Intrathoracic lymphoproliferative disorders and lymphoma

INTRATHORACIC LYMPHOPROLIFERATIVE DISORDERS AND LYMPHOMA

ABSTRACT.-The spectrum of lymphoproliferative disorders is truly a continuum from benign diseases to malignant aggressive lymphomas. Remarkable advances in laboratory techniques of monoclonal antibody production and molecular biology over the last decade allow more sophisticated analysis of these diseases. It is now apparent that some entities previously labeled “benign” are actually non-Hodgkin’s lymphomas. We review the current knowledge of this spectrum including the histopathologic and clinical findings, as well as the radiographic characteristics. Understanding the diseases, treatment challenges, and follow-up requirements aids the radiologist in a more efficient and cost-effective evaluation of these patients.

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Kathleen A. Murray MD, is an assistant professor of radiology and director of thoracic imaging at the University of Utah Health Sciences Center in Salt Lake City She received a BS, summa cum laude, in mathematicsfrom Gonzaga University in Spokane, Washington, aud her MD, with highest distinction, from Indiana University. She completed an internship in internal medicine at the University of Nebraska and a diagnostic radiology residency at the University of Utah Health Sciences Center. She also completed a pediatric radiology fellowship at The Children’s Hospital in Boston under the direction of the late Dr John Kirkpatrick and a thoracic radiology fellowship at University of California at San Francisco. Her interests include thoracic oncologic imaging and trauma as well as resident and medical student education.

Paula J. Char, MD, practices pathology at St. John’s Mercy Medical Center in St. Louis, Missouri. She received her MD degree from Washington University in 1988 and then completed a pathology residency at St. John’s Mercy Medical Center in St. Louis. Her hematopathology fellowship was completed at the University of Utah.

John E Turnen Jr, MD, is an assistant professor of pathology in the section of hematopathology at the University of Iowa. Diagnostic hematopathology and teaching are his major responsibilities. He received his MD degree from the Medical College of Georgia. His internship was at Roanoke Memorial Hospital, Roanoke, Virginia. He completed his residency in anatomic and clinical pathology at the Medical University of South Carolina. He was a fellow in hematopathology at the University of Utah. His orea of interest is neoplastic hematopathology 80

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INTRATHORACIC LYMPHOPROLIFERATIVE DISORDERS AND LYMPHOMA

INTRODUCTION

Thoracic involvement is not uncommon in the lymphoproliferative disorders (LPDs) and lymphomas. LPDs form a spectrum from benign lesions to those with malignant potential.1,2 Stimulation of bronchus-associated lymphoid tissue (BALT) by antigens or other factors is thought to be the initial event leading to the development of LPDs.~ Historically most pulmonary lymphoproliferative processes were classified as benign because of a prolonged and indolent clinical course. Within the past decade, however, advances in the study of these diseases with monoclonal antibody techniques and new molecular biology developments have made it possible to perform a more specific and precise analysis of the LPDs. With increasing frequency, some of the LPDs are found to represent true non-Hodgkin’s lymphoma (NHL) . Through the application of newer and more sophisticated laboratory tests, monoclonality or polyclonality of lymphoid populations can be established with assurance. This is important because polyclonal proliferations are usually benign, and the finding of monoclonal proliferation is usually an indicator of malignancy. Benign, reactive proliferations of BALT do occur, but much less frequently than previously thought. The current criteria for benign lymphoproliferative disease require the demonstration of polyclonality. The prevalence of organ transplantation worldwide and the development of more intensive immunosuppressive therapy has altered the clinical and radiographic features of LPDs that occur in transplant recipients. Before the use of aggressive immunosuppressive drugs, the latent period and organ sites of involvement differed from the current experience. The Epstein-Barr viral (EBV) genome has been implicated in the cause of the LPDs, as either a reactivated or a primary infectious agent3 In infectious mononucleosis and posttransplant LPDs (PTLPDs) a direct causal link seems likely. In angioimmunoblastic lymphadenopathy and lymphomatoid granulomatosis, the significance of EBV remains to be established. Curr

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Advances in the understanding of both Hodgkin’s disease (HD) and NHL have also occurred because of the availability of monoclonal antibody techniques and molecular genetic analysis. The incidence of HD has been increasing progressively since 1973, predominantly as a result of an increase in the incidence of the subtype nodular sclerosing HD.4 The less common subtype of lymphocytic depletion occurs predominantly in the elderly, and its incidence has decreased, as many cases are being reclassified as NHL. The human immunodeficiency virus (HIV) appears to be associated with an increased incidence of HD. NHL has also significantly increased in incidence in the past 20 years. Part of this is attributable to the acquired immunodeficiency syndrome (AIDS) epidemic, as well as the reclassification of some of the LPDs.’ Although the spectra of LPDs and lymphoma overlap, a few generalizations can be made and are important (Table 1). Both an older age at onset (patients older than 50 years) and the presence of signs and symptoms suggest a more aggressive process, such as lymphoma. The more benign LPD entities tend to involve only one intrathoracic compartment (lymph nodes or lung parenchyma) and tend not to be associated with pleural effusions. Certain intrathoracic locations are involved more often with TABLE

1. Lymphoproliferative

disorders

1. An older age group and the presence of clinical symptoms characterize a more aggressive process and should suggest the diagnosis of true lymphoma. 2. The “benign” LPDs tend to involve only one thoracic area [lung parenchyma or lymph nodes) but rarely affect multiple compartments. Similarly, pleural effusions are very unusual with “benign” LPDs. 3. Certain members of the LPD spectrum seem to select specific thoracic areas. A. Lung parenchymal involvement (mass/infiltrates) is characteristic of plasma cell granuloma, pseudolymphoma, and lymphomatoid granulomatosis. B. Mediastinal lymph node enlargement is more typically found with Castleman’s disease, infectious mononucleosis, and angioimmunoblastic lymphadenopathy. C. Patients with posttransplant lymphoproliferative disorders may have an infiltrate, nodular masses or adenopathy or both.

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TABLE

2. Characteristics

of lymphoproliferative

Entity

Plasma

Common

cell granuloma

Castleman’s Infectious

Solitary

disease mononucleosis

Pseudolymphoma Posttransplantation lymphoproliferative

disorders

of the chest

features

mass

of

Association Epstein-Barr

with virus

Constitutional signs and symptoms

10 to 30

Unknown

Usually

Solitary mass in the middle or posterior mediastinum

20 to 30

Unknown

None

Mediastinal

10 to 20

Yes

Mild

30 to 70

Unknown

None

Yes

None

Solitary

lung

Age at time onset (yr)

adenopathy lung

mass

Solitary or multiple lung masses

Variable (usually after transplantation)

Angioimmunoblastic lymphadenopathy

Diffuse mediastinal adenopathy: may have lung masses or infiltrates

50 to 70

Yes

Moderate

to severe

Lymphoid pneumonia

Poorly defined interstitial or alveolar opacities or both

40 to 70; also seen in children with AIDS

Possible

Moderate

to severe

Poorly defined interstitial or alveolar opacities or both

30 to 50

Yes

Moderate

to severe

disorder

interstitial

Lymphomatoid granulomatosis

From Bragg DG, Char PJ, Murray KA, Kjeldsberg CR. Lymphoproliferative features. AJR 1994;163:273-81. Reproduced by permission.

specific entities. For example, involvement of the pulmonary parenchyma is typical of plasma cell granuloma, pseudolymphoma, and lymphomatoid granulomatosis, whereas involvement of mediastinal lymph nodes is more likely to be found with Castleman’s disease, infectious mononucleosis, and angiocentric immunoproliferative lesions (AILDs). The common features of the LPDs reviewed in this article are summarized in Table 2. LYMPHOPROLIFERATIVE

DISORDERS

PLASMA CELL GRANULOMA Plasma cell granuloma (PCG) has been called inflammatory pseudotumor, but frequently, no evidence of prior inflammatory illness7 or histologic features of infection are identified.8 Other names for this disorder include histiocytoma, xanthogranuloma, fibroxanthoma, and inflammatory myofibroblastic tumor.gJO Histologic Characteristics Plasma cell granuloma is a circumscribed cellular proliferation that is sharply demarcated from the surrounding pulmonary parenchyma. This mass obliterates the normal pulmonary architecture, and the histologic hallmark is a proliferation of spindle cells, arranged haphazardly or in a storiform pattern Admixed are a variable number of histiocytes and a reactive, polyclonal infiltrate of lymphocytes 82

disorders

months

none

of the lung:

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to mild

and imaging

and plasma cells that is often of sufficient intensity nearly to obscure the fibrohistiocytic component. The classification of PCG as neoplastic or reactive is not settled. Some authors believe that PCG is a low-grade fibrous histiocytoma, whereas others favor a reactive process.g,lo It is likely that cases called PCG are heterogeneous etiologic groups that manifest a similar histologic picture. Clinical Findings and Treatment PCG usually occurs in patients younger than 30 years and often younger than 13 years.7 It is the most commonly found tumorlike abnormality in the lungs of children younger than 16 years.ll This is usually an incidental finding in an asymptomatic young patient (Fig. 1). When signs and symptoms occur, they are nonspecific and include cough, chest pain, low-grade fever, weight loss, and hemoptysis.7 No consistent abnormal laboratory findings have been reported. The appropriate treatment for intrathoracic PCG is surgical removal with limited resection.12J3 Recurrence after resection is rare. Radiologic Findings The chest radiograph in the patient with PCG most often reveals a solitary mass lesion, usually within the lower lobe, and varying in size from 1 to 1.2 cm.14 Cavitation and calcification are uncommon.15 The masses are slow growing, sometimes without change for 1 to 2 years or may gradually increase with timee7 Pleural effusions and mediasCurr

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tinal adenopathy should not be present. Endobronchial PCGs with peripheral atelectasis, as well as juxtamediastinal plasma cell granuloma with invasion and compression of the esophagus, have been reported? CASTLEWS

DISEASE

Castleman’s disease was initially described by Castleman, Iverson, and Menedez17 in 1956 as a condition mimicking thymoma. This is usually manifested as a solitary mediastinal mass, but occasionally pulmonary parenchymal involvement occurs. Other names for this disorder include angiofollicular mediastinal lymph node hyperplasia, giant lymph node hyperplasia, and lymph node hamartoma.14 Histologic Characteristics The pathologic lesion of Castleman’s disease is divided into two variants, the hyaline-vascular and the plasma cell types. The overwhelming majority of mediastinal and pulmonary lesions are of the hyaline-vascular type,18-22 which is characterized by follicular hyperplasia, with atypical germinal centers distributed haphazardly in a vascular lymphoid stroma. This is a well-circumscribed mass with prominent features including a proliferation of small hyalinized blood vessels that radiate through the germinal centers and a concentric array of small lymphocytes about the centers. Interfollicular zones are expanded by a heterogeneous lymphoid population of small lymphocytes, plasma cells, eosinophils, and immunoblasts. The plasma cell type of Castleman’s disease less commonly involves the mediastinum and is characterized by expansion of interfollicular zones by sheets of mature plasma cells that surround reactive germinal centers.18z20 Hyalinized vasculature is absent in this type. This histologic appearance is relatively nonspecific, so the diagnosis of plasma cell variant of Castleman’s disease can be established only after other causes of plasmacytosis are excluded. These include autoimmune disorders (particularly rheumatoid arthritis), syphilis, adjacent malignant neoplasm, and lymph nodes draining sites of cutaneous disease.lgJO Clinical Features and Treatment Like PCG, Castleman’s disease is seen in a young age group, typically in adolescent children or young adults, with the majority of patients younger than 30 years. These patients tend to be slightly older than the preteen children with plasma cell granuloma. Signs and symptoms are not a prominent feature of Castleman’s disease, and the mass lesion is usually incidentally detected on a chest radiograph. Curr

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FIG 1. A, PA chest radiograph in 16-year-old male renal transplant recipient shows 2 cm nodule in periphery of right lung. He had no pulmonary symptoms at this time. B, Axial CT scan shows well-demarcated homogeneous peripheral mass in right lower lobe.Thorascopic resection confirmed plasma cell granuloma. (From Bragg DG, Chor PJ, Murray KA, Kjeldsberg CR. Lymphoproliferative disorders of the lung: histopathology, clinical manifestations, and imaging features. AJR 1994;163:273-81. Reproduced by permission.)

The plasma cell variant of Castleman’s disease, the less common form, may be more often associated with symptoms and a more aggressive course.8 However, these conclusions were based on data and case reviews from before modern histopathologic classification techniques and may no longer be appropriate to the current understanding of Castleman’s disease.‘O Surgical excision of the mass is the treatment of this disorder with a reported low incidence of recurrence and malignant transformation.14 Radiologic Findings The radiographic features of Castleman’s disease are typically those of a solitary mass lesion arising 83

Sternberg cells of HD. In others, the immunoblastic proliferation may be so prominent that a diagnosis of NHL is considered. In cases in which the diagnosis of infectious mononucleosis cannot be established by morphologic analysis, a thorough immunophenotypic and molecular genetic analysis may be helpful. In this disease, polyclonality can be demonstrated in the lymphoid population. EBV can often be identified in the hyperplastic lymph nodes by in situ hybridization or the polymerase chain reactionz3 This is not pathognomonic of infectious mononucleosis, however, as EBV is has now been described in a wide variety of both benign and malignant proliferative lesions.

FIG 2. PA chest radiograph shows hilar and mediastinal adenopathy in 1 g-year-old man with infectious mononucleosis. This is usually symmetric and mimics lymphoma, both radiographically and histologically. (From Bragg DG, Chor PJ, Murray KA, Kjeldsberg CR. Lymphoproliferative disorders of the lung: histopathology, clinical manifestations, and imaging features. AJR 1994;163:273-81. Reproduced by permission.)

in the mediastinum, usually in the mid or posterior mediastinum and occasionally with calcifications seen within the mass. If serial radiographs are available, the lesions are usually characterized by relatively slow growth. An evaluation by computed tomography (CT) will reveal contrast enhancement.22 INFECTIOUS

MONONUCLEOSIS

Intrathoracic involvement by infectious mononucleosis is uncommon, but when it occurs, it usually is seen as a mediastinal mass, or rarely, interstitial pulmonary infiltrates.23 A biopsy is usually not done, as clinical and serologic findings are usually characteristic. However, if biopsy material is obtained, the lymph node distortion and alteration may be quite striking and closely resemble malignant lymphoma. Histologic Characteristics The histologic pattern is that of follicular hyperplasia and florid interfollicular expansion by an admixture of lymphocytes, plasma cells, and immunoblasts.24J5 In some cases, atypical immunoblasts may be seen that closely resemble the Reed84

Clinical Features and Radiologic Findings Infectious mononucleosis is common in older teenagers and occasionally in patients 20 to XI years old. Because of the mild signs and symptoms, chest radiographs are usually not obtained, so the true prevalence of intrathoracic involvement is unknown. Occasionally, dramatic abnormalities are reported,z4 but the more typical findings on the chest radiograph of the symptomatic patient are adenopathy symmetrically involving hilar and mediastinal lymph nodes, often with splenomegaly (Fig. 2). The enlarged lymph nodes are usually subtle and may easily be overlooked. Adenopathy is usually combined with palpnble, tender, cervical and epitrochlear lymph node enlargement together with mild constitutional symptoms and characteristic laboratory findings. The clinical course of infectious mononucleosis is that of gradual involution of enlarged lymph nodes over a period of weeks to months. PSEUDOLYMPHOMA Pulmonary pseudolymphoma (PL), or nodular lymphoid hyperplasia, is the localized, mass-like counterpart of lymphoid interstitial pneumonia (LIP). 26~27Historically it has been noted that some PLs progressed to malignant lymphoma. It is now apparent that the majority of lesions classified as PLs were actually monoclonal proliferations at the onset and therefore low-grade NHLs2* PL has become a rare diagnosis, and the establishment of polyclonality is now integral to the diagnosis. Polyclonality may be confirmed by the immunohistochemical demonstration of polyclonal light chains in the lymphoid cells or a germline immunoglobulin gene configuration by Southern blot or polymerase chain reaction, Histologic Characteristics Histologically PL may be a relatively Curr

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scribed mass and may show limited interstitial extension at the periphery,2” but the lesion may not be well marginated, and satellite nodules may be found. The lymphoid population consists of an admixture of small, round lymphocytes and mature plasma cells. A variable number of histiocytes are typical and may form epithelioid granulomas. Intralesional fibrosis is common. Sheets of small cleaved cells or large transformed lymphocytes are not a feature of PL, and such a finding should intensify the search for monoclonality, as these features are more typical of lymphoma. Clinical Features and Treatment The largest series of patients with PL was reported by Saltzsteir? in 1963, long before modern criteria for classification were developed. At that time, patients with PL were usually asymptomatic and 40 to 70 years old. The reported range of malignant transformation of PL varies from 15% to as high as 80% of cases.8,11 In many of these instances of malignant transformation, an NHL was probably present at the onset of the disease. The treatment of PL is local surgical excision, but recurrence after excision can occur.14 Radiologic Findings The radiologic evaluation may show a solitary mass lesion or alveolar infiltrate (Fig. 3). Neither adenopathy nor effusion should be present as, if they are found in a patient with PL, NHL should be suspected. They are usually confined to one lobe or segment of the lung, but multiple lesions have been reported.*lJg POSTTRANSPLANT DISORDERS

LNl4PHOPROLIFERAT~

Transplant recipients who receive multiagent immunosuppression are well known to have an increased incidence of both solid tumors and lymphoid neoplasms. 30-33Posttransplant LPDs (PTLPDS) are an increasingly well-characterized subset of posttransplantation neoplasia. The prevalence varies with the organ transplanted and the immunosuppressive regimen used.34 The spectrum of expression of PTLPDs varies from that of a mild benign polyclonal proliferation of lymphoid tissue, with few if any signs and symptoms, to NHL. 35 The clinical features of PTLPDs have changed with the more aggressive use of potent immunosuppressive agents. After the introduction of cyclosporine, the latent period to the onset of a PTLPD has shortened considerably from an average of 44 months to 4 months after transplant. The sites of involvement also have Curr

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FIG 3. Multiple bilateral ill-defined masses in 44-year-old man evident on PA and lateral chest films. Biopsy showed pseudolymphoma, now an uncommon diagnosis, as many lesions given this diagnosis years ago were really non-Hodgkin’s lymphomas.

are 10

85

changed, with the central nervous system (CNS) now less often affected.36 Usual sites of involvement are the thorax, gastrointestinal tract, oropharyngeal tissues, cervical lymph nodes, and less often, peripheral lymph nodes.37 Involvement is usually localized to a regional group of nodes or an extranodal site, although the abnormal proliferation can be widely disseminated.37a38 PTLPDs have an almost invariable association with EBV.3gj40j41The prognosis is more favorable if the disease is detected and treated early. When immunosuppressive therapy is stopped, some cases spontaneously and completely resolve.

isolated lymphadenopathy or extranodal disease, and to widely disseminated disease.37s46 The time from transplantation to onset of disease varies from 1 month to several years and seems to be related to the immunosuppressive regimen used.34,37,40The reported prevalence of PTLPD is 4%, with the highest incidence reported in lung-transplant patients, in whom the incidence may reach 8%.47 The interval between transplantation and onset of disorder now is usually less than 1 year and can be even shorter in children. The course of PTLPD in patients with early onset (within 1 year of transplantation) versus lateonset disease have been different.47 In early-onset disease, mortality was less (36%), and the patients responded more predictably to decrease or withdrawal of immunosuppressive therapy (89%). In late-onset disease, mortality was greater, reported at 70%. Withdrawal of immunotherapy had less effect, and widespread disease was more frequently observed. Adjunctive treatment with antiviral agents has not been uniformly successful and is not routinely used.

Histologic Characteristics The histopathologic appearance of this disorder is a proliferation of immunoblasts and large cleaved and noncleaved lymphoid cells with a variable number of plasma cells. Reed-Sternberg-like immunoblasts may be seen. Immunoblasts and other lymphoid cells are arranged in sheets, often showing central necrosis. Infiltration of vascular walls and fibrinoid necrosis are also features. The histologic features may be quite variable in different sites of involvement. 3g,40Lymph node involveRadiologic Findings ment is typically diffuse with ablation of normal Intrathoracic involvement is most commonly architecture. Schemes to classify PTLPDs on a hischaracterized by the presence of discrete nodules, tologic basis have been proposed, but attempts to either solitary or multiple (Fig. 4). Less frequently, correlate histologic pattern to clinical outcome have infiltrative disease may be seen. Radiographic feabeen inconclusive. It has been empirically detertures are nonspecific, overlapping those of infecmined that PTLPDs responding to a decrease in tion and bronchiolitis obliterans-organizing pneuimmunosuppression or antiviral therapies have a monia. A recent report found mediastinal nodes more favorable outcome. were more frequently noted at autopsy than on raStudies of clonality reveal that some PTLPDs are diographs obtained before death. Thymic, pericarpolyclonal, whereas others are monoclona1.37 In dial, and pleural involvement also was found.35 general, polyclonal tumors tend to be polymorRadiographic abnormalities are often detected inphous in appearance, and monoclonal tumors are cidentally on routine chest studies, and findings monomorphic in appearance. Most PTLPDs are a can be verified by percutaneous transthoracic B-cell phenotype, although rare cases of T-cell pheneedle biopsy. notypes have been reported.34s42.43 EBV genome has been identified in nearly all cases of PTLPD.37 DeANGIOIMMUNOBLASTIC LJ’MPHALlENOPA7YHY tection methods include serologic results, culture, and molecular biology techniques.34 Angioimmunoblastic lymphadenopathy most often involves lymph nodes in multiple sites.48 Clinical Features and Treatment Although mediastinal lymph nodes are a frequent The natural history and specific prognostic presite, this process can also involve pulmonary padictors of PTLPD are not well established.34 Widerenchyma and pleura.4g,50 spread disease seems to portend a bad prognosis, whereas mild constitutional signs and symptoms Histologic Characteristics or involvement of a single site is associated with a Lymph node architecture is diffusely effaced in better outcome.34 Reduction in immunosuppresthis disorder, although residual atrophic germinal sion is an essential component in treatment and centers are often seen. Rich vascularity, along with may result in complete resolution of the disorthe presence of a ramifying array of small blood der.44,45 The clinical features of PTLPD range from vessels, is characteristic. The lymphoid population an infectious mononucleosis-like syndrome (fe- is heterogeneous, and the number of immunoblasts ver, pharyngitis, cervical lymphadenopathy), to is variable. If the number is high, and the 86

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FIG 4. A, PA chest radiograph shows multiple bilateral subtle parenchymal nodules (arrows) in a 62-year-old man who was asymptomatic 10 months after heart transplant. 6, Axial CT scan through one nodule shows nonspecific peripheral opacity. Thoracotomy and biopsy of mass showed non-Hodgkin’s lymphoma, a posttransplant complication. (From Bragg DG, Chor PJ, Murray KA, Kjeldsberg CR. Lymphoproliferative disorders of the lung: histopathology, clinical manifestations, and imaging features. AJR 1994;163:273-81. Reproduced by permission.)

immunoblasts are arranged in sheets or showing clear cell change, malignant lymphoma should be considered. Such lymphomas are called AILD-like T-cell lymphomas. Most AILDs are T-cell proliferations.51-53 Results of studies on clonality have been variable.54z55 Extranodal sites of involvement, including pulmonary and pleural sites, show variable patterns. Features diagnostic of AILD may be present, or there may be nonspecific lymphoid infiltrates.56 Recently, EBV genome has been detected in most cases of AILD and AILD-like lymphomas analyzed.57Js Curr Probl Diagn Radiol, May/June

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Clinical Features and Treatment Patients with AILD are usually older than 50 years and usually have rather dramatic constitutional signs and symptoms. An association with drug reactions or other hypersensitivity responses has been suggested. Even common drugs such as halothane, penicillin, and insulin have been associated with possible hypersensitivity reactions leading to AILD.5g Three clinical courses have been described.8J1,47,5g The first is a rapidly progressing clinical course in spite of aggressive treatment. The second is prolonged survival with chemotherapy that 87

FIG 5. PA (A) and lateral (B) chest radiographs show extensive mediastinal and hilar adenopathy in 59-year-old man with weight loss, fever, malaise, and generalized lymphadenopathy. Poorly defined parenchymal opacities are present bilaterally. Nodal biopsy showed angioimmunoblastic lymphadenopathy; radiographic appearance mimics lymphoma. (From Bragg DG, Chor PJ, Murray KA, Kjeldsberg CR. Lymphoproliferative disorders of the lung: histopathology, clinical manifestations, and imaging features. AJR 1994;163:273-81. Reproduced by permission.)

includes corticosteroids and antineoplastic treatments. The third is survival without therapeutic intervention. Radiologic Findings Rather than localized adenopathy, patients with AILD usually have more extensive mediastinal adenopathy with enlargement of multiple nodal groups (Fig. 5). This mimics a more aggressive lymphoma both clinically and radiographically. Although the prominent radiographic feature is enlargement of mediastinal lymph nodes, pulmonary infiltration may occur also. The combination of enlarged lymph nodes, parenchymal involvement, and pleural effusion should suggest an aggressive lymphoma. Enlargement of the liver and spleen and peripheral adenopathy have also been seen. Angioimmunoblastic lymphadenopathy is therefore a diagnostic problem for both clinicians and radiologists. A generalization of the lymphoproliferative disorders is that multicompartment intrathoracic disease (i.e., involving both mediastinal nodes and lung parenchyma) should suggest an aggressive lymphoma rather than benign LPD. AILD is the exception to this rule. LYMPHOMATOID

GRANULOMATOSIS

Liebow and CarringtonGo are credited with the initial description of lymphomatoid granulomatosis 88

(LG) in 1969. They suggested that this disorder is a variant of limited Wegener’s granulomatosis. Although it was thought to be nonneoplastic, progression or transformation to malignant lymphoma was noted in a significant number of patients.“l LG is now considered to be an aggressive multiorgan disease that primarily affects the lung and has a poor prognosis. Other sites that can be involved include the CNS, skin, abdomen, eyes, kidney, and heart. When the CNS is involved, the prognosis is particularly poor.62,63 Histologic Characteristics The original description of the histologic features is still appropriate, 61,62although theories on pathogenesis and malignant potential have evolved dramatically.63-67 LG is characterized by an angiocentric and angiodestructive lymphoid infiltrate. Three grades are described, and the classification reflects the extent of cytologic atypia and necrosis.64,66,67 This histologic grading system is correlated with response to therapy and clinical outcome.64,66 Grade 1 lesions may response to conservative treatment with prednisone and cyclophosphamide. Grade 2 lesions may respond to the same treatment or require more aggressive therapy. Grade 3 lesions can achieve clinical remission with intensive chemotherapy. 64 Recently EBV genome has been. detected in most cases of LG investigated. This finding suggests that Curr

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as in many other lymphoproliferative processes, LG may be causally linked to infections with this virus.63,65 LG is also known as angiocentric immunoproliferative lesion (AIL), and this term is favored by some investigators. AIL is thought more clearly to characterize the nature of lesion, emphasizing the proliferative nature, angiocentricity, and cytologic composition .66,68The majority of LGs (or AILS) are T-cell proliferations, usually of T-helper phenotype.64,66,67 Studies of clonality have shown T-cell receptor gene rearrangement in only a minority of cases.66-68 Nevertheless, the clinical behavior of most cases is clearly that of a malignant lymphoma. The discordance between clonality and clinical behavior remains to be settled. Clinical Features and Treatment LG occurs most often in men, with a male-to-female ratio of 2:1.14 The average age of onset of disease is 50 years with a range of 40 to 70 years. Pulmonary signs and symptoms predominate, with cough, fever, dyspnea, weight loss, and rash noted. These precede the diagnosis of LG often by weeks to months. A variety of associated diseases have been found in patients with LG, including lymphomas (both Hodgkin’s and non-Hodgkin’s), chronic lymphocytic leukemia, cancers of the gastrointestinal tract and breast, rheumatoid arthritis, ulcerative colitis, psoriasis, sarcoid, and infectious hepatitis.@ The clinical behavior of most cases of LG is clearly that of malignant lymphoma. Aggressive therapy with antimetabolites prolonged patients’ survival from t2 years to 72 months in a recent report.6g Radiologic Findings The radiographic findings in LG are most often bilateral poorly defined nodular lesions that predominantly involve the lung bases. These lesions can result from the histologic angiocentric process and represent areas of pulmonary infarctions. A few patients will have a nonspecific reticulonodular parenchymal infiltrate. 70,71The lesions can progress rapidly, commonly form cavities, and therefore mimic the radiographic features of Wegener’s granulomatosis or metastasis (Fig. 6). Although enlargement of mediastinal lymph nodes is uncommon, pleural effusions may be seen in one third of patients.14 LYMPHOID

INTERSTITLAL

Lymphoid interstitial lymphoid hyperplasia, Curr

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PNEUMONIA

pneumonia (LIP), or diffuse is an unusual diagnoses in

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FIG 6. PA chest radiograph of 71-year-old woman with rheumatoid arthritis and mild pulmonary symptoms shows multiple large bilateral masses. Biopsy confirmed lymphomatoid granulomatosis. Appearance mimics metastasis and Wegener’s granulomatosis. (From Bragg DG, Chor PJ, Murray KA, Kjeldsberg CR. Lymphoproliferative disorders of the lung: histopathology, clinical manifestations, and imaging features. AJR 1994;163:273-81. Reproduced by permission.)

immunocompetent patients. Originally described by Carrington and Liebow, LIP exclusively involved the pulmonary parenchyma. LIP was considered a benign process, although the transformation to malignant lymphoma was noted in some patients. Since the initial description, LIP is now known to be associated with several diseases. These diseases are associated with alteration in immune status (Table 3). LIP usually does not occur in immunocompetent patients, and its cause is not well understood. In some cases, the EBV genome has been identified.73-75 LIP is now considered an index disorder in establishing the diagnosis of AIDS in a child with HIV infection.74,76 Histologic Characteristics Advances in immunohistochemical and molecular techniques have led to the realization that most cases originally described as LIP are actually monoclonal proliferations from the onset and therefore better considered low-grade NHLs.‘~,~~ Currently, for unequivocal diagnosis of LIP polyclonality in the lymphoid population should be established. The histologic features of LIP are similar in immunocompetent and immunocompromised patients. In both groups, infectious causes must be diligently excluded.78-80 Histologically infiltrates of LIP are diffuse, interstitial, and typically peribronchial and perivascular in distribution, with variable exten89

TABLE

3. Summary

of diseases

associated

with

LIP

Immunodeficiency states AIDS Common variable immunodeficiency Autoimmune diseases Systemic lupus erythematosus Hashimoto’s thyroiditis Sjiigren’s syndrome Primary biliary cirrhosis Viral diseases EBV Chronic active hepatitis Other Allogeneic bone marrow transplantation Tuberculosis

tempered by changes in the immunohistochemical classification. The report’ed prevalence of lymphomatous transformation has varied from a very small percentage to approximately half of the cases.14 The lymphoid infiltrate consists of a benignappearing admixture of sma.11 lymphocytes, plasmacytoid lymphocytes, immunoblasts, and plasma cells.81 Germinal centers are often identifiable, whereas granulomas are a less frequent feature.

FIG 7. PA and lateral chest radiographs of 15-month-old girl with AIDS shows diffuse linear and nodular parenchymal disease. Lung biopsy confirmed lymphoid interstitial pneumonia. (From Bragg DG, Chor PJ, Murray KA, Kjeldsberg CR. Lymphoproliferative disorders of the lung: histopathology, clinical manifestations, and imaging features. AJR 1994;163:273-81. Reproduced by permission.)

sion along alveolar septa. The basic process is diffuse, although nodules may be formed by confluence.27~*1 Pleural involvement is unusual. Pseudolymphoma and LIP are similar histologically, and some reports suggest PL may be a localized mass-like form of LII?11,82 Malignant transformation of LIP is controversial and certainly has been 90

Clinical Features and Treatment LIP does occur with some frequency in those who are immunosuppressed and in patients with a wide variety of systemic disorders, including autoimmune diseases. LIP is relatively common in children with AIDS (Fig. 7) In adults, the onset is usually between the ages of 30 and 50 but cases in patients as old as 70 have occurred. Patients are usually symptomatic, and it is often difficult to separate the underlying disease from the evolution of LIF! Other nonspecific signs and symptoms include cough, dyspnea, weight loss, fever, and fatigue. Although these may be rather chronic, they can be catastrophic with dramatic clinical evo1ution.14 Treatment has centered on the administration of corticosteroids, but response is valriable. Significant clinical and radiographic improvement is seen in some, but progression to end-stage lung disease with honeycombing is seen in others. Radiologic Findings The radiographic appearance of LIP reflects the diffuse nature of the disease. The chest radiograph may show a purely linear intersti-tial process affecting primarily the lung bases and perihilar regions. Nodules may be formed by conflu.ence, and a nodular pattern is seen more often in patients with HIV infection. Hilar and mediastinal lymphadenopathy and pleural effusions are rare. Curr

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LYMPHOMAS INTRODUCTlON The lymphomas consist of a group of neoplasms that share many common elements but also differ in important aspects of classification, staging requirements, treatment, follow-up, and patterns of organ involvement, We outline the newer pathologic classifications, the staging requirements, therapeutic requirements, and follow-up obligations. Intrathoracic involvement by lymphoma occurs frequently. Filly et a1.84 noted a 67% incidence of intrathoracic HD and a 43% incidence of intrathoracic NHL in their radiographic study of 300 untreated patients. Sites of involvement may be mediastinum, hilum, and pulmonary parenchyma. Although extranodal lymphomas represent 24%84 to 40%~~ of lymphoid neoplasms, only 4% of the extranodal lymphomas arise in the 1ung.B4 More commonly, the lung is involved secondarily during the course of disseminated nodal lymphoma.86 Pleural effusions occur less frequently than enlarged intrathoracic lymph nodes in patients with lymphoid neoplasms. However, when malignant lymphoid cells are identified in the effusion, the prognosis is extremely poor.86 It is important for radiologists to be familiar with the lymphoid neoplasms to suggest a differential diagnosis and to aid in staging and evaluating for recurrent disease. Any type of lymphoid neoplasm can involve the thorax. Fortunately, only a few disorders are responsible for the majority of lymphoid neoplasms in the chest. We present HD and NHL according to their site of occurrence. The clinical, radiographic, and morphologic features are discussed. HODGKIN’S

DISEASE

Hodgkin’s disease (HD) is heterogeneous, and epidemiologic studies suggest that there are two different diseases. One occurs in younger patients aged 15 to 34 years, and the other affects patients older than 55 years. The incidence of HD in the younger age group has increased progressively in the last 20 years. This has been the result of a marked increase in the incidence of the nodular sclerosis subtype. Nodular sclerosing HD now represents 60% of all cases and occurs most often in whites, with an equal sex ratio. This increase has been most dramatic in young adult women. The incidence of the mixed cellularity and lymphocytic predominance subtypes has remained stable. The Curr

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lymphocytic depletion subtype represents 4% of all cases of HD and occurs predominantly in the elderly. Its incidence has now decreased, most likely the result of better classification, with many cases now reclassified as NHL. In the younger group, epidemiologic studies suggest that the disease is the result of delayed exposure to a common infectious agent. Social factors that correlate with increased risk are small family size, fewer neighborhood playmates, higher national education, and higher paternal social class. These factors are consistent with the hypothesis that the risk of HD is greater in patients who are less likely to be exposed to a common infectious agent than other children or young adults. The data are very similar to those for the risk of poliomyelitis. In older patients, social factors show little to no increased risk. For patients between 34 and 55 years, social factors correlate with the risk of HD similar to that of the younger group, but the correlation is less strong.87 Histologic Characteristics All cases of HD are characterized by malignant Reed-Sternberg cells. Mononuclear variants are admixed with numerous reactive cells because of host response to the tumor. The quantity and quality of the malignant cells and the host response vary. Histologic features may overlap with NHL. The Rye Conference in 1966 gave its name to a histologic classification of HD that is used today. Four histologic groups of lymphocytic predominance, nodular sclerosis, mixed cellularity, and lymphocytic depletion were described.88 A miscellaneous group of unclassifiable types has slightly decreased in incidence since 1973 as a result of improved laboratory methods of analysis. The availability of monoclonal antibodies and molecular genetic analysis has improved our understanding and has facilitated the exclusion of NHL that may resemble HD. Evidence of a chromosomal translocation has been identified in approximately one third of cases. The link to EBV is now firmly established by using molecular methods.87 Clinical Features and Treatment The identification of “more favorable” groups of patients (women with a small number or size of supradiaphragmatic sites or men with clinical stage I lymphocytic predominance or nodular sclerosing subtypes) has resulted in a decreasing incidence of staging laparotomy, splenectomy, and adjuvant chemotherapy. More focused radiation-therapy ports are used. Knowing the histologic subtype of HD can help the radiologist in structuring the imaging approach (Table 4). With the most common nodular sclerosing subtype, mediastinal involvement is 91

TABLE

4. Hodgkin’s

disease

Subtype Lymphocyte Nodular Mixed

predominance sclerosis

cellularity

Lymphocyte Miscellaneous

depletion [unclassifiable)

Incidence

Location/presentation

6%

Peripheral

58%

Mediastinum

23%

Usually peripheral nodes but may mediastinum or lung parenchyma Often advanced stage Peripheral nodes More frequently advanced stage Variable

4% 9%

nodes,

quite frequent, and a persistent mediastinal mass is often noted after treatment (Fig. 8). This is caused by abundant fibrous tissue stroma associated with this histologic type. The Ann Arbor staging system has been used to define the clinical stage of lymphoma since 1971 and is summarized in Table 5. This system has its limitations, as similar-stage lymphomas may vary considerably in treatment and prognosis. HD may be noted initially as a painless enlargement of lymph nodes in the neck or groin. When associated with systemic symptoms such as fevers, night sweats, or weight loss, the disease is often associated with intraabdominal extension and is denoted “B” symptoms. Until recently, patients with the stage I, II, or III disease underwent staging laparotomy and splenectomy. Recommendations for laparotomy and splenectomy are now tailored to those in whom there is a probability that the results of these invasive procedures would change the approach to treatment. In a patient in whom chemotherapy will be used, staging laparotomy in most centers is thought to be unnecessary. Laparotomy is also seldom done in patients with clinically advanced stage III and IV disease. Radiologic Findings The most common thoracic location for HD is the anterior mediastinum and hila. The mediastinum is involved much more often in patients with nodular sclerosing disease. 8g Massive disease is defined as mediastinal tumor exceeding one third of the thoracic diameter, and this involves a poorer prognosis (Fig. 9). Massive mediastinal involvement may compromise the airway and be life threatening when the patient is recumbent. These patients have a higher incidence of intrathoracic recurrence, approximately three times greater than that of patients with similar tumors but without large mediastinal masses.go An unusual associated finding of cystic thymic involvement may be seen in children with mediastinal tumor. In addition, thymic cysts have 92

Age/symptoms usually

frequently

limited

stage

All ages, usually

involved

2 peaks involve

(15-34

asymptomatic and )55 yr)

Peak at 30-40 yr, more have B symptoms Usually &O yr, most B symptoms Variable

often

have

been reported in patients after treatment with radiation for HD.gl These areas probably represent focal regions of thymic degeneration. Parenchymal involvement occurs in ~~~11112% of patients with concurrent lymph node disease.84 This is more likely to be the nodular sclerosing subtype and is seen as one or more nodules. After radiation therapy, the mediastinal mass may not completely regress. The imaging evaluation of this problem is controversial. Traditionally CT has been used to evaluate residual mediastinal masses, but the density of the residual mass may appear very similar to the tumor, and it may not be possible to distinguish tumor from fibrotic collagenous residual stroma. Magnetic resonance imaging (MRI) has been suggested as a means more accurately to differentiate radiation change from active disease but may require baseline examinations after radiation therapy. Calcification within mediastinal diseased lymph nodes may develop after treatment. These tend to be in the anterior mediastinum and resemble large granulomatous lymph nodes, larger than we would expect with typical tuberculosis effect. They may be detected in abdominal lymph nodes but are far more commonly seen in the thorax. Rarely diseased lymph nodes will calcify before treatment. Second neoplasms are reported in increasing frequency in patients treated for lymphomas, both HD and NHL. Aggressive leukemia is reported in nearly 5% of patients with HD treated with chemotherapy. The reevaluation of a patient with HD should be prejudiced by the natural history of the disease. Most patients who have recurrence will do so within 2 years of completion of their treatment.g2zg3 Twenty percent of patients with #stage I or IIA, 30% of patients with stage III, and 50% of patients with stage IV may relapse in nodal or extranodal sites.g4 Patterns of recurrence are usunlly concentrated within the thorax. It has been estimated that 70% of HD recurrence will first be noted on the chest radiograph or CT scan. g5 The areas of recurrence are usually found in the adjacent untreated areas, Curr

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postpartum 17-year-old woman with nodular sclerosing Hodgkin’s disease shows mediastir FIG 8. A, F‘A radiog graph on a recently B, Six months later, mediastinum remains slightly wide, whereas other sites of adenopathy subca rinal , and left cervical adenopathy. shows extensive adenopathy. D, After treatment, CT continues to show abnorn 1t. c, CT at lel vel of aortic arch before treatment with nodularsclerosing subtype of HD, collagenous stroma may persist and is indistinguishable densit y in I nediastir Iurn. Particularly

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ral, rig1 it hilar, are no longer ial soft -tissue from rf ?sidual

93

FIG 9. A, Massive tumor in a 35-year-old man with Hodgkin’s chest dimension at that leveLThis portends poorer prognosis.

TABLE Staae I IE II IIE III III-E III-S III-ES IV

5. Ann Areas

Arbor

Staging

disease. Bulky tumor B, Lateral radiograph

System

involved

Single lymph node region Single extralymphatic nodal site or organ Two or more nodal regions, on same side of diaphragm Disease localized to an extralymphatic site and a nodal group, on same side of diaphragm Node groups on both sides of diaphragm Above plus localized extralymphatic site Stage III plus involvement of spleen Stage IIE plus involvement of spleen Extension beyond above limits

Systemic symptoms: Each stage is divided into A: no defined symptoms, and B: defined symptoms that consist of (1) unexplained weight loss of 10% body weight in the preceding 6 months, (2) unexplained fever )38’ C, or (3) night sweats.

close to but not within the radiation-treatment port margins. These recurrences may occur as nodular mass lesions within the lung parenchyma or as illdefined enlargements of hilar structures just outside the port. Masses with or without cavitation, extension to the mediastinum, and pleural effusions can be seen. A “sentinel” node for recurrence of HD is within the rosette of nodes at the base of the heart (Fig. 10). These are usually not included in 94

is defined by mediastinal width greater than one third shows mass is filling anterior mediastinum.

of PA

the mantle radiation-treatment port. Any patient with “an enlarging fat pad” or increase in the right cardiac contour and a history of treated HD should be evaluated by CT to determine whether this is fat or progressive nodes. ” The histologic features of the relapse may be different from the initial subtype. Overall cellularity may be reduced and ReedSternberg cells may be atypical. Primary Pulmonary Hodgkin’s Disease Primary pulmonary Hodgkin’s disease is a rare entity, accounting for ~1% of the cases of HD.g7-gg The criteria for classifying a case as primary pulmonary HD are (1) histologic fleatures diagnostic of HD; (2) primary lung parenchymal disease, excluding pulmonary involvement from direct extension from the mediastinum or hilar lymph nodes; and (3) exclusion of HD elsewhere by routine staging procedures.g8-*00 Histologically the cellular infiltrate in the lung is identical with that of HD in lymph nodes. Nodular sclerosis is the most frequent subtype of HD in primary as well as secondary parenchymal lung disease.89,g8aggBands of fibrosis separate small nodules. Reed-Sternberg cells, although sometimes infrequent, are present in the typical polymorphic Curr

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cellular infiltrate of HD (lymphocytes, histiocytes, eosinophils, and granulocytes). The infiltrate follows the lymphatic distribution of the lung and occurs along bronchovascular structures, interlobular septa, and the pleura.gg Small nodules may coalesce to form larger aggregates. The infiltrate may fill alveoli and give a pneumonic appearance.86,gg In addition, secondary inflammatory changes of the lung are seen in almost all cases.gg At times, the morphologic features of HD may be simulated by a peripheral T-cell NHL or a granulomatous reactive condition. Immunohistochemical stains or molecular studies may assist in resolving the differential diagnosis. Patients with primary pulmonary HD range in age from 12 to 82 years. g8There is a bimodal age distribution, with the majority of patients first seen as young adults. A second peak occurs in adults aged 60 to 80 years.g8sgg The male/female incidence is 1:1.4. Most patients are first seen with respiratory symptoms, and one third of patients have “B” symptoms.g8 A minority of patients are asymptomatic, and pulmonary disease is discovered incidentally on chest radiographs. The clinical outcome is variable. Poor prognostic features are older age, “B” symptoms, bilateral disease, multilobe involvement, cavitation of nodules, and pleural extension.gg Radiographically primary pulmonary HD most often is seen as a solitary mass or as multinodular disease.g8~gg When solitary nodules occur, the upper lobes are involved more frequently than the lower lobes.g8J01 The radiographic pattern also includes bilateral reticulonodular infiltrates, localized pneumonic consolidation, cavitation of masses, and rarely, pleural effusions. g8,gg,86 Endobronchial lesions may occur.1oz NON-HODGKIN’S

LYMPHOIw1

When NHL involves the chest, the main sites of involvement are the mediastinum and pulmonary parenchyma. Rarely does NHL arise de novo in the lung, but more commonly, the lung is involved secondarily during the course of disseminated nodal lymphoma. Pulmonary effusions occur less frequently than enlarged intrathoracic lymph nodes. As noted earlier, when malignant lymphoid cells are identified in the effusion, the prognosis is extremely poor. NHLs are a diverse, complex group of neoplasms that derive from lymphocytes. The diversity of these neoplasms is thought to reflect different stages in lymphocyte development and transformation. Over time, NHL can change to a different form within the same host, usually differentiating into a more aggressive, higher grade NHL. A peculiar feature of NHL is that intermediate and Curr

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FIG 10. A, PA chest radiograph in patient with history of Hodgkin’s disease shows surgical slips from prior biopsy of left supraclavicular mass and splenectomy. Nodular infiltrate is present in right base. B, Four months later, this has progressed. Biopsy showed recurrent Hodgkin’s disease within parenchyma in peribronchiolar distribution.

high-grade lesions are more effectively treated and controlled with chemotherapy than are low-grade lesions. Low-grade NHL is often widespread at diagnosis (85% of patients are first seen in stage III or 95

IV), but complete remission is uncommon, and their disease usually recurs. These patients have a significant risk of transformation into a higher grade, more aggressive neoplasm. Classification of Non-Hodgkin’s Lymphoma The classification of NHL presents a challenge to pathologists and epidemiologists. Before 1982, there were six competing classification schemes for NHL, including Rappaport, Lukes-Collins, Kiel, World Health Organization, British, and Dorfman systems. A National Cancer Institute (NCI) workshop in 19821°3 studied the various classifications and found all were useful. A Working Formulation was developed to help give clinicians prognostic information for the various types of NHL, as well as to provide a common language so that clinical trials from different treatment centers could actually be compared. The Working Formulation was not designed to be a classification system and in fact is now incomplete. The discovery of the many types of Tcell lymphomas has complicated the issue, as they do not fit well within the Working Formulation. Some of the more recently described B-cell lymphomas, including low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), are difficult to place in the Working Formulation. The advances that have occurred in the understanding of the classification of NHL and the changes in terminology and classification practices have affected the analysis of incidence in epidemiologic studies. From 1973 to 1988, NHL has increased significantly by SO%, in part because of reclassification.lo4 Diffuse large-cell lymphoma is the most frequently diagnosed NHL and accounts for nearly 30% of all cases. The AIDS epidemic is thought to be the cause for the increase in incidence of large-cell immunoblastic and small-cell noncleaved NHL observed in the 1980s. The increase in extranodal lymphomas is thought to be the result of the application of more modern immunophenotypic and genotypic methods. This, for instance, has led to the reclassification of most PLs as monoclonal B-cell neoplasms. The decline in incidence of diffuse small, cleaved NHL is rather dramatic but also appears to be artifactual because of changes in classifications.lo4 The application of immunologic and molecular techniques developed recently has established new disease entities, including human T-cell leukemia/ lymphoma virus-I (HTLV-I)-associated adult T-cell lymphoma/leukemia, MALT lymphomas, and the angiocentric lymphomas (frequently associated with EBV).*04 None of these diseases fits into the Working Formulation. Although the Working Formulation is useful to provide general guidance for general management, it is not truly a classification 96

scheme nor does it incorporate immunophenotypic or molecular data. It uses a group of morphologic descriptors that permit the pathologist to divide lymphomas into several broad clinical grades. It appears obvious that further modifications of generally used classification schemes are necessary. A recent proposal from the International Lymphoma Study Group has been made and may be very helpful in acquiring data with which to compare incidence of the subtypes of lymphoma.lo5 This group of experienced European and American hematopathologists reviewed the lymphoid neoplasms and proposed a list of recognized entities. The major categories are Hodgkin’s disease, malignant B-cell, and malignant T-cell disorders. Morphologic, additional immunologic, genetic, and clinical features are used further to subclassify the disorders. Lowgrade B-cell lymphoma of MAIT, primary mediastinal large B-cell lymphoma, and angiocentric Tcell lymphoma are examples of NHLs that occur in the thorax. These lymphomas are not specifically addressed by the NC1 Working Formulation. Lowgrade B-cell lymphoma of MALT occurs in lung parenchyma and shares histologic and immunologic features with other nodal lymphomas that commonly arise in the gastrointestinal tract. Primary mediastinal large B-cell lymphoma has distinct clinical features that must be differentiated from those of HD in the mediastinum. Angiocentric T-cell lymphoma is at one end of the spectrum of lymphomatoid granulomatosis described earlier. MEDLASTINAL

INVOLVEMENT

The mediastinum is less frequently involved by lymphoma and NHL than by HD. 83 Lymphoblastic a variant of large B-cell lymphoma characteristically are seen in the mediastinum. Lymphoblastic lymphoma is a well-known 1y:mphoma that classically occurs in the anterior mediastinum of an adolescent child or a young adult. It accounts for 40% of childhood lymphomas.105 The majority of lymphoblastic lymphomas are of T-cell lineage. The neoplasm is highly aggressive but is responsive to therapy. Primary large B-cell lymphoma of the mediastinum is a distinct clinicopathologic entity. It occurs in women in the fourth decade and is seen as an anterior mediastinal mass originating in the thymus. It is locally invasive and causes frequent airway compromise and superior vena cava syndr0rne.l”” The neoplasm is composed of large lymphoid cells with variable nuclear features. Fibrosis often surrounds single cells and clusters of cells. Cells that resemble Reed-Sternberg cells are seen. Immunohistochemical stains assist in resolving the Cum Probl

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1996

differential diagnosis between primary mediastinal B-cell lymphoma and nodular sclerosing HD. These studies are especially needed on small biopsy specimens. Relapses tend to occur in extranodal sites, but the lymphoma may be cured with aggressive therapy. The mediastinum also is involved by systemic lymphoma. In fact, the only evidence of intrathoracic disease associated with a systemic lymphoma may occur in the posterior mediastinum.82 This is in contrast to HD, which infrequently involves the posterior mediastinum and usually involves contiguous lymph node groups.106,107

cases.110z112In most patients, the nodules are surgically removed, because the clinical and radiographic differential diagnosis includes carcinoma. The clinical course is indolent. There is 80% to 90% survival at 5 years,1ogz111and survival at 10 years is not uncommon.116 In a small number of cases, patients have a history of an autoimmune disorder such as Sjogren’s syndrome.108J10J11 The radiographic findings are not specific. Solitary nodules are identified on chest radiographs in slightly more than one half of cases.108J12 The size varies from 2 to 20 cm.112z117Most nodules are 2 to 5 cm.lo8 Air bronchograms are observed in 50% of the nodules.108J12 There may be multiple nodules, localized consolidation, or multiple areas of conLOW-GRADE PRIMARY PULMONARY NHL solidation.83J03J17 Hilar or mediastinal lymph nodes Low-grade B-cell lymphomas compose the maare rarely invo1ved,100 and pleural effusions are jority of primary NHL lymphomas of the 1ung.100s108- rarely seen.llz II3 These are neoplasms of small lymphoid cells that The histologic features of these lesions show solid have been classified as malignant lymphoma, small lymphoma with little or no necrosis.1o8 At the pelymphocytic type, or malignant lymphoma, small riphery of the lesion, the infiltrate expands interlymphocytic, plasmacytoid type, in the Working lobular septa and tracks along bronchovascular Formulation.100J14 Frequently there is a spectrum of structures, giving a reticulonodular pattern.110J11J18 cytologic features in these lymphomas. Currently Peripheral tumors may penetrate the visceral pleura, most of the low-grade lymphomas of the lung are producing a nodular surface. The infiltrate is combelieved to represent lymphomas of MALT.111,112 posed of a diffuse population of small lymphoid The concept of lymphomas of MALT has evolved cells containing a variable number of reactive folover the past decade. lo5j115MALT occurs naturally licles. The cytologic features are similar to those of or is acquired from antigenic stimulation in many lymphomas of MALT in other sites such as the stomdifferent organs. In the lung, the lymphoid tissue ach or salivary gland. There is a heterogeneous is associated with the bronchial mucosa. Lymphomixture of small lymphocytes with round to slightly mas are postulated to arise from this BALT of the irregular nuclear contours, monocytoid B cells, lung.log The malignant cells of MALT share plasmacytoid lymphocytes, and plasma cells.2*J11 morphologic features with normal MALT, just as Small lymphocytes often infiltrate the bronchiolar small cleaved cells of follicular lymphomas reepithelium. Immunohistochemical stains demonsemble small cleaved cells in germinal centers of strate light-chain monoclonality of the small lymnormal lymph nodes. phocytes, plasmacytoid lymphocytes, and plasma In the lung, as well as in other organs, many of cells. The reactive follicles are polyclonal. However, these lesions were previously described as PLs. We the neoplastic cells may colonize the follicleslo and now realize that the majority of lesions previously give a monotypic appearance.lll Molecular studies called PLs are low-grade B-cell proliferations. Immay be performed on frozen tissue to demonstrate munohistochemical techniques and molecular B-cell clonality.llg studies have demonstrated B-cell monoclonality in the majority of these lesions.111 The presence of OTHER PRIWY PULMONARY NHLs germinal centers is no longer accepted as a definite Low-grade B-cell lymphomas of MALT constitute benign criterion. Small lymphocytic proliferations that contain germinal centers at initial diagnosis the majority of primary pulmonary lymphomas. may recur in the lung and in other extranodal Follicular, mantle cell, and T-cell lymphomas rarely sites~1113112 occur primarily in the lung. Intermediate or highgrade lymphomas account for the remainder of priThese low-grade lymphomas occur most frequently in patients in the fifth to sixth decade.108,110- mary pulmonary lymphomas. Intermediate or high-grade NHLs represent 13% II3 No consistent gender difference is apparent. Most patients are asymptomatic, and solitary nodules are to 19%111,112of primary lymphomas of the lung. The of these lymphomas are classified as incidentally discovered on chest radiograph (Fig. majority either a diffuse, large-cell lymphoma or a large cell, 11). Patients have a monoclonal serum protein, comlymphoma in the Working Formumonly immunoglobulin M, in 22% to 30% of immunoblastic Curr

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97

FIG 11. A, PA radiograph in 14-year-old boy with nodular sclerosing Hodgkin’s disease shows bulky mediastinal radiation port. B, Eight months later, primary tumor has regressed in size, but cardiac contour has changed, border. C, Axial CT scan just above diaphragm shows large mass in right cardiophrenic angle.This was recurrent which occurs more often in bulky disease and usually within 2 years of treatment of the initial tumor.

98

Curr

Probl

tumor that was encompassed in with more prominent right atrial tumor outside the radiation port,

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FIG 12. A, PA chest radiograph in 72-year-old shows nodule contains an air bronchogram, carcinoma.

man shows an unusual

right lower radiographic

lobe nodule (arrow), which was primary non-Hodgkin’s feature that has been noted with both lymphoma

lation and are of B-cell lineage.l*l In the lung, as well as in lymph nodes, it may be difficult to subclassify large-cell lymphomas from routine histologic sections. Furthermore, subclassification is not important because treatment is similar for all subtypes. As a result of the recent international review of lymphomas by European and American hematopathologists, the current recommendation is to classify these lymphomas as diffuse, large B-cell lymphomas. lo5 The majority of patients with diffuse, large B-cell NHL are symptomatic. Respiratory symptoms, fever, and weight loss are frequent symptoms. Male and female patients are equally affected, and most patients are of middle to older ages. Solitary or multiple nodules are the most common radiographic pattern. A diffuse infiltrative pattern occurs less commonly.*12 Cavitation occurs in sssll130°~ of cases 110(Fig. 12). Hilar or mediastinal lymph nodes may be involved when the lung parenchyma is the primary site of disease.lll However, mediastinal lymph node involvement occurs more frequently in systemic lymphomas.l10 Histologically, the diffuse, large B-cell lymphomas are characterized by cytologically malignantappearing cells. The cells are large with vesicular nuclei, clumped chromatin, and multiple or large central nucleoli. Sometimes morphologic features of a low-grade lymphoma of MALT are present in the background.1**~112 Similar to other lymphomas of the lung, the tumor infiltrates the interlobular septa and visceral pleura. However, the lymphoma is predominantly located in the alveolar spaces.108,111 The malignant cells infiltrate medium or large vessels and bronchi. Focal or massive necrosis occurs, Curr Probl Diagn Radiol,

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1996

lymphoma. B, CT and bronchoalveolar

and the mitotic rate is increased. Immunohistochemical stains demonstrate B-cell lineage in the majority of the high-grade lymphomas.lll Because an undifferentiated carcinoma can histologically mimic a large-cell lymphoma, immunohistochemical stains can assist in determining cell lineage and help resolve the differential diagnosis. SECONDARY INVOLVEMENTAND IN THE LUNG BY NHLs

RECURRENCE

The lung is more commonly secondarily involved by NHL than it is the site of primary disease. A recent study indicated that the lung is secondarily involved in 5% of patients with NHLa8” Although the lung can be secondarily involved by any histologic type of NHL, diffuse, large-cell lymphoma is the most frequently seen. Low-grade lymphomas that occur in the lung are less likely to be associated with extrapulmonary disease.86~120 Patients are more frequently symptomatic when systemic lymphoma is present. The symptoms are similar to those of primary pulmonary lymphoma.l1° Intrathoracic lymphadenopathy is observed in approximately half of the patients who have secondary involvement of the lung by NHL. The mediastinal lymph nodes are frequently involved in these patients. Nodular, pneumonic, and bronchovascular-lymphangitic radiographic patterns are seen.lzl Large-cell lymphomas can have a rapid and diffuse radiographic presentationl” (Fig. 13). The histologic features of the lymphoma in the lung are usually similar to those in the lymph nodes. Low-grade B-cell lymphomas of MALT recur in 30% to 40% of patients. 10~~ Relapse may occur 99

FIG 13. A, PA radiograph in 54-year-old man with primary pulmonary non-Hodgkin’s lymphoma shows central pattern of air-space opacification.This is less common than nodular pattern. B, Two years later, extent of disease has decreased and cavitation is evident.

10 years after diagnosis. The lymphoma usually recurs in the lung, remains localized, and is clinically indolent 111~112 (Fig. 14). Recurrence in lymph nodes or other extranodal MALT sites occurs less frequently. There is evolution to a high-grade lymphoma in 5% of the cases. Primary large B100

FIG 14. A, This 18-year-old man was diagnosed with large-cell lymphoma from biopsy of groin mass. His chest film was normal. B, Fourteen days later, patient has rapid deterioration in pulmonary status, and chest film now shows mediastinal and hilar adenopathy, as well as bilateral lower lobe infiltrates. Patient died 2 days after this film was obtained. Autopsy showed extensive lymphoma in lung bases and in nodes. Aggressive large-cell lymphomas can progress so rapidly they mimic more acute events such as aspiration pneumonia.

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FIG 15. A, PA radiograph of 30-year-old man with AIDS growth.This was non-Hodgkin’s lymphoma. Lymphoma

shows right lower in AIDS population

cell Iymphomas may relapse in the lung, usually within 3 years of diagnosis. The outcome is worse than that for lymphomas of MALT.111s112 The CT appearance is indistinguishable from relapse of HD.g3 Curr Probl Diagn Radiol, May/June

1996

lobe mass. B, PA and(C) lateral radiographs 3 weeks later show may be very rapid and aggressive, mimicking abscess.

rapid

ACQUIRED IMMUNODEFICIENCYSYNDROMERELATED NHL Lymphomas occur in 2% to 5% of patients with AIDS and are the second most common malig101

nancy encountered in these patients.l” Intrathoracic involvement occurs in 10% to 20% of AIDSThe lymphomas most frerelated lymphomas.lz3 quently occur in extranodal sites and are seen with advanced stages of the disease. The radiographic appearance does not differ from that of intrathoracic lymphomas found in nonimmunocomproor poorly defined mised patients. lz2 Nodular patchy densities occur in the lung. Rapidly enlarging nodules in the appropriate clinical context should suggest the possibility of a high-grade AIDS-related pulmonary lymphomalz3 [Fig. 15). Hilar or mediastinal lymph nodes may be involved. HIV-infected patients with persistent diffuse lymphadenopathy infrequently have intrathoracic lymph node enlargement.122 When intrathoracic lymph nodes are detected, lymphoma, as well as Kaposi’s sarcoma and mycobacterial infections, should be considered in the differential diagnosis. Most AIDS-related lymphomas are intermediateto high-grade B-cell NHLs. Diffuse large-cell lymphoma, small noncleaved cell lymphoma, or large-cell immunoblastic lymphoma are the most frequent histologic types.lZ4 EBV DNA is detected in ~~~11140% of all AIDS-related lymphoma, suggesting a contribution of EBV in evolution of the lymphoma.lz4 INTMVASCULAR

LYMPHOhlATOSIS

Intravascular lymphomatosis is a rare NHL that may be seen radiographically as interstitial lung disease. lz5-lz7More commonly, it is seen with CNS or cutaneous involvement, but any organ system can be affected.127z128 Intravascular lymphomatosis is characterized by a neoplastic proliferation of large lymphoid cells confined to capillaries and small vessels. B-cell lineage is demonstrated in the majority of the cases, but T-cell lineage is occasionally observed.lZ7 Patients are typically 50 to 80 years old and are first seen with dyspnea, weight loss, fever, and often CNS symptoms. Bilateral reticulonodular infiltrates without mass lesions and without lymphadenopathy occur in the chest.125-*28 The diagnosis is made by examining tissue from an open lung biopsy. Angiodestructive lesions characteristic of angiocentric lymphomas are not seen.lz6 Malignant lymphoid cells are usually not identified in peripheral blood smears, differentiating this disorder from leukemia.lz6 Immunohistochemical stains aid in differentiating the lymphoma from metastatic solid tumors. Long-term survival can occur with chemotherapy, but many cases are not diagnosed until autopsy.lz8 102

MYCOSIS FUNGOIDES Mycosis fungoides is a cutaneous T-cell lymphoma that has distinct clinicopathologic features.lzg It occurs in middle-aged adults and usually is seen as multiple patches or plaques of the skin. As the disease progresses, cutaneous nodules develop. Involvement of lymph nodes and visceral organs such as the lung occurs late in the course of the disease. S6zary syndrome, a clinical variant of mycosis fungoides, is seen with generalized erythroderma and leukemic involvement of the peripheral blood. Clonal T cells with cerebriform nuclear morphology and a T-helper immunophenotype characterize the disorder. A chest radiograph is recommended in staging a patient with mycosis fungoides because visceral organ involvement portends a poor prognosis and influences treatment decisions. Usually there is no evidence of extracutaneous disease when there is limited skin invo1vement.12gJ30 Visceral organ involvement is commonly accompanied by peripheral lymphadenopathy. 131The lung is the most frequently involved internal organ.132 The radiographic pattern includes bilateral pulmonary nodules of varying size with either discrete or ill-defined borders, patchy areas of consolidation, and bilateral reticulonodular infiltrates. Hilar and mediastinal lymphadenopathy and pleural effusions may be present.132x133 SUMMARY

The lymphoproliferative disorders are truly a spectrum, ranging from benign lesions to complex, aggressive lymphomasi with a poor prognosis. They are a diverse and heterogeneous group of disorders. Advances in immunohistochemical and genetic analysis in the past decade have allowed better understanding of the diseases, with better classification schemes and reclassification of some. The description of polyclonality and monoclonality have helped separate the benign from malignant processes. The EBV and HIV have influenced the appearance of the disease. It behooves the radiologist to understand the natural history, classification, staging decisions, and treatment options optimally to design the imaging workup for these patients. Acknowledgments We thank Dr. David Bragg and Dr. Carl Kjeldsberg for

their support, encouragement, in producing

and editorial assistance

the manuscript. Curr

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