Pulmonary Lymphoid Proliferations: A Practical Diagnostic Approach
Jeffrey L. Myers
- Recognize distinctive histologic features of various primary pulmonary lymphoproliferative disorders.
- Understand the key morphologic clues to distinguishing various forms of small lymphocytic lesions.
- Understand the role of specialized studies in separating primary pulmonary lymphoproliferative disorders.
- Recognize the histologic and immunophenotypic features that distinguish lymphomatoid granulomatosis from other forms of pulmonary lymphoma.
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|
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.
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
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
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
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
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.
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
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