The patient is a 63 year-old woman with coronary artery
disease who developed a progressive neurologic illness that resembled spinocerebellar ataxia. As her
physician thought her neurologic illness may have been a manifestation of a paraneoplastic syndrome, she
underwent chest and upper abdomen computed tomography (CT) looking for a primary lung malignancy. The
chest CT showed a 2.0-cm in diameter nodule in the left lung apex. Contrast studies suggested it was
likely malignant and she had the nodule resected. Sections are from this nodule.
Diagnosis: Consistent with nodular lymphoid hyperplasia (mantle cell/marginal
zone B-cell hyperplasia); type 2 pneumocyte hyperplasia with "Dutcher Body-like inclusions.
Case 5 - Figure 1 - Low magnification view of the biopsy. It shows a localized, nodular lymphoid lesion that largely replaces the underlying lung architecture. The lesion is unencapsulated and shows mild extension into the surrounding lung around vessels.
Case 5 - Figure 2 - Scattered nodules composed of small lymphocytes are present within the lesion.
Case 5 - Figure 3 - This view shows the edge of a lymphocytic nodule and the intervening parenchyma. The nodule consist of small lymphocytes with round or oval nuclei and scant cytoplasm. The intervening parenchyma shows sheets of plasma cells of mature appearance with intermixed small lymphocytes.
Case 5 - Figure 4 - Another view of the parenchyma between nodules. This shows abundant plasma cells, small lymphocytes, and cuboidal cells (presumably type 2 cells) lining alveolar spaces. At least one of these alveolar lining cells contains an intranuclar inclusion, which can lead to its mistaken identification as a Dutcher body.
The patient never developed signs or symptoms of hematolymphoid
malignancy and died 3 years later of aspiration pneumonia secondary to her neurologic illness.
Light Microscopic Findings:
The sections show a lymphoid nodule whose
border is unencapsulated and somewhat ill defined. The principal finding is effacement of much of the
underlying architecture by a lymphoplasmacytic lesion. Specifically, there are scattered nodular
aggregates of small lymphocytes with round uniform nuclei, occasional small germinal centers of reactive
appearance, and intervening sheets of plasma cells with Russell bodies amid hyaline fibrous connective
tissue. Scattered small germinal centers are present. While there appear to be abundant "Dutcher
bodies" at medium magnification, on closer inspection the intranuclear inclusions lie within type 2 cells
proliferating along the surface of residual alveolar spaces. Although a few lymphocytes infiltrate among
bronchiolar cells, they are not sufficiently abundant in number to state that there are lympho-epithelial
lesions present. The lymphoid cells do not invade pleura or bronchial cartilage; there are only a few
perivascular aggregates of lymphoid cells at the margin of the lesion.
The lymphoid nodules are composed principally of B cells, as shown by staining with CD20,
with only a small admixture of CD-3+ T cells. Somewhat greater numbers of CD3+ cells surround the
nodules, and they are also present in the interstitium.
The key question is whether these nodular aggregates of B cells are follicular center
cells, mantle cells, or marginal zone lymphocytes. Although a bcl-6 stain is not available, the
lymphocytes do not have the indented or cleaved nuclei of follicular center cell lymphomas.
Morphologically, the cells could be mantle cells, but an IgD immunohistochemical stain decorated only
about 20-40% of them, which means that 60-80% of the cells do not stain as mantle cells. Thus, by
elimination, these non-staining cells are probably marginal zone cells (unfortunately a CD21 stain is not
available and the bcl-2 stain did not work), although a subset of mantle cells cannot be excluded. A CD5
stain was negative. Finally, scattered nodules of CD23+ dendritic cells were present, supporting the
presence of residual germinal centers.
Antibodies against kappa and lambda light chains did not stain the small lymphocytes, but
they did show the abundant plasma cells to stain in a polytypic manner. Molecular studies showed no
evidence of clonal rearrangements of immunoglobulin genes (mu, lappa, IgH) or of T cell receptor genes
In sum, the nodular B cells are most likely marginal zone cells with an admixture of
mantle cells. It is not clear whether the lesion is benign or malignant on histological grounds; this
distinction requires immunohistochemical and molecular studies. Those results support a reactive
lymphoid process or at least do not show a clonal process. Therefore, I favor a very unusual reactive
lesion, that is, a form of nodular lymphoid hyperplasia with features of hyperplasia of mantle/marginal
zone B cells.
Pulmonary nodular lymphoid
hyperplasia is a term first suggested by Kradin and Mark 9 to refer to one or more nodules or
localized lung infiltrates consisting of reactive lymphoid cells. A less favored synonym is
pseudolymphoma. The concept of masses of reactive lymphoid tissue in lung is controversial because most
microscopically low-grade lymphoid proliferations in lung, including those with abundant germinal
centers, are overwhelmingly extra-nodal marginal zone B-cell lymphomas of MALT type.2, 6, 11 This has
led to suggestions, particularly from Europe, that the term "pseudolymphoma" be disregarded as redundant
or inaccurate and that reactive lymphoid nodules or masses do not occur in lung.2, 5, 12 However, a
recent immunohistochemical and molecular pathologic study has confirmed the existence of rare cases of
pulmonary nodular lymphoid hyperplasia.1 This case provides further support to the existence of these
lesions, but it is histologically different and indeed unique, as far as I can tell.
Cases of nodular lymphoid hyperplasia of lung (NLH) that we reported in the literature
share some histologic features with the present case.1 Most lesions are solitary. The pulmonary
nodules measure from 0.6 cm to 6 cm in greatest dimension, but most are 2-4 cm (the present case was
almost 2 cm in maximum dimension).1
The lymphoid lesion is usually subpleural, but it can be peribronchial. Of interest,
despite the subpleural location of the lesions, the plaque-like invasion of the overlying pleura by the
lymphoid infiltrate seen commonly in MALTomas is rarely seen.
NLH is by definition histologically localized. In classic cases, the most striking
feature is the numerous reactive germinal centers with well-preserved mantle zones and sheets of
interfollicular mature plasma cells associated with fibrosis. The germinal centers in classic cases of
NLH stain for the B-cell marker CD20, while interfollicular lymphocytes are immunoreactive for CD3, CD43
and CD5.1 Stains for bcl-2 do not decorate the follicles. The CD20-positive lymphocytes in cases of
NLH do not co-express either CD43 or CD5. The immunoglobulin light chain reactivity is typically
polyclonal in NLH. Molecular genetic analyses show no rearrangement of the immunoglobulin heavy chain
gene or for the T cell gene receptor in NLH.1 The plasma cells in NLH show Russell bodies, but as in
this case, they don't contain Dutcher bodies.
Case 5 differs from these previously reported cases of NLH in that it shows only
occasional small follicles and only scattered clusters of follicular dendritic cells, as shown by
staining for CD23. Instead, there are the peculiar small lymphoid nodules. However, it does have the
interfollicular sheets of mature plasma cells and interfollicular fibrosis that obliterates the
underlying lung parenchyma typically seen in NLH. It is therefore reasonable to assume that it could be
a related lesion, but it certainly differs histologically and is unique in the lung, in my experience.
Has a similar lesion been described elsewhere? Hunt and associates 14 described reactive lesions of
unusual histologic appearance in peripheral lymph nodes that they termed "hyperplasia of mantle/marginal
zone B cells". These lesion shared some features with the present case, in that they consisted of
nodules of monomorphic small B cells, identified as either marginal zone cells or mantle cells, with
round nuclei, with few, small and scattered germinal centers present. These nodular B cells lacked
monotypic staining for light chains and failed to show molecular evidence of clonality (except in one
case). However, these lesions differed from case 5 in failing to show the extensive plasmacytosis so
prominent in it.
Certainly, the most important disease in differential diagnosis is
low-grade marginal zone B-cell lymphoma of MALT (MALToma).6, 8, 11 This low-grade B-cell
lymphoma of lung is far more frequent than nodular lymphoid hyperplasia; hence, any solitary lymphoid
mass in lung is much more likely to be lymphoma than not. The clinical presentation of patients with
extra-nodal marginal zone B-cell lymphomas, including the age distribution, symptoms and chest
radiographic appearance, greatly ovelaps that of individuals with nodular lymphoid hyperplasia (6, 8,
11). Typically, these lymphomas are of low histological grade and they often contain reactive germinal
centers, nodules of small lymphocytes, monocytoid B cells, and admixed plasma cells.6, 8, 10 A
subset show Dutcher bodies, which, if present, point towards a diagnosis of lymphoma. Case 5 shows
nodules of small lymphocytes and sheets of plasma cells; histologically, it could be a MALT lymphoma.
Case 5 also shows numerous eosinophilic intra-nuclear inclusions that resemble Dutcher bodies. However, these nuclear inclusions, which are also PAS-positive, are
present in replicating type 2 cells, not in lymphocytes or plasmacytoid lymphocytes. These type 2
cellular inclusions are well known to occur in bronchioloalveolar carcinomas derived from type 2 cells
and of course can occur in their non-neoplastic counterparts.3 Misidentification of type 2 cell
inclusions as Dutcher bodies is therefore an important pitfall in diagnosis of MALT lymphomas (and
lymphoplasmacytic lymphomas) in the lung.
Pulmonary MALT lymphoma is far more invasive of surrounding lung than NLH. It can show
penetration of bronchial cartilage plates (occurring in up to 66% of cases), plaque-like involvement of
pleura over a low-power field (over 50% of cases), lymphoepithelial lesions, and extensive lymphangitic
spread. These features are not prominent in case 5 and thus a diagnosis of MALT lymphoma cannot be made
based using them.4, 8
MALT lymphomas usually (about 75% of cases) show a monoclonal pattern for immunoglobulin
light chains in paraffin sections and they consist of CD20+, CD43+ cellular infiltrates with smaller
numbers of infiltrating T cells. Despite the absence of a CD43 stain in this case (the presence of
numerous plasma cells that usually stain for CD43 can also cause confusion), the absence of a monotypic
pattern of light chain staining in a case with a prominent plasmacytic component, and the absence of a
clonal population by gene rearrangement serve to make a pulmonary MALT lymphoma unlikely. The same
argument can be used to exclude lymphoplasmacytic lymphoma.
Giant lymph node hyperplasia or Castleman disease also needs to
be considered in differential diagnosis. The disease is of two types: the hyaline vascular and plasma
cell types, although mixed or transitional forms can also occur. It is the plasma cell and mixed types
that must be considered in the differential diagnosis of this case because they show hyperplastic or
involuted follicles, aberrant mantle zone lymphocytes and an interfollicular stroma that is both
hyalinized and rich in polytypic plasma cells.13 However, Castleman disease rarely involves lung, and
most cases that do so are of the hyaline vascular type. Typically, pulmonary lesions present as solitary
hilar masses due to involvement of the hilar lymph nodes. In the plasma cell type, there is typically
multicentric disease in the thorax and the lesions are systemic, with associated hepatosplenomegaly and
massive systemic lymphadenopathy. Polyclonal hypergammaglobulinemia is typical, and patients with HIV
seropositivity show an increased incidence of this variant. There are no clinical findings in this case
to support this scenario, as far as I am aware. Further, these lesions typically occur within lymph
nodes in the lung, although an LIP pattern in the lung has been reported in the plasma cell variant.7
Histologically, a concentric pattern of sclerosis is not seen in case 5, the lesion is not lymph
node-based and there is no evidence of LIP.
- Abbondanzo SL, Rush W, Bijwaard KE, et al. Nodular lymphoid hyperplasia of the lung: A
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- Addis B, Hyjek E, Isaacson P. Primary pulmonary lymphoma: a re-appraisal of its histogenesis and is
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- Clayton F. Bronchoalveolar carcinomas. Cell types, patterns of growth and prognostic correlates.
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- Colby T, Yousem S. Pulmonary lymphoid lesions. Semin Diagn Pathol 1985;2:183-.
- Corrin B. Pathology of the Lungs. London: Churchill Livingstone, 2000.
- Kennedy J, Nathwani B, Burke J, et al. Pulmonary lymphomas and lymphoid lesions. Cancer
- Johkoh T, Muller NL, Ichikado K, et al.: Intrathoracic multicentric Castleman disease: CT findings
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- Koss M, Hochholzer L, Nichols P, et al. Primary non-Hodgkin's lymphoma and pseudolymphoma of lung:
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- Kradin R, Mark E. Benign lymphoid disorders of the lung, with a theory regarding their development.
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- L'Hoste R, Filippa D, Lieberman P, et al. Primary pulmonary lymphomas. A clinicopathologic analysis
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- Li G, Hansmann M-L, Zwingers T, et al. Primary lymphoma of the lung: morphological,
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- Nicholson A, Wotherspoon A, Diss T, et al. Reactive lymphoid disorders. Histopathology
- Weisenberger, DD, Nathwani, BN, Winberg CD, Rappoport, H. Multicentric angiofollicular lymph node
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- Hunt JP, Chan JA, Samoszuk M, Brynes RK, et al. Hyperplasia of mantle/marginal zone cells with clear
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