis.

Figure 22.

Chronic Pyothorax lymphoma. Higher-power view shows that the cytologically atypical cells are large, with occasionally prominent nucleoli. Apoptotic bodies are also present.

Figure 23.

Chronic pyothorax lymphoma. The cytologically atypical cells stain positively for CD-20, a pan B-cell marker. The cells also stain positively for Epstein Barr virus on in situ hybridization.

Pulmonary involvement by leukemia / lymphoma

Examination of tissue reveals several patterns of secondary pulmonary involvement by lymphoma/leukemia, including nodular, alveolar, interstitial, and peri-bronchovascular involvement. These patterns differ according to histologic subtype. For example, peripheral T-cell lymphoma tends to demonstrate an interstitial pattern, whereas Hodgkin’s disease more often presents as parenchymal nodules. Myeloid leukemias typically spread along bronchovascular bundles, interlobular septa and pleura in a lymphangitic distribution.

Pulmonary involvement by myeloid leukemia leads to several unique clinicopathologic syndromes, including pulmonary leukostasis, leukemic cell lysis pneumopathy, and hyperleukocytic reaction. Pulmonary leukostasis develops in the setting of AML when the WBC count is elevated over 100,000/mm3. Histologically, numerous blasts distend small pulmonary vessels. Leukemic cell lysis pneumopathy is characterized by an acute respiratory distress, (ARDS)-like syndrome that develops within 48 hours of treatment onset.

Histologically, there are aggregates of blasts within capillaries, hemorrhage, small infarcts, edema, and subsequent progression to diffuse alveolar damage. Hyperleukocytic reaction is characterized by the development of ARDS in association with a rapid increase in the peripheral blast count (greater than 245,000/ul). As in leukostasis, there is distension of arteries, arterioles, and capillaries by numerous blast cells, along with edema and foci of hemorrhage (See Figure 24, Figure 25, and Figure 26).

Figure 24.

Pulmonary involvement by chronic myelogenous leukemia: low-power view shows a malignant cellular infiltrate present along bronchovascular bundles in a lymphangitic distribution.

Figure 25.

Pulmonary involvement by chronic myelogenous leukemia: high-power view shows the immature myeloid cells that compose the infiltrate.

Figure 26.

Pulmonary involvement by chronic myelogenous leukemia. Immunohistochemical staining for myeloperoxidase confirms the myeloid differentiation of the infiltrate and highlights the pattern of lymphangitic spread.

Rare pulmonary presentations of hematologic malignancies

The pathologic features of pulmonary presentation of Hodgkin’s disease, anaplastic large cell lymphoma, extramedullary plasmayctoma, intravascular lymphoma, and peripheral T-cell lymphoma are similar to their nodal -based counterparts. Hodgkin’s disease consists of nodules of a mixed cellular infiltrate with characteristic Reed-Sternberg cells.

Anaplastic large-cell lymphoma consists of pleomorphic lymphoid cells, which stain positively for CD-30 and anaplastic lymphoma kinase (ALK). Extramedullary plasmacytoma consists of sheets of plasma cells with varying degrees of maturation. Intravascular lymphoma consists of large CD-20-positive lymphoid cells within the lumens of small pulmonary vessels and capillaries. Peripheral T-cell lymphoma consists of aggregates of atypical CD-3-positive T-cells. (Figure 27, Figure 28, Figure 29, Figure 30)

Figure 27.

Primary pulmonary Hodgkin’s disease. Low power shows a nodule with a polymorphous lymphoid infiltrate effacing the underlying pulmonary parenchyma.

Figure 28.

Primary pulmonary Hodgkin’s disease. At higher power, scattered Reed-Sternberg cells and variants are present.

Figure 29.

Intravascular lymphoma. An aggregate of large cytologically malignant lymphoid cells occludes the lumen of this small pulmonary vessel.

Figure 30.

Intravascular lymphoma. The atypical lymphoid cells stain diffusely and strongly positive for CD-20, a pan B-cell marker.

Primary pulmonary AIDS-related lymphoma

Most cases of primary pulmonary AIDS-related lymphoma consist of a diffuse large B-cell lymphoma. Epstein-Barr virus is more often present in AIDS-related lymphoma than in cases without HIV infection.

If you decide the patient has a malignant lymphoproliferative disorder of the lung, how should the patient be managed?

Low-grade lymphoma of BALT

When disease is localized, treatment usually consists of surgical excision with or without chemotherapy. Observation is often employed for multifocal disease, given the indolent nature of this disease. Chemotherapy and rituximab are also frequently used.

Diffuse large B-cell lymphoma

Treatment consists of conventional chemotherapy and rituximab similar to that used for extrapulmonary diffuse large B-cell lymphoma.

Lymphomatoid granulomatosis

Treatment of grade III and some grade II lymphomatoid granulomatosis includes combination chemotherapy typically used to treat B-cell lymphomas, including rituximab. Grade I-II LYG has been treated with Alpha interferon 2b or rituximab alone. Successful treatment with autologous stem cell transplant has also been reported. Occasional cases have been reported to undergo spontaneous remission.

Post-transplant lymphoproliferative disorder (PTLD)

Treatment of PTLD begins with a reduction in immunosuppressive therapy. Decreased immunosuppression has resulted in remission in some cases. In more aggressive disease, chemotherapy regimens used in non-Hodgkins lymphoma, rituximab, or both are used in addition to reduction in immunosuppression.

Primary effusion lymphoma

Treatment includes highly active antiretroviral therapy (HAART) with or without chemotherapy. Remissions have been noted with effective antiretroviral therapy. There is limited evidence that conventional chemotherapy improves outcome in PEL, and a variety of experimental approaches have been advocated.

Cases in HIV-negative patients are rare and are sometimes associated with immunosuppression. In these cases, reduction of immunosuppression is recommended based on extrapolation from use of HAART in HIV-positive patients.

Pyothorax-associated lymphoma

Treatment of pyothorax-associated lymphoma typically consists of chemotherapy regimens that are effective against non-Hodgkins lymphoma. External beam radiation and surgical resection have also been used. The largest published series suggests that a significant number of patients had advanced age with significant co-morbidities, so they were poor candidates for curative treatment.

Pulmonary involvement by leukemia / lymphoma

Treatment of pulmonary involvement by leukemia or lymphoma is as appropriate for the specific disease. For leukostasis and the hyperleukocytic syndrome, treatment with leukopheresis, along with chemotherapy appropriate to the specific diagnosis (e.g., hydroxyurea for chronic myelogonous leukemia), should be promptly administered.

Rare Pulmonary Presentation of Hematologic Malignancies

The treatment of pulmonary presentations of Hodgkin’s disease, anaplastic large cell lymphoma, intravascular lymphoma, and peripheral T-cell lymphoma is specific to each hematologic malignancy. Treatment, which is similar to their nodal-based counterparts, includes combined chemotherapy and radiation therapy.

Solitary pulmonary plasmacytomas are surgically resected if localized within the lung and if extensive evaluation for systemic disease is unrevealing. In addition, some patients receive chemotherapy and/or radiation therapy.

Primary pulmonary AIDS-related lymphoma

Treatment for primary pulmonary AIDS-related lymphoma consists of highly active antiretroviral therapy (HAART) and conventional chemotherapy. The advent of HAART has vastly improved the ability of HIV-infected individuals to tolerate chemotherapy for AIDS-related lymphoma, resulting in improved outcomes. Rituximab amplifies the risk of infection in HIV-infected individuals and is sometimes omitted from treatment regimens when CD4 counts are very low.

What is the prognosis for patients managed in the recommended ways?

Low-grade lymphoma of BALT

The prognosis for low-grade lymphoma of BALT is superior to that for other forms of extranodal and nodal lymphoma. The five-year survival is 80-90 percent, and median survival exceeds ten years. Low-grade lymphomas of BALT tend to remain localized to the lung for long intervals before disseminating. Surveillance is indicated to detect relapse. Transformation to high-grade lymphoma has been reported.

Diffuse large B-cell lymphoma

The prognosis for diffuse large B-cell lymphoma of the lung is similar to that for diffuse large B-cell lymphoma arising elsewhere.

Lymphomatoid granulomatosis

The prognosis for lymphomatoid granulamotosis is generally poor, with a mortality rate of 50-60 percent and a median overall survival of fourteen months. Progression to overt lymphoma occurs in 13-47 percent of cases. However, a small fraction of patients experience spontaneous remission. Higher-grade histology and the presence of CNS involvement are adverse prognostic indicators. Recurrences tend to be of higher grade than the initial histology.

Post-transplant lymphoproliferative disorder (PTLD)

Prognosis in patients with PTLD is poor, with median survival of 9-13 months and one-year and five-year survival rates of 64 percent and 36 percent, respectively. The prognosis in thoracic PTLD is identical to that in extrathoracic presentations. The prognosis is worse with disseminated disease and in heart and lung transplantation, probably because of reluctance to withdraw immunosuppression aggressively for fear of rejection.

Primary effusion lymphoma

The prognosis for primary effusion lymphoma is poor, with a median survival of 2-3 months without treatment, and 6 months with treatment. Remissions achieved with chemotherapy are typically brief, although remission has been described with highly active antiretroviral therapy.

Pyothorax-associated lymphoma

The largest published series showed a five-year survival rate of 35 percent and median survival of 33 months. However, in this series, advanced stage disease and poor performance status were common: 17 percent received only supportive care, etiologies other than artificial pneumothorax were not well represented, and rituximab was not included in treatment regimens. Therefore, actual prognosis may be better than that reported above.

Pulmonary involvement by leukemia/lymphoma

The prognosis for pulmonary involvement by leukemia/lymphoma depends upon the specific hematologic malignancy. Secondary pulmonary involvement by lymphomatous or leukemic infiltrates is relatively common but may not be clinically significant.

Rare pulmonary presentation of hematologic malignancies

Because the primary pulmonary presentation of Hodgkin’s disease, anaplastic large-cell lymphoma, extramedullary plasmacytoma, intravascular lymphoma, and peripheral T-cell lymphoma is very rare, information about the prognosis for disease presenting in the lung is limited. However, the prognosis is generally thought to be similar to nodal-based or extrapulmonary presentations.

Primary pulmonary AIDS-related lymphoma

More than half of patients who receive full-dose conventional chemotherapy for non-Hodgkins lymphoma (NHL) have long-term survival, with survival rates approaching that in non-HIV-infected individuals with NHL.

What other considerations exist for patients with malignant lymphoproliferative disorders of the lung?

None

What’s the evidence?

Low-grade lymphoma of BALT

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Borie, R, Wislez, M, Thabut, G. “Clinical characteristics and prognostic factors of pulmonary MALT lymphoma”. Eur Respir J. vol. 34. 2009. pp. 1408-16. (Current review of clinical characteristics of pulmonary MALT lymphoma.)

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Kurtin, PJ, Myers, JL, Adlakha, H. “Pathologic and clinical features of primary pulmonary extranodal marginal zone B-cell lymphoma of MALT type”. The American Journal of Surgical Pathology. vol. 25. 2001. pp. 997-1008. (Seminal article defining low-grade lymphomas of BALT as variants of extranodal marginal zone B-cell lymphomas.)

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Okabe, M, Inagaki, H, Ohshima, K. “API2-MALT1 fusion defines a distinctive clinicopathologic subtype in pulmonary extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue”. The American Journal of Pathology. vol. 162. 2003. pp. 1113-22. (Description of the finding of AP12-MALT1 fusions in pulmonary MALT lymphomas.)

Papiris, SA, Kalomenidis, I, Malagari, K. “Extranodal marginal zone B-cell lymphoma of the lung in Sjogren's syndrome patients: reappraisal of clinical, radiological, and pathology findings”. Respiratory Medicine. vol. 101. 2007. pp. 84-92.

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Remstein, ED, Dogan, A, Einerson, RR. “The incidence and anatomic site specificity of chromosomal translocations in primary extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) in North America”. Am J Surg Pathol. vol. 30. 2006. pp. 1546-1553. (Excellent article detailing the frequency of the different types of chromosomal translocations in the various types of MALT lymphomas.)

Royer, B, Cazals-Hatem, D, Sibilia, J. “Lymphomas in patients with Sjogren's syndrome are marginal zone B-cell neoplasms, arise in diverse extranodal and nodal sites, and are not associated with viruses”. Blood. vol. 90. 1997. pp. 766-75.

Rubenstein, JN, Beatty, C, Kinkade, Z. “Extranodal marginal zone lymphoma of the lung: Evolution from an underlying reactive lymphoproliferative disorder”. J Clin Exp Pathol. vol. 5. 2015. pp. 208-222.

Sagaert, X, De Wolf-Peeters, C, Noels, H, Baens, M. “The pathogenesis of MALT lymphomas: where do we stand”. Leukemia. vol. 21. 2007. pp. 389-96. (Excellent review of the underlying pathogenesis of MALT lymphomas with a description of the types of associated chromosomal translocations.)

Seker, M, Bilici, A, Ustaalioglu, BO. “Extended rituximab schedules may result in increased efficacy in pulmonary malt lymphoma”. Leuk Res. vol. 33. 2009. pp. e154-6.

Shoji, F, Yano, T, Soejima, Y. “Multiple pulmonary mucosa-associated lymphoid tissue lymphomas after living donor liver transplantation”. Liver Transpl. vol. 15. 2009. pp. 1891-3.

Streubel, B, Simonitsch-Klupp, I, Mullauer, L. “Variable frequencies of MALT lymphoma-associated genetic aberrations in MALT lymphomas of different sites”. Leukemia. vol. 18. 2004. pp. 1722-6.

Yoon, RG, Kim, MY, Song, JW, Chae, EJ, Choi, CM, Jang, SJ. “Primary endobronchial marginal zone B-cell lymphoma of bronchus-associated lymphoid tissue: CT findings in 7 patients”. Korean J Radiol. vol. 14. 2013. pp. 366-374.

Zinzani, PL, Tani, M, Gabriele, A. “Extranodal marginal zone B-cell lymphoma of MALT-type of the lung: single-center experience with 12 patients”. Leukemia & Lymphoma. vol. 44. 2003. pp. 821-4.

Diffuse large B-cell lymphoma

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Kurtin, PJ, Myers, JL, Adlakha, H. “Pathologic and clinical features of primary pulmonary extranodal marginal zone B-cell lymphoma of MALT type”. The American Journal of Surgical Pathology.. vol. 25. 2001. pp. 997-1008.

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Maeshima, AM, Taniguchi, H, Toyoda, K. “Clinicopathological features of histological transformation from extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue to diffuse large B-cell lymphoma: an analysis of 467 patients”. British Journal of Haematology. vol. 174. 2016. pp. 923-931.

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Post-transplant lymphoproliferative disorder

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Ferry, JA, Jacobson, JO, Conti, D, Delmonico, F, Harris, NL. “Lymphoproliferative disorders and hematologic malignancies following organ transplantation”. Mod Pathol. vol. 2. 1989. pp. 583-92.

Halkos, ME, Miller, JI, Mann, KP, Miller, DL, Gal, AA. “Thoracic presentations of post-transplant lymphoproliferative disorders”. Chest. vol. 126. 2004. pp. 2013-20. (Description of thoracic presentation of PTLD, including several occurring in the lung.)

Harris, NL, Swerdlow, SH, Frizzera, G, Knowles, DM, Jaffe, ES, Harris, NL, Stein, H, Vardiman, JW. “Post-transplant lymphoproliferative disorders”. Pathology and genetics of tumours of haematopoietic and lymphoid tissue. 2001. pp. 264-9.

Khedmat, H, Taheri, S. “Early versus late outset of lymphoproliferative disorders post-heart and lung transplantation: The PTLD International Survey”. Hematol Oncol Stem Cell Ther. vol. 4. 2011. pp. 10-6.

Knoop, C, Kentos, A, Remmelink, M. “Post-transplant lymphoproliferative disorders after lung transplantation: first-line treatment with rituximab may induce complete remission”. Clinical Transplantation. vol. 20. 2006. pp. 179-87.

Kremer, BE, Reshef, R, Misleh, JG. “Post-transplant lymphoproliferative disorder after lung transplantation: A review of 35 cases”. J Heart Lung Transplant. vol. 31. 2012. pp. 296-304. (Recent study of clinicopathologic features of a series of 35 patients with PTLD following lung transplantation.)

Lucioni, M, Capello, D, Riboni, R. “B-cell post-transplant lymphoproliferative disorders in heart and/or lungs recipients: clinical and molecular-histogenetic study of 17 cases from a single institution”. Transplantation. vol. 82. 2006. pp. 1013-23.

Nalesnik, MA. “Clinicopathologic characteristics of post-transplant lymphoproliferative disorders”. Recent Results in Cancer Research Fortschritte der Krebsforschung. vol. 159. 2002. pp. 9-18.

Nelson, BP, Nalesnik, MA, Bahler, DW, Locker, J, Fung, JJ, Swerdlow, SH. “Epstein-Barr virus-negative post-transplant lymphoproliferative disorders: a distinct entity”. The American Journal of Surgical Pathology. vol. 24. 2000. pp. 375-85.

Oertel, SH, Verschuuren, E, Reinke, P. “Effect of anti-CD 20 antibody rituximab in patients with post-transplant lymphoproliferative disorder (PTLD)”. Am J Transplant. vol. 5. 2005. pp. 2901-6.

Parker, A, Bowles, K, Bradley, JA. “Diagnosis of post-transplant lymphoproliferative disorder in solid organ transplant recipients – BCSH and BTS Guidelines”. British Journal of Haematology. vol. 149. 2010. pp. 675-92. (General overall review and updated criteria for the diagnosis of PTLD in solid organ transplant recipients.)

Ramalingam, P, Rybicki, L, Smith, MD. “Post-transplant lymphoproliferative disorders in lung transplant patients: the Cleveland Clinic experience”. Mod Pathol. vol. 15. 2002. pp. 647-56. (One of the only series looking specifically at pulmonary occurrence of PTLD.)

Reshef, R, Luskin, MR, Kamoun, M. “Association of HLA polymorphisms with post-transplant lymphoproliferative disorder in solid-organ transplant recipients”. Am J Transplant. vol. 11. 2011. pp. 817-25.

Richendollar, BG, Hsi, ED, Cook, JR. “Extramedullary plasmacytoma-like post-transplantation lymphoproliferative disorders: clinical and pathologic features”. American Journal of Clinical Pathology. vol. 132. 2009. pp. 581-8.

Walker, RC, Marshall, WF, Strickler, JG. “Pre-transplantation assessment of the risk of lymphoproliferative disorder”. Clin Infect Dis. vol. 20. 1995. pp. 1346-53.

Walker, RC, Paya, CV, Marshall, WF. “Pre-transplantation seronegative Epstein-Barr virus status is the primary risk factor for post-transplantation lymphoproliferative disorder in adult heart, lung, and other solid organ transplantations”. J Heart Lung Transplant. vol. 14. 1995. pp. 214-21.

Lymphomatoid granulomatosis

Ammannagari, N, Srivali, N, Price, C, Ungprasert, P, Leonardo, J. “Lymphomatoid granulomatosis masquerading as pneumonia”. Ann Hematol. vol. 92. 2013. pp. 981-983.

Anders, KH, Latta, H, Chang, BH, Tomiyasu, U, Quddusi, AS, Vinters, HV. “Lymphomatoid granulomatosis and malignant lymphoma of the central nervous system in the acquired immunodeficiency syndrome”. HumPathol. vol. 20. 1989. pp. 326-34.

Bartosik, W, Raza, A, Kalimuthu, S, Fabre, A. “Pulmonary lymphomatoid granulomatosis mimicking lung cancer”. Interactive Cardiovascular and Thoracic Surgery. vol. 14. 2012. pp. 662-664.

Colby, TV, Carrington, CB. “Pulmonary lymphomas simulating lymphomatoid granulomatosis”. AmJSurgPathol. vol. 6. 1982. pp. 19-32.

Dimitriades, VR, Devlin, V, Pittaluga, S. “DOCK 8 deficiency, EBV+ lymphomatoid granulomatosis, and intrafamilial variation in presentation”. Front Pediatr. vol. 5. 2017. pp. 38-41.

Guinee, D, Jaffe, E, Kingma, D. “Pulmonary lymphomatoid granulomatosis. Evidence for a proliferation of Epstein-Barr virus infected B-lymphocytes with a prominent T-cell component and vasculitis”. AmJSurgPathol. vol. 18. 1994. pp. 753-64. (First report to note that atypical lympoid cells are of B-cell origin.)

Guinee, DG, Perkins, SL, Travis, WD, Holden, JA, Tripp, SR, Koss, MN. “Proliferation and cellular phenotype in lymphomatoid granulomatosis: implications of a higher proliferation index in B cells”. AmJSurgPathol. vol. 22. 1998. pp. 1093-100.

Hammar, S, Mennemeyer, R. “Lymphomatoid granulomatosis in a renal transplant recipient”. HumPathol. vol. 7. 1976. pp. 111-6.

Haque, AK, Myers, JL, Hudnall, SD. “Pulmonary lymphomatoid granulomatosis in acquired immunodeficiency syndrome: lesions with Epstein-Barr virus infection”. Mod Pathol. vol. 11. 1998. pp. 347-56.

Hu, YH, Liu, CY, Chiu, CH, Hsiao, LT. “Successful treatment of elderly advanced lymphomatoid granulomatosis with rituximab-CVP combination therapy”. European Journal of Haematology. vol. 78. 2007. pp. 176-7.

Ilowite, NT, Fligner, CL, Ochs, HD. “Pulmonary angiitis with atypical lymphoreticular infiltrates in Wiskott-Aldrich syndrome: possible relationship of lymphomatoid granulomatosis and EBV infection”. ClinImmunolPathol. vol. 41. 1986. pp. 479-84.

Jaffe, ES, Wilson, WH. “Lymphomatoid granulomatosis: pathogenesis, pathology and clinical implications”. Cancer Surveys. vol. 30. 1997. pp. 233-48.

James, WD, Odom, RB, Katzenstein, AL. “Cutaneous manifestations of lymphomatoid granulomatosis: report of 44 cases and a review of the literature”. Archives of Dermatology. vol. 117. 1981. pp. 196-202.

Jung, KH, Sung, HJ, Lee, JH. “A case of pulmonary lymphomatoid granulomatosis successfully treated by combination chemotherapy with rituximab”. Chemotherapy. vol. 55. 2009. pp. 386-90.

Kameda, H, Okuyama, A, Tamaru, J, Itoyama, S, Iizuka, A, Takeuchi, T. “Lymphomatoid granulomatosis and diffuse alveolar damage associated with methotrexate therapy in a patient with rheumatoid arthritis”. Clinical Rheumatology. vol. 26. 2007. pp. 1585-9.

Katzenstein, AL, Carrington, CB, Liebow, AA. “Lymphomatoid granulomatosis: a clinicopathologic study of 152 cases”. Cancer. vol. 43. 1979. pp. 360-73.

Katzenstein, AL, Doxtader, E, Narendra, S. “Lymphomatoid granulomatosis: insights gained over 4 decades”. The American Journal of Surgical pathology. vol. 34. 2010. pp. 35-48. (Excellent current state-of-the-art review of lymphomatoid granulomatosis.)

Katzenstein, AL, Peiper, SC. “Detection of Epstein-Barr virus genomes in lymphomatoid granulomatosis: analysis of 29 cases by the polymerase chain reaction technique”. ModPathol. vol. 3. 1990. pp. 435-41.

Makol, A, Kosuri, K, Tamkus, D, de, MCW, Chang, HT. “Lymphomatoid granulomatosis masquerading as interstitial pneumonia in a 66-year-old man: a case report and review of literature”. J Hematol Oncol. vol. 2. 2009. pp. 39

Michaud, J, Banerjee, D, Kaufmann, JC. “Lymphomatoid granulomatosis involving the central nervous system: complication of a renal transplant with terminal monoclonal B-cell proliferation”. Acta Neuropathol (Berl). vol. 61. 1983. pp. 141-7.

Miyashita, T, Yoshioka, K, Nakamura, T. “A case of lymphomatoid granulomatosis-like lung lesions with abundant infiltrating IgG4-positive plasma cells whose serum IgG4 levels became high following the start of corticosteroid therapy”. Internal Medicine (Tokyo, Japan). vol. 49. 2010. pp. 2007-11.

Myers, JL, Kurtin, PJ, Katzenstein, ALA. “Lymphomatoid granulomatosis: evidence of immunophenotypic diversity and relationship to Epstein-Barr virus infection”. AmJSurgPathol. vol. 19. 1995. pp. 1300-12.

Nicholson, AG, Wotherspoon, AC, Diss, TC. “Lymphomatoid granulomatosis: evidence that some cases represent Epstein-Barr virus-associated B-cell lymphoma”. Histopathology. vol. 29. 1996. pp. 317-24.

Oyama, T, Yamamoto, K, Asano, N. “Age-related EBV-associated B-cell lymphoproliferative disorders constitute a distinct clinicopathologic group: a study of 96 patients”. Clin Cancer Res. vol. 13. 2007. pp. 5124-32.

Shimada, K, Matsui, T, Kawakami, M. “Methotrexate-related lymphomatoid granulomatosis: a case report of spontaneous regression of large tumours in multiple organs after cessation of methotrexate therapy in rheumatoid arthritis”. Scandinavian Journal of Rheumatology. vol. 36. 2007. pp. 64-7.

Song, JY, Pittaluga, S, Dunleavy, K. “Lymphomatoid granulomatosis, a single institute experience: pathologic findings and clinical correlations”. The American Journal of Surgical Pathology. vol. 39. 2015. pp. 141-156. (Largest single institutional series of clinical and pathologic findings of lymphomatoid granulomatosis.)

Wilson, WH, Kingma, DW, Raffeld, M, Wittes, RE, Jaffe, ES. “Association of lymphomatoid granulomatosis with Epstein-Barr viral infection of B lymphocytes and response to interferon-alpha 2b”. Blood. vol. 87. 1996. pp. 4531-7.

Zaidi, A, Kampalath, B, Peltier, WL, Vesole, DH. “Successful treatment of systemic and central nervous system lymphomatoid granulomatosis with rituximab”. Leukemia & Lymphoma. vol. 45. 2004. pp. 777-80.

Zhang, Y-X, Ding, M-P, Zhang, T. “Lymphomatoid granulomatosis with CNS involvement can lead to spontaneous remission: Case study”. CNS Neuroscience & Therapeutics. vol. 19. 2013. pp. 536-538.

Primary effusion lymphoma

Ansari, MQ, Dawson, DB, Nador, R. “Primary body cavity-based AIDS-related lymphomas”. Am J Clin Pathol. vol. 105. 1996. pp. 221-9.

Antar, A, Hajj, HE, Jabbour, M. “Primary effusion lymphoma in an elderly patient effectively treated by lenalidomide: case report and review of literature”. Blood Cancer Journal. vol. 4. 2014. pp. e190

Arora, N, Gupta, A, Sadeghi, N. “Primary effusion lymphoma: current concepts and management”. Curr Opin Pulm Med. 2017. Up to date review of clinical and pathologic features of primary effusion lymphoma.

Boulanger, E, Daniel, MT, Agbalika, F, Oksenhendler, E. “Combined chemotherapy including high-dose methotrexate in KSHV/HHV8-associated primary effusion lymphoma”. American Journal of Hematology. vol. 73. 2003. pp. 143-8.

Brimo, F, Michel, RP, Khetani, K, Auger, M. “Primary effusion lymphoma: a series of 4 cases and review of the literature with emphasis on cytomorphologic and immunocytochemical differential diagnosis”. Cancer. vol. 111. 2007. pp. 224-33.

Cesarman, E, Chang, Y, Moore, PS, Said, JW, Knowles, DM. “Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas”. N Engl J Med. vol. 332. 1995. pp. 1186-91. (One of the initial reports linking HHV8 to primary effusion lymphomas.)

Chadburn, A, Hyjek, E, Mathew, S, Cesarman, E, Said, J, Knowles, DM. “KSHV-positive solid lymphomas represent an extra-cavitary variant of primary effusion lymphoma”. The American Journal of Surgical Pathology. vol. 28. 2004. pp. 1401-16.

Chen, YB, Rahemtullah, A, Hochberg, E. “Primary effusion lymphoma”. The Oncologist. vol. 12. 2007. pp. 569-76.

Cobo, F, Hernandez, S, Hernandez, L. “Expression of potentially oncogenic HHV-8 genes in an EBV-negative primary effusion lymphoma occurring in an HIV-seronegative patient”. The Journal of Pathology. vol. 189. 1999. pp. 288-93.

Dupin, N, Fisher, C, Kellam, P. “Distribution of human herpes virus-8 latently infected cells in Kaposi's sarcoma, multicentric Castleman's disease, and primary effusion lymphoma”. Proceedings of the National Academy of Sciences of the United States of America. vol. 96. 1999. pp. 4546-51.

Ferrozzi, F, Tognini, G, Mulonzia, NW, Bova, D, Pavone, P. “Primary effusion lymphomas in AIDS: CT findings in two cases”. Eur Radiol. vol. 11. 2001. pp. 623-5.

He, X-L, Yu, F, Guo, T. “T-cell lymphoblastic lymphoma presenting with pleural effusion: A case report”. Respiratory Medicine Case Reports. vol. 12. 2014. pp. 55-58.

Hisamoto, A, Yamane, H, Hiraki, A. “Human herpes virus-8-negative primary effusion lymphoma in a patient with common variable immunodeficiency”. Leukemia & Lymphoma. vol. 44. 2003. pp. 2019-22.

Horenstein, MG, Nador, RG, Chadburn, A. “Epstein-Barr virus latent gene expression in primary effusion lymphomas containing Kaposi's sarcoma-associated herpes virus/human herpes virus-8”. Blood. vol. 90. 1997. pp. 1186-91.

Karcher, DS, Alkan, S. “Human herpes virus-8-associated body cavity-based lymphoma in human immunodeficiency virus-infected patients: a unique B-cell neoplasm”. Human Pathology. vol. 28. 1997. pp. 801-8.

Katano, H, Sato, Y, Kurata, T, Mori, S, Sata, T. “Expression and localization of human herpes virus 8-encoded proteins in primary effusion lymphoma, Kaposi's sarcoma, and multicentric Castleman's disease”. Virology. vol. 269. 2000. pp. 335-44.

Klein, U, Gloghini, A, Gaidano, G. “Gene expression profile analysis of AIDS-related primary effusion lymphoma (PEL) suggests a plasmablastic derivation and identifies PEL-specific transcripts”. Blood. vol. 101. 2003. pp. 4115-21.

Klepfish, A, Zuckermann, B, Schattner, A. “Primary effusion lymphoma in the absence of HIV infection – clinical presentation and management”. QJ Med. vol. 108. 2015. pp. 481-488.

Kobayashi, Y, Kamitsuji, Y, Kuroda, J. “Comparison of human herpes virus 8-related primary effusion lymphoma with human herpes virus 8-unrelated primary effusion lymphoma-like lymphoma on the basis of HIV: report of 2 cases and review of 212 cases in the literature”. Acta Haematologica. vol. 117. 2007. pp. 132-44.

Licci, S, Narciso, P, Morelli, L. “Primary effusion lymphoma in pleural and pericardial cavities with multiple solid nodal and extra-nodal involvement in a human immunodeficiency virus-positive patient”. Leukemia & Lymphoma. vol. 48. 2007. pp. 209-11.

Matolcsy, A. “Immunoglobulin VH gene mutational analysis suggests that primary effusion lymphomas derive from different stages of B cell maturation”. Am J Pathol. vol. 153. 1998. pp. 1609-14.

Munichor, M, Cohen, H, Sarid, R, Manov, I, Iancu, TC. “Human herpes virus 8 in primary effusion lymphoma in an HIV-seronegative male: a case report”. Acta Cytologica. vol. 48. 2004. pp. 425-30.

Nador, RG. “Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus”. Blood. vol. 88. 1996. pp. 645-56.

Paner, GP, Jensen, J, Foreman, KE, Reyes, CV. “HIV and HHV-8 negative primary effusion lymphoma in a patient with hepatitis C virus-related liver cirrhosis”. Leukemia & Lymphoma. vol. 44. 2003. pp. 1811-4.

Patel, S, Xiao, P. “Primary Effusion Lymphoma”. Arch Pathol Lab Med. vol. 137. 2013. pp. 1152-1154. (Another excellent review of pathologic features of primary effusion lymphoma.)

Said, JW, Tasaka, T, Takeuchi, S. “Primary effusion lymphoma in women: report of two cases of Kaposi's sarcoma herpes virus-associated effusion-based lymphoma in human immunodeficiency virus-negative women”. Blood. vol. 88. 1996. pp. 3124-8.

Shimazaki, M, Fujita, M, Tsukamoto, K. “An unusual case of primary effusion lymphoma in a HIV-negative patient not pathogenetically associated with HHV8”. European Journal of Haematology. vol. 71. 2003. pp. 62-7.

Shin, J, Lee, J-O, Choe, J-Y, Bang, S-M, Lee, J-S. “Human herpesvirus 8-unrelated primary effusion lymphoma-like lymphoma in an elderly Korean patient with a good response to rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone”. Cancer Res Treat. vol. 49. 2017. pp. 274-278.

Sunil, M, Reid, E, Lechowicz, MJ. “Update on HHV-8-associated malignancies”. Curr Infect Dis Rep. vol. 12. 2010. pp. 147-54.

Pyothorax-associated lymphoma

Fukayama, M, Ibuka, T, Hayashi, Y, Ooba, T, Koike, M, Mizutani, S. “Epstein-Barr virus in pyothorax-associated pleural lymphoma”. The American Journal of Pathology. vol. 143. 1993. pp. 1044-9. (Initial report describing EBV in pyothorax-associated lymphoma.)

Halezeroglu, S, Akcevin, A. “Extrapleural pneumonectomy for pyothorax-associated lymphoma”. Interact Cardiovasc Thorac Surg. vol. 9. 2009. pp. 554-5.

Hibino, M, Irie, T, Ohe, M, Nakamura, N, Kondo, T. “Usefulness of diffusion-weighted magnetic resonance imaging-guided biopsy: pyothorax-associated lymphoma”. Intern Med. vol. 54. 2015. pp. 2661-2665.

Ito, K, Shida, Y, Kubota, K. “The management of pyothorax-associated lymphoma using 18F-FDG PET/CT”. Ann Nuci Med. vol. 24. 2010. pp. 649-54.

Moriya, Y, Iyoda, A, Hayashi, R. “Pyothorax-associated lymphoma diagnosed by preoperative pleural effusion aspiration cytology: a case report”. Acta Cytologica. vol. 54. 2010. pp. 66-70.

Narimatsu, H, Ota, Y, Kami, M. “Clinicopathological features of pyothorax-associated lymphoma: a retrospective survey involving 98 patients”. Ann Oncol. vol. 18. 2007. pp. 122-8.

Petitjean, B, Jardin, F, Joly, B. “Pyothorax-associated lymphoma: a peculiar clinicopathologic entity derived from B cells at late stage of differentiation and with occasional aberrant dual B- and T-cell phenotype”. The American Journal of Surgical Pathology. vol. 26. 2002. pp. 724-32. (Seminal article describing the clinical and pathologic features of pyothorax-associated lymphoma.)

Sasajima, Y, Yamabe, H, Kobashi, Y, Hirai, K, Mori, S. “High expression of the Epstein-Barr virus latent protein EB nuclear antigen-2 on pyothorax-associated lymphomas”. The American Journal of Pathology. vol. 143. 1993. pp. 1280-5.

Sekine, A, Hagiwara, E, Hashiba, Y, Ogura, T, Takahashi, H. “Clinical analysis of eight cases with pyothorax-associated lymphoma”. Nihon Kokyuki Gakkai Zasshi (The Journal of the Japanese Respiratory Society). vol. 48. 2010. pp. 186-91.

Ueda, T, Andreas, C, Itami, J. “Pyothorax-associated lymphoma: imaging findings”. AJR. vol. 194. 2010. pp. 76-84.

Pulmonary involvement by leukemia/lymphoma

Berkman, N, Breuer, R, Kramer, MR, Polliack, A. “Pulmonary involvement in lymphoma”. Leukemia & Lymphoma. vol. 20. 1996. pp. 229-37.

Callahan, M, Wall, S, Askin, F, Delaney, D, Koller, C, Orringer, EP. “Granulocytic sarcoma presenting as pulmonary nodules and lymphadenopathy”. Cancer. vol. 60. 1987. pp. 1902-4.

Costa, MB, Siqueira, SA, Saldiva, PH, Rabe, KF, Mauad, T. “Histologic patterns of lung infiltration of B-cell, T-cell, and Hodgkin lymphomas”. American Journal of Clinical Pathology. vol. 121. 2004. pp. 718-26. (Excellent article describing the various pathologic patterns of secondary pulmonary involvement by B and T-cell lymphomas.)

Green, RA, Nichols, NJ. “Pulmonary involvement in leukemia”. AmRevRespirDis. vol. 80. 1959. pp. 833-44.

Heyneman, LE, Johkoh, T, Ward, S, Honda, O, Yoshida, S, Muller, NL. “Pulmonary leukemic infiltrates: high-resolution CT findings in 10 patients”. AJR. vol. 174. 2000. pp. 517-21.

Hicklin, GA, Drevyanko, TF. “Primary granulocytic sarcoma presenting with pleural and pulmonary involvement”. Chest. vol. 94. 1988. pp. 655-6.

Koh, TT, Colby, TV, Muller, NL. “Myeloid leukemias and lung involvement”. Seminars in Respiratory and Clinical Care Medicine. vol. 26. 2005. pp. 514-9. (Excellent review of pulmonary involvement by myeloid leukemias.)

Lewis, ER, Caskey, CI, Fishman, EK. “Lymphoma of the lung: CT findings in 31 patients”. AJR. vol. 156. 1991. pp. 711-4.

Oyama, K, Kanekura, T, Yoshii, N. “Case of adult T-cell leukemia with pulmonary involvement presenting as nodular shadows”. The Journal of Dermatology. vol. 35. 2008. pp. 225-8.

Podgaetz, E, Kriegsmann, M, Dincer, EH, Allan, JS. “Myeloid sarcoma: an unusual presentation for acute tracheal stenosis”. The Clinical Respiratory Journal. vol. 10. 2016. pp. 800-804.

Shimada, M, Fukuda, M, Horio, K. “Primary mediastinal large B-cell lymphoma exhibiting endobronchial involvement”. Intern Med. vol. 55. 2016. pp. 3147-3150.

Stafford, CM, Herndier, B, Yi, ES, Weidner, N, Harrell, JH. “Granulocytic sarcoma of the tracheobronchial tree: bronchoscopic and pathologic correlation”. Respiration: International Review of Thoracic Diseases. vol. 71. 2004. pp. 529-32.

Tanaka, N, Matsumoto, T, Miura, G. “CT findings of leukemic pulmonary infiltration with pathologic correlation”. Eur Radiol. vol. 12. 2002. pp. 166-74.

Tryka, AF, Godleski, JJ, Fanta, CH. “Leukemic cell lysis pneumonopathy: a complication of treated myeloblastic leukemia”. Cancer. vol. 50. 1982. pp. 2763-70.

Rare pulmonary presentations of hematologic malignancies

Bae, HJ, Chon, GR, Kim, DJ, Lee, SH, Ahn, J-Y. “A case of intravascular large B-cell lymphoma of lung presenting with progressive multiple nodules on chest computed tomography”. Respiratory Medicine Case Reports. vol. 21. 2017. pp. 108-112.

Cartier, Y, Johkoh, T, Honda, O, Muller, NL. “Primary pulmonary Hodgkin's disease: CT findings in three patients”. Clin Radiol. vol. 54. 1999. pp. 182-4.

Evert, M, Lehringer-Polzin, M, Mobius, W, Pfeifer, U. “Angiotropic large-cell lymphoma presenting as pulmonary small vessel occlusive disease”. Human Pathology. vol. 31. 2000. pp. 879-82.

Gabor, EP, Sherwood, T, Mercola, KE. “Intravascular lymphomatosis presenting as adult respiratory distress syndrome”. American Journal of Hematology. vol. 56. 1997. pp. 155-60.

Kagiyama, N, Takayanagi, N, Ishiguro, T. “A surgical case of extramedullary plasmacytoma in the left main bronchus”. Nihon Kokyuk Gakkai Zasshi (The Journal of the Japanese Respiratory Society). vol. 47. 2009. pp. 1020-4.

Koss, MN, Hochholzer, L, Moran, CA, Frizzera, G. “Pulmonary plasmacytomas: a clinicopathologic and immunohistochemical study of five cases”. Annals of Diagnostic Pathology. vol. 2. 1998. pp. 1-11.

Malur, PR, Gaude, GS, Bannur, HB. “Primary endobronchial Hodgkin's disease”. Lung India. vol. 26. 2009. pp. 136-8.

Montero, C, Souto, A, Vidal, I, Fernandez Mdel, M, Blanco, M, Verea, H. “Three cases of primary pulmonary plasmacytoma”. Arch Bronconeumol. vol. 45. 2009. pp. 564-6.

Okada, A, Hirakawa, R, Yamashita, M, Aono, H, Choh, S, Obayashi, C. “Two cases of intravascular diffuse large B-cell lymphoma diagnosed by transbronchial lung biopsy”. Nihon Kokyuk Gakkai Zasshi (The Journal of the Japanese Respiratory Society). vol. 48. 2010. pp. 779-85.

Poletti, V, Gurioli, C, Piciucchi, S. “Intravascular large B-cell lymphoma presenting in the lung: the diagnostic value of transbronchial cryobiopsy”. Sarcoidosis Vasculitis and Diffuse Lung Diseases. vol. 31. 2014. pp. 354-358.

Owa, M, Koyama, J, Asakawa, K, Hikita, H, Kubo, K, Ikeda, SI. “Intravascular lymphomatosis presenting as reversible severe pulmonary hypertension”. Int J Cardiol. vol. 75. 2000. pp. 283-4.

Radin, AI. “Primary pulmonary Hodgkin's disease”. Cancer. vol. 65. 1990. pp. 550-63.

Rodriguez, J, Tirabosco, R, Pizzolitto, S, Rocco, M, Falconieri, G. “Hodgkin lymphoma presenting with exclusive or preponderant pulmonary involvement: a clinicopathologic study of 5 new cases”. Annals of Diagnostic Pathology. vol. 10. 2006. pp. 83-8.

Rush, WL, Andriko, JA, Taubenberger, JK. “Primary anaplastic large cell lymphoma of the lung: a clinicopathologic study of five patients”. Mod Pathol. vol. 13. 2000. pp. 1285-92.

Shinoda, H, Maejima, A, Shimizu, K, Onaka, A, Boku, T, Oyamada, Y. “A case of intravascular lymphoma with diffuse centrilobular opacities”. Nihon Kokyuk Gakkai Zasshi (The Journal of Japanese Respiratory Society). vol. 48. 2010. pp. 76-80.

Snyder, LS, Harmon, KR, Estensen, RD. “Intravascular lymphomatosis (malignant angioendotheliomatosis) presenting as pulmonary hypertension”. Chest. vol. 96. 1989. pp. 1199-200.

Takahashi, E, Kajimoto, K, Fukatsu, T, Yoshida, M, Eimoto, T, Nakamura, S. “Intravascular large T-cell lymphoma: a case report of CD30-positive and ALK-negative anaplastic type with cytotoxic molecule expression”. Virchows Arch. vol. 447. 2005. pp. 1000-6.

Takamura, K, Nasuhara, Y, Mishina, T. “Intravascular lymphomatosis diagnosed by transbronchial lung biopsy”. Eur Respir J. vol. 10. 1997. pp. 955-7.

Yousem, SA, Colby, TV. “Intravascular lymphomatosis presenting in the lung”. Cancer. vol. 65. 1990. pp. 349-53.

Yousem, SA, Weiss, LM, Colby, TV. “Primary pulmonary Hodgkin's disease”. Cancer. vol. 57. 1986. pp. 1217-24. (Seminal article describing the pathologic features of primary pulmonary Hodgkin's lymphoma.)

Zhao, Q, Liu, Y, Chen, H. “Successful chemo-radiotherapy for primary anaplastic large cell lymphoma of the lung: A case report and literature review”. Am J Case Rep. vol. 17. 2016. pp. 70-75.

Primary pulmonary AIDS-related lymphoma

Bazot, M, Cadranel, J, Benayoun, S, Tassart, M, Bigot, JM, Carette, MF. “Primary pulmonary AIDS-related lymphoma: radiographic and CT findings”. Chest. vol. 116. 1999. pp. 1282-6. (Excellent series describing imaging features in primary pulmonary AIDS-related lymphomas.)

Boulanger, E, Meignin, V, Baia, M. “Mucosa-associated lymphoid tissue lymphoma in patients with human immunodeficiency virus infection”. British Journal of Haematology. vol. 140. 2008. pp. 470-4.

Corti, M, Villafane, MF, Trione, N, Schtirbu, R, Narbaitz, M. “Primary pulmonary AIDS-related lymphoma”. Rev Inst Med Trop Sao Paulo. vol. 47. 2005. pp. 231-4.

Ray, P, Antoine, M, Mary-Krause, M. “AIDS-related primary pulmonary lymphoma”. American Journal of Respiratory and Critical Care Medicine. vol. 158. 1998. pp. 1221-9. (One of the initial small series of patients defining the clinical features of primary pulmonary AIDS-related lymphoma.)

Sigel, K, Pitts, R, Crothers, K. “Lung malignancies in HIV infection”. Semin Respir Crit Care Med. vol. 37. 2016. pp. 267-276. (Excellent review of AIDS defining lung malignancies including HIV-related pulmonary lymphoma.)

Verma, V, Jain, S, Singhal, S. “AIDS-associated primary pulmonary MALT lymphoma”. Respiratory Care. 2011.

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