Objectives

1. Recognize distinctive histologic features of various primary pulmonary lymphoproliferative disorders.
   
   
2. Understand the key morphologic clues to distinguishing various forms of small lymphocytic lesions.
   
   
3. Understand the role of specialized studies in separating primary pulmonary lymphoproliferative disorders.
   
   
4. Recognize the histologic and immunophenotypic features that distinguish lymphomatoid granulomatosis from other forms of pulmonary lymphoma.

Introduction
A number of lymphoproliferative diseases, including benign and malignant disorders, may involve the lung primarily (Table 1). The following discussion briefly outlines some of the entities that present as lung tumors, focusing on key histopathologic features useful in differential diagnosis.

Table 1: Classification of Pulmonary Lymphoproliferative Disorders

Benign lymphoproliferative disorders Follicular bronchitis/bronchiolitis Localized/nodular lymphoid hyperplasia ("pseudolymphoma") Lymphoid interstitial pneumonia Malignant lymphoproliferative disorders Non-Hodgkin lymphoma Extranodal marginal zone B-cell lymphoma (MALT lymphoma) Intermediate/high grade lymphoma Lymphomatoid granulomatosis Intravascular lymphomatosis Hodgkin lymphoma Secondary pulmonary lymphoma/leukemia Miscellaneous conditions Posttransplant lymphoproliferative disorders EBV-related lymphoid infiltrates in other immunocompromised patients

Benign Lymphoproliferative Disorders
Follicular bronchitis/bronchiolits and lymphoid interstitial pneumonia (LIP) represent overlapping ends of a spectrum of diffuse pulmonary lymphoid hyperplasia. Together with localized ("nodular") lymphoid hyperplasia, referred to historically as "pseudolymphoma", these conditions represent the benign forms of small lymphocytic proliferations, a topic covered in greater detail elsewhere in the program. From a practical histopathologic diagnosis point of view the features most helpful in separating these entities from low grade B-cell lymphomas/leukemias, principally extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT lymphoma), are summarized in Table 2.

Table 2: Histopathologic Differential Diagnosis of Small Lymphocytic Proliferations of the Lung

	FB	LIP	NLH	MALT
Tumefactive growth	absent	absent	present	present
Lymphangitic growth	limited to bronchovascular bundles	absent	absent	present
Lymphoepithelial complexes	rare	rare	rare	common
Lymphoid follicles with germinal centers	main finding, bronchovascular bundles	focal finding, bronchovascular bundles	localized finding, randomly distributed	focal with mantle zone "colonization", randomly distributed
Cytology	typical of benign follicles	polymorphic, including plasma cells	polymorphic including typical benign follicles and plasma cells	monomorphic including centrocyte-like/monocytoid small lymphocytes ± plasmacytic differentiation/plasma cells

Abbreviations:
FB – follicular bronchitis/bronchiolitis
LIP – lymphoid interstitial pneumonia
NLH – nodular lymphoid hyperplasia
MALT – extranodal maginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)

Malignant Lymphoproliferative Disorders

Extranodal marginal zone B-cell lymphoma (MALT lymphoma)
Low grade pulmonary lymphomas account for over 80 per cent of primary pulmonary lymphomas, and nearly all are MALT lymphomas analogous to those described in other extranodal sites. The histological findings in low lymphoma are distinctive and most cases can be diagnosed on the basis of routinely stained sections alone. At low magnification the main change is the presence of a dense lymphoid infiltrate with both tumefactive and lymphangitic growth patterns. The lymphoid infiltrate is accentuated along bronchovascular bundles, interlobular septa, and visceral pleura. In contrast to diffuse forms of lymphoid hyperplasia, the infiltrate is expansive and forms scattered microscopic or macroscopic nodules that obscure the underlying lung structures. Lymphoepithelial complexes involving bronchiolar epithelium are common but can also occur in other lymphoproliferative lesions. Involved bronchoalveolar bundles may show vascular infiltration ("angiitis"), a nonspecific findings seen in a range of lymphoproliferative disorders. At higher magnification the lymphoid infiltrate is relatively monomorphic and is composed of "centrocyte-like" cells with slightly irregular nuclear contours and scant or clear cytoplasm. Plasmacytic differentiation is seen in about a third of cases and includes the presence of plasmacytoid lymphocytes and mature plasma cells. PAS-positive intranuclear inclusions (Dutcher bodies) are present in some cases. Dutcher bodies are much more commonly associated with lymphomas than reactive lymphoid infiltrates and can be a helpful feature in distinguishing low grade lymphoma from benign conditions. Synchronous or metachronous transformation to large cell lymphoma has been described in as many as 10 to 15 per cent of cases, a finding of uncertain prognostic significance.

Secondary changes are frequently seen in MALT lymphomas and may cause difficulties in diagnosis. Patchy areas of organizing intraluminal fibrosis are seen in some cases and may be confused with organizing pneumonia, also termed bronchiolitis obliterans organizing pneumonia (BOOP). The key to diagnosis is recognition of the underlying lymphoid infiltrate with a lymphangitic distribution. Non-necrotizing granulomas can also occur, particularly in patients with underlying Sjogren's syndrome, and can mimic granulomatous infection, hypersensitivity pneumonia, or sarcoidosis. Again, distinguishing these conditions depends on recognition of a prominent monomorphic lymphoid infiltrate with a distribution more typical of lymphoma. Amyloid is an uncommon finding in low grade lymphomas of the lung and can take the form of either diffuse alveolar septal or nodular amyloidosis.

Malignant lymphomas of follicular center cell origin are distinctly uncommon among primary pulmonary lymphomas, representing only 15 per cent of the 121 low grade lymphomas reported by Koss et al. Most form destructive tumorous masses. Recognition of a follicular center cell lymphoma in the lung should prompt a careful search for evidence of extrapulmonary disease.

Lymphomatoid granulomatosis
Liebow and colleagues first described pulmonary lymphomatoid granulomatosis (LYG) as a distinct clinicopathologic entity in 1972. It was defined as an angiocentric lymphoproliferative process with prominent pulmonary involvement. As originally described, the diagnosis hinged on recognition of a characteristic histologic triad: 1) polymorphic lymphoid infiltrate, 2) angiitis, and 3) "granulomatosis". The most distinctive feature was the presence of a polymorphic mononuclear cell infiltrate composed of small lymphocytes, plasma cells, and variable numbers of large immunoblasts. Angiitis was a consistent finding characterized by transmural infiltration of the walls of arteries and veins by mononuclear cells. The term "granulomatosis" was used to describe the necrosis occurring within the lymphoid nodules rather than true granuloma formation.

The intimate relationship between LYG and malignant lymphoma was well recognized from the outset. The original authors balked at designating the condition lymphoma because most patients lacked nodal disease, the liver and spleen were rarely involved, occasional patients spontaneously recovered, and the polymorphic nature of the infiltrate defied existing histological criteria for diagnosis of lymphoid malignancy. Recognition of extranodal lymphomas over the intervening decades has explained some of the "deviant characteristics" of LYG and there is now little doubt regarding the neoplastic nature of this lesion.

LYG has characteristic clinical features. Males are affected more often than females by a ratio of 2-3:1; patients usually present in the fifth or sixth decade of life. Respiratory symptoms, most commonly cough, occur in the majority of patients and are frequently associated with systemic complaints such as fever and weight loss. Extrathoracic manifestations are common and include skin involvement in 37% and central or peripheral nervous system involvement in 30% of patients. Chest roentgenograms and CT scans typically show bilateral discrete rounded nodules which may show cavitation. Intrathoracic adenopathy is rare as is peripheral adenopathy. Traditionally, LYG-lymphoma has carried a poor prognosis with a cumulative mortality of 57% in the two largest retrospective series. Recent experience suggests that aggressive chemotherapy substantially improves survival. Wilson and colleagues reported success in 4 patients using interferon-a2b as a single agent, and suggested further investigation of antiviral/immunomodulating drugs in this condition.

Most cases of LYG are EBV-related B-cell lymphoproliferative disorders with an exuberant reaction of non-neoplastic T lymphocytes analogous to "T-cell rich B-cell lymphomas". Historically most cases of LYG were analyzed using frozen section immunostains and were thought to have a mature T-cell phenotype consistent with peripheral T-cell lymphoma. An aberrant T-cell phenotype was reported in a few cases, although clonal rearrangements of the T-cell receptor gene were documented only rarely and never in lung tissue. In 1994 Guinee and colleagues demonstrated a minor population of EBV-infected CD20 positive B lymphocytes in biopsies of LYG with clonal rearrangements of the immunoglobulin heavy chain gene in two thirds. They concluded that most cases of LYG involving the lung were EBV related B-cell lymphoproliferative disorders with a prominent component of reactive T lymphocytes. Several authors subsequently confirmed the unique phenotype that characterizes most cases of LYG. Indeed the current WHO classifications of lymphoid and lung neoplasms limits the term to lesions with this phenotype. There is, however, a small subset of histologically identical lesions that lack the anticipated population of EBV-infected B lymphocytes with no discernable difference in clinical features, treatment response or outcome. Whether these represent true peripheral T-cell lymphomas or cases in which the host response has obscured the underlying clonal expansion of B cells is unresolved. For that reason the precise role of immunophenotyping studies in this context remains controversial.

The differential diagnosis of LYG in lung biopsy specimens includes mainly Wegener's granulomatosis and other forms of malignant lymphoma. Wegener's granulomatosis differs from LYG that the cellular infiltrate is composed of acute and chronic inflammatory cells and the vasculitis consists of focal vessel wall necrosis rather than transmural infiltration by lymphoid cells. Other forms of malignant lymphoma, including Hodgkin's disease and non-Hodgkin's lymphomas, can involve the lung and show histologic features that overlap with LYG. Recognition of Hodgkin's disease requires identification of diagnostic Reed-Sternberg cells as it does in extrapulmonary sites. Distinguishing LYG from other types of non-Hodgkin's lymphomas is more problematic. The term LYG should be reserved for those cases with the histologic triad initially outlined by Dr. Liebow et al: a polymorphic lymphoid infiltrate, vascular infiltration, and necrosis. It is the presence of a polymorphic infiltrate in at least a portion of the tumor that is most useful in distinguishing LYG from other forms of pulmonary lymphoma. Vascular infiltration alone is an insufficient criterion because it can occur in other types of malignant lymphoma.

Other non-Hodgkin's lymphomas
Intermediate and high grade lymphomas account for a minority of primary pulmonary lymphomas. At least some represent transformation of MALT lymphomas. Most patients with lung involvement by intermediate and high grade lymphomas other than transformed MALT or LYG have evidence of disease elsewhere. Indeed the lung may be second only to the liver as a site of extranodal involvement in patients with either Hodgkin or non-Hodgkin lymphomas, occurring in as many as 38% and 24% of patients respectively. Affected patients are usually symptomatic and complain of dyspnea and cough. The most common radiographic pattern is the presence of solitary or multiple nodules. Diffuse forms of lung involvement also occur an may be linked to the type of underlying lymphoma (see Table 3). Patients with intermediate and high grade lymphomas have a worse prognosis than patients with low grade lymphoma, but it is unclear whether this is related to the increased frequency of higher stage disease or is independently tied to histological grade.

Table 3: Histologic Growth Patterns in Secondary Lung Lymphomas^*

Lymphoma Type	N	Peribronchial-vascular	Nodular	Alveolar	Interstitial	Pleural
B-cell	43 (56%)	30 (70%)	14 (32%)	6 (14%)	11 (25%)	31 (76%)
T-cell	20† (26%)	15 (75%)	6 (30%)	6 (30%)	10 (50%)	11 (55%)
Hodgkin	14 (18%)	11 (79%)	9 (64%)	4 (29%)	5 (36%)	9 (64%)

^*modified from Costa et al. Am J Clin Pathol 2004; 121: 718-26.
^†includes 1 patient with primary lung lymphoma

Intermediate and high grade lymphomas show a combination of lymphangitic and nodular growth and can usually be diagnosed on the basis of their malignant cytological characteristics. Necrosis is a common finding and can result in cavitation of tumor nodules; indeed, necrosis is a prominent feature in some cases and can obscure the neoplastic nature of the lesion. Anaplastic (CD30 positive) large cell lymphomas can also present with primary pulmonary involvement. Secondary findings such as germinal centers, granulomas, and areas of organizing pneumonia are uncommon in intermediate and high grade tumors.

Differential diagnosis of primary intermediate and high grade lymphomas is limited. Intermediate and high grade lymphomas are usually easily recognized as malignant tumors, but can be confused with either Hodgkin's disease or poorly differentiated epithelial neoplasms. Paraffin section immunoperoxidase stains can be very helpful in resolving the differential diagnosis in difficult cases, and can also be used to immunophenotype histologically recognizable malignant lymphomas. Fresh tissue is rarely required for diagnosis or immunophenotyping in this circumstance. It should be noted that epithelial membrane antigen expression is not limited to carcinomas and can occur in some lymphomas, particularly CD30-positive anaplastic large cell types, and that CD15 can be expressed in carcinomas. Therefore these antibodies should be employed as part of a panel that includes antibodies to keratin and CD45.

Intravascular lymphomatosis, formerly referred to as malignant angioendotheliomatosis, is a rare form of lymphoma in which tumor cells predominate within vascular lumens. Patients usually present with systemic complaints including prominent skin and central nervous system involvement. Less commonly patients may present with respiratory symptoms prompting lung biopsy for diagnosis. The main change is the presence of atypical lymphoid cells distributed in an exquisitely intraluminal and perivascular pattern. Immunostains usually show positive staining for leukocyte common antigen within the neoplastic cells and are helpful in excluding metastatic carcinoma or sarcoma.

Hodgkin lymphoma
Although autopsy series have shown pulmonary involvement in a substantial percentage of patients with Hodgkin's disease, primary pulmonary Hodgkin's disease is rare. Primary pulmonary Hodgkin's disease affects women more often than men and tends to occur in older individuals. Most are symptomatic and complain of cough, dyspnea or chest pain in addition to systemic symptoms. Chest radiographs typically show nodular opacities which can be solitary or multiple. The presence of B symptoms, age > 60 years, and multiple/bilateral nodules are associated with a more aggressive course. Histologically, macroscopic nodules are common and are frequently associated with microscopic satellite nodules and patchy interstitial infiltrates distributed along lymphatic routes. Necrosis is common and occasionally mimics the appearance of necrotizing granulomatous inflammation. Non-necrotizing sarcoidal granulomas can also occur. Diagnosis hinges on recognition of characteristic Hodgkin's cells, just as it does in extrapulmonary sites.

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