California Tumor Tissue Registry
Case of the Month
June, 2003
“A 29 y/o Man with Malaise and a Mass in the
Neck”
A 29-year-old male presented to his family physician with a
two week history of malaise, fever, sore throat, and a neck
mass. A monospot test was negative. On physical exam, a
four cm mass in the left neck was palpated, eventually
excised, and submitted for pathologic examination.
Fig. 1. Lymph node follicles were enlarged and irregular and were separated by
interfollicular zones filled with pale-staining cells. Insert: High magnification showed
these “monocytoid B cells” to have small, round, mature nuclei and moderate amounts of
pale or clear cytoplasm.
Fig. 2. Some interfollicular regions showed early necrosis (insert).
Fig. 3. Some cells contained large, eosinophilic intranuclear inclusions. Note that many
of the surrounding lymphocytes had increased amounts of pale cytoplasm.
Fig. 4. More viral inclusions. Note the engulfed granulocyte (insert).
Fig. 5. An immunohistochemical stain for CMV showed only rare positive cells.
DIAGNOSIS: Cytomegalovirus (CMV) lymphadenitis
Christopher Poulos, M.D., Resident in Pathology, and
Dennis P. O’Malley, M.D., Assistant Professor
Department of Pathology and Laboratory Medicine
Indiana University School of Medicine
Reactive lymphadenopathies are usually categorized by the structural and immunologic
areas of the lymph node that are affected (4). Generally:
 those that involve follicles are associated with B-cells and humoral immunity,
 those that involve the interfollicular spaces are associated with T-cell
abnormalities and cell-mediated immunity, and
 those that involve the sinuses are part of a monocyte/macrophage response.
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June, 2003
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Follicular responses are seen in a wide variety of disorders including HIV
lymphadenopathy, syphilis, and others. Diffuse lymph node involvement (usually
paracortical) (5) is seen with Epstein-Barr virus (EBV) infection, Varicella-Zoster virus
(VZV) infection, Herpes simplex virus (HSV) infection, and postvaccinial
lymphadenopathy (4). Involvement of the lymph node sinuses is seen in Rosai-Dorfman
disease, other histiocytic proliferations, and in certain non-infectious disorders. A mixed
pattern of nodal involvement may be encountered in a variety of entities including
Toxoplasmosis, and in granulomatous infections such as cat-scratch disease and Yersinia.
Classic acute EBV infection or infectious mononucleosis (IM) usually has distinctive
clinical findings and usually do not require lymph node biopsy. Occasional cases,
however, may require biopsy to rule out other causes of lymphadenopathy including
malignancy (4).

IM lymphadenitis is the prototype of a group of reactive lymphadenopathies
which display diffuse paracortical involvement (5). The typical appearance of IM
is of an expanded and mottled paracortex, immunoblastic proliferation, germinal
centers that are usually small (but can be hyperplastic with follicular lysis), and a
prominent vascular proliferation. The mottled appearance of the paracortex is
primarily due to large transformed immunoblasts that are admixed with small
paracortical T-cells, plasma cells and plasmacytoid lymphocytes. Although the
presence of atypical immunoblasts, mitoses, and focal necrosis may cause
confusion with large cell lymphoma, the polymorphous nature of the
accompanying cells helps identify the proliferation as being reactive.
Additionally, an unusual vascular prominence of venules with plump endothelial
cells (perhaps incited as part of a generalized immune response) further supports a
benign interpretation (5). In reactive lymphadenopathies (such as IM) the nodal
sinuses are typically patent and filled with the reactive immunoblasts (2). The
sinuses are usually unapparent in lymphomas. In reactive conditions the nodal
architecture tends to be intact (but distorted), but is effaced in lymphoma.
Besides large cell lymphomas, the differential diagnosis of IM lymphadenitis may
include anaplastic large cell lymphomas and classical Hodgkin lymphoma (cHL).
In addition to morphology, immunohistochemistry may be helpful in these
situations. An immunostain for EBV may highlight large lymphocytes in IM,
however it should be noted that some lymphomas are also EBV positive.
Reactive lymphadenopathies due to CMV infection, HSV infection, VZV infection, or
the post-vaccination state can all produce nearly identical morphologic changes to those
seen in the previously-described prototypic EBV infection.

CMV lymphadenitis may show localized lymphadenopathy with follicular
hyperplasia and paracortical proliferations of monocytoid B-cells (4). Some cases
will reveal the characteristic brick-red CMV intranuclear inclusions as are seen in
our discussion case. These inclusions are usually found in T-cells or more often,
within stromal or endothelial cells (5). Some infected large lymphocytes will be
positive for CD15 and this may cause confusion with the RS cells of cHL. As in
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the current case, IHC for CMV, or FISH may provide confirmation of the
diagnosis.

HSV lymphadenitis can produce a very similar histologic picture as IM or CMV
lymphadenitis, however the skin lesions are so characteristic that lymph node
biopsy is rarely performed (4). But occasionally, HSV may present only with
lymphadenitis and be otherwise asymptomatic, leading to biopsy. HSV
lymphadenopathy tends to involve regional lymph nodes (i.e. inguinal) and the
presence of isolated HSV lymphadenitis is often associated with hematopoietic
malignancies (1,5).
HSV lymphadenitis usually shows a paracortical
immunoblastic proliferation, a polymorphous interfollicular infiltrate, and
prominent necrosis. Multinucleated giant cells and typical Cowdry type A viral
inclusions are only occasionally seen. The inclusion-bearing cells are often
within the areas of necrosis (3). The primary differential diagnosis of HSV
lymphadenitis is between other causes of necrotizing lymphadenitis, such as
Kikuchi’s disease, other infectious lymphadenopathies, and high-grade
lymphomas. As with other forms of viral lymphadenitis, diagnosis of HSV
lymphadenitis can be confirmed using either viral immunostains or hybridization.

Yet another form of lymphadenitis that can cause confusion with lymphoma is
postvaccinial lymphadenitis. It has been reported that 50% of reported cases of
postvaccinial lymphadenitis have previously been misdiagnosed as lymphoma of
either the Hodgkin or Non-Hodgkin type (4). This emphasizes the need for
adequate clinical history in evaluation of lymph nodes. Most cases present with
enlarged, painful, lymph nodes presenting 7-15 days after vaccination in the area
draining the injection site. The prototype of postvaccinial (“post immunization”)
lymphadenitis occurs after administration of the smallpox vaccine. In the classic
case, post-vaccinial lymphadenitis is histologically seen as a diffuse (before 15
days), or follicular (after 15 days) hyperplasia of immunoblasts with a mottled
paracortex (4). The immunoblastic proliferation can resemble other forms of viral
lymphadenitis and is accompanied by the typical changes seen in other reactive
lymphadenitis. As with other viral lymphadenitis, the architecture of the node is
distorted but not effaced as in lymphomas. Despite the fact that a postvaccinial
lymph node may have Reed-Sternberg-like cells, the changes appear reactive and
are unlike those seen in cHL (4). Nodes that are post-measles vaccination can
appear very similar, but have increased numbers of plasma cells and usually
contain Warthin-Finkeldy giant cells (4).
The array of histologic lymph node changes associated with HIV infection are
collectively known as “Persistent Generalized Lymphadenopathy” (PGL). Baroni and
Uccini have stated that patients with PGL have an increased rate of progression to AIDS
(1). As with the previously discussed forms of lymphadenopathy, the findings of HIV
lymphadenopathy are nonspecific and may be confused with other viral
lymphadenopathies requiring clinical and laboratory correlation to exclude other causes.
PGL most often affects cervical or axillary lymph nodes, and histologically shows
follicular abnormalities, either hyperplastic or regressive. Histologically, the first stage is
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follicular hyperplasia, consisting of increased numbers of follicles, many of which are
enlarged and poorly formed. In the hyperplastic stage, there is also a proliferation of
small blood vessels in the germinal centers, and the presence of interfollicular aggregates
of monocytoid B-lymphocytes. The germinal centers are mainly composed of B-cells
and rare T-cells. These hyperplastic changes may be with or without follicular
fragmentation, which is marked by hemorrhage in germinal centers, foci of necrosis, and
small lymphocyte infiltration of the necrotic foci. During follicular fragmentation there
is a reduction in the number of CD4+ T cells with an increase in the number of CD8+ T
cells, accompanied by follicular lysis and dissolution of the follicular dendritic cell
network (1). This follicular fragmentation may represent early regressive changes of the
lymph node and is associated thinning of the mantle zones.
The regressive changes, subclassified into follicular involution and follicular depletion,
are associated with an advanced stage of HIV disease (5).
 Follicular involution is characterized by small germinal centers with hyaline
vascular-type centers, a surrounding layer of nucleolated follicular dendritic cells,
and prominent paracortical HEVs, similar to the findings seen in Castleman’s
Disease.
 Follicular depletion, is characterized by dominant nodal fibrosis, paracortical
lymphocyte depletion, and effacement of the nodal architecture.
Toxoplasmosis, a protozoan disease, can produce lymphadenitis with a mixed histologic
pattern of nodal involvement similar to viral lymphadenopathies (4). It is estimated that
up to 50% of US adults have been infected by the organism. Toxoplasmosis typically
presents as a flu-like or IM-like syndrome. Lymphadenopathy may involve many nodes,
but most often involves only the posterior cervical lymph nodes. Although serology (not
histology) is the primary means of diagnosis, there are distinctive lymph node changes
that can aid in a diagnosis. Toxoplasma lymphadenitis is characterized by follicular
hyperplasia, marginal zone or monocytoid B cell hyperplasia, and microgranulomas that
often encroach on germinal centers. The germinal centers have ragged, indistinct
borders, many tingible body macrophages, and numerous mitotic figures.
Microgranulomas are composed of small clusters of epithelioid histiocytes without giant
cells (5). Microgranulomas may also be seen in various forms of lymphoma and
sarcoidosis, which can lead to diagnostic confusion. Other common findings in
Toxoplasmosis include the presence of subcapsular sinuses filled with the monocytoid Bcells and the presence of plasma cells and immunoblasts in the medullary cords.
Toxoplasma cysts are rarely seen in the nodes and the genomes of the organism are only
rarely detected, suggesting that the nodal findings are reactions to products of the
organism, not to the organism itself (4).
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Summary Chart of Findings in Reactive Lymphadenopathies
Type of
Lymphadenopathy
Nodal Compartment
Involved
Key Histologic
Findings
EBV (IM)
Diffuse, Paracortical
HSV
Diffuse, Paracortical
CMV
Diffuse, Paracortical
Postvaccinial
Diffuse, Paracortical
HIV
Follicular
Toxoplasmosis
Mixed
1. Atypical
immunoblastic
proliferation with
“mottled
appearance”
2. Polymorphous
background
3. Proliferation of
HEVs
4. Variable necrosis
1. Findings similar to
IM
2. Rare intranuclear
inclusions
3. Discrete foci of
necrosis; often
extensive
1. Follicular
Hyperplasia
2. Marginal zone
hyperplasia
3. Characteristic
inclusions
1. Follicular (after 15
days) or diffuse
(before 15 days)
immunoblastic
proliferation
2. Polymorphic
background
1. Follicular
hyperplasia with or
without
fragmentation
2. Follicular regression
with eventual
lymphoid depletion
1. Follicular
hyperplasia
2. Marginal zone
hyperplasia
2. Microgranulomas
Differential Diagnosis
1. Large Cell NHL
2. HD
Key Factors in
Establishing Final
Diagnosis
1. Distorted but intact
nodal architecture
2. Open sinuses
3. Polymorphic
background
4. Staining for EBVLMP
1. Kikuchi’s Disease
2. Necrotic viral,
bacterial, and
fungal
lymphadenitis
1. Immunostaining
2. In-situ hybridization
1. Other viral
adenopathies
2. CHL
1. CD 15 staining
2. In-situ hybridization
3. Immunostaining
1. cHL
2. NHL
1. History critical
1. Other viral
adenopathies
1. History
2. Viral serology
1. Sarcoid
2. NHL
1. Serology
2. Isolated posterior
cervical lymph
node involvement
REFERENCES
1. Baroni CD, Uccini S. The Lymphadenopathy of HIV Infection, Am J Clin
Pathol, 1993, 99: 397-401.
2. Childs CC, Parham DM, Berard C. Infectious Mononucleosis, The Spectrum
of Morphologic Changes Simulating Lymphoma in Lymph Nodes and
Tonsils. Am J Surg Pathol, 1987, 11(2): 122-132.
3. Gaffey MJ, Ben-Ezra JB, Weiss LM. Herpes Simplex Lymphadenitis. Am J
Clin Pathol, 1991, 95: 709-714.
4. Knowles DM, Ed. Neoplastic Hematopathology, 2nd Ed. Lippincott Williams
and Wilkins, Philadelphia, 2001, pp. 537-561.
5. Krishnan J, Danon AD, Frizzera G. Reactive Lymphadenopathies and Atypical
Lymphoproliferative Disorders. Am J Clin Pathol, 1993, 99: 385-396.
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