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Neonatal hyperimmune T-cell reaction mimicking T-cell non-Hodgkin's lymphoma following BCG and hepatitis B co-vaccination

Article · September 2012with155 Reads
DOI: 10.1007/s00428-012-1314-z · Source: PubMed
Abstract
We describe a case of a 2-week-old male infant who presented with a rapidly enlarging inguinal mass after having received both the bacille Calmette-Guérin (BCG) and hepatitis B vaccines at birth. The clinical picture raised suspicion of a neoplasm, and an excision biopsy was performed. It showed complete effacement of the lymph node architecture by a diffuse proliferation of monomorphic, mitotically active, and medium-sized T-cell blasts with strong expression of CD99. Coalescent necrotizing granulomas were also seen. The lymph node culture was negative for BCG. Upon expert review and additional molecular diagnostics, the initial pathological diagnosis of lymphoblastic T-cell lymphoma was changed to ectopic BCG lymphadenitis and hyperimmune post-vaccinal reaction. The atypical T-cell proliferation was most likely a result of the adjuvant effects of the co-administered vaccines. Post-vaccinal reactions usually involve the injection site or result in localized lymph node enlargements in the areas draining the inoculation site. This case highlights the importance of the clinical context for accurate interpretation of the pathological findings. In the setting of post-vaccinal lymphadenopathy, a biopsy is rarely needed but, when performed, should be interpreted with great caution.
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Virchows Archiv
The European Journal of Pathology
ISSN 0945-6317
Volume 461
Number 5
Virchows Arch (2012) 461:601-605
DOI 10.1007/s00428-012-1314-z
Neonatal hyperimmune T-cell reaction
mimicking T-cell non-Hodgkin's lymphoma
following BCG and hepatitis B co-
vaccination
Snjezana Dotlic, Semir Vranic,
Gordana Jakovljevic, Ivana Ilic, Mirjana
M.Kardum-Paro & Stefan D.Dojcinov
1 23
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CASE REPORT
Neonatal hyperimmune T-cell reaction mimicking T-cell
non-Hodgkin's lymphoma following BCG and hepatitis B
co-vaccination
Snjezana Dotlic &Semir Vranic &Gordana Jakovljevic &
Ivana Ilic &Mirjana M. Kardum-Paro &
Stefan D. Dojcinov
Received: 30 June 2012 /Revised: 23 August 2012 / Accepted: 3 September 2012 /Published online: 12 September 2012
#Springer-Verlag 2012
Abstract We describe a case of a 2-week-old male infant
who presented with a rapidly enlarging inguinal mass after
having received both the bacille CalmetteGuérin (BCG)
and hepatitis B vaccines at birth. The clinical picture raised
suspicion of a neoplasm, and an excision biopsy was per-
formed. It showed complete effacement of the lymph node
architecture by a diffuse proliferation of monomorphic, mi-
totically active, and medium-sized T-cell blasts with strong
expression of CD99. Coalescent necrotizing granulomas
were also seen. The lymph node culture was negative for
BCG. Upon expert review and additional molecular diag-
nostics, the initial pathological diagnosis of lymphoblastic
T-cell lymphoma was changed to ectopic BCG lymphade-
nitis and hyperimmune post-vaccinal reaction. The atypical
T-cell proliferation was most likely a result of the adjuvant
effects of the co-administered vaccines. Post-vaccinal reac-
tions usually involve the injection site or result in localized
lymph node enlargements in the areas draining the inocula-
tion site. This case highlights the importance of the clinical
context for accurate interpretation of the pathological find-
ings. In the setting of post-vaccinal lymphadenopathy, a
biopsy is rarely needed but, when performed, should be
interpreted with great caution.
Keywords BCG lymphadenitis .Blastic T-cell prolifera-
tion .Post-vaccinal reaction .Immunohistochemistry
Introduction
Bacille CalmetteGuérin (BCG)-associated lymphadenitis
usually involves the ipsilateral, axillary, supraclavicular, or
cervical lymph nodes following BCG vaccination [1]. This
uncommon post-vaccinal complication is associated with
risk factors such as young age, high vaccine concentration,
vigor of administration, and immune-suppressed settings
[1]. The enlarged lymph nodes usually spontaneously re-
gress, but in a minority of cases, they may suppurate and
drain through the overlying skin. Presentation is mostly
within 6 months from vaccination. The involved lymph
nodes are often up to 2 cm in diameter but could also be
massively enlarged [1,2]. The diagnosis is clinical and
management conservative, so biopsies are seldom taken.
The histological appearances are of suppurative granuloma-
tous inflammation with a rich infiltrate of small lymphocytic
T cells.
Hepatitis B vaccine at birth is being added to routine
immunization protocols in many countries. Most reactions
S. Dotlic (*):I. Ilic
Department of Pathology and Cytology,
University Hospital Centre Zagreb,
10000 Zagreb, Croatia
e-mail: sdotlic30@gmail.com
S. Vranic
Department of Pathology, Clinical Center of the
University of Sarajevo,
Sarajevo, Bosnia and Herzegovina
G. Jakovljevic
Department of Hematology and Oncology, Pediatric Clinic,
Childrens Hospital Zagreb,
Zagreb, Croatia
M. M. Kardum-Paro
Institute of Clinical Chemistry and Laboratory Medicine,
University Hospital Merkur,
Zagreb, Croatia
S. D. Dojcinov
All Wales Lymphoma Panel, University Hospital of Wales,
Cardiff, UK
Virchows Arch (2012) 461:601605
DOI 10.1007/s00428-012-1314-z
Author's personal copy
associated with this vaccine are confined to the injection
site, resulting in cutaneous lymphoid hyperplasia [3].
Lymphadenopathy is exceedingly rare and is due to poly-
clonal growth of both B and T cells [3].
We present a case of an infant who developed inguinal
lymphadenopathy following BCG and hepatitis B immuni-
zation at birth. The unusual clinical and challenging patho-
logical features of this post-vaccinal reaction (PVR) had
initially resulted in a diagnosis of lymphoma.
Clinical history
A 2-week-old immunocompetent male baby without a his-
tory of HIV infection presented with an isolated right ingui-
nal mass rapidly growing to a diameter of 3 cm over a period
of 1 week. At birth, he had received consecutively the BCG
and hepatitis B (Engerix B®) vaccines as part of the routine
immunization protocol in Croatia. At presentation, the only
detected abnormality was a mildly elevated erythrocyte
sedimentation rate, but otherwise the baby was well. An
ultrasound scan revealed a conglomerate of lymph nodes
in the right inguinal region. As lymphadenopathy was not in
the lymphatic drainage area of the vaccination sites, there
was high clinical suspicion of malignancy.
Materials and methods and results
Histopathology
A fine needle aspiration showed atypical lymphoid cells
suspicious of lymphoma. The bone marrow aspirate showed
no abnormality on flow cytometrical examination. A 2-cm
lymph node was excised which macroscopically appeared
homogeneous and showed small foci of necrosis. Histolog-
ically, the architecture of the lymph node was completely
effaced (Fig. 1a). There was a diffuse infiltrate of medium-
sized, regular, and mitotically active lymphoid blasts
(Fig. 1c). Coalescent palisading granulomas with copious
necrosis were also noted, but no acid-fast bacilli could be
identified (Fig. 1b).
Immunohistochemistry and molecular diagnostics
The immunostains highlighted effacement of the lymph
node architecture. The diffuse proliferation of blasts was
of T-cell phenotype with virtually no residual B-cell areas
(the lack of CD20-positive cells, Fig. 1d). There was a
considerable restriction to the expression of CD8 over
CD4 (Fig. 1gh). The majority of the cells had an activated
cytotoxic TIA1/granzyme B/perforin-positive phenotype
(Fig. 1i) in a background of abundant evenly distributed
histiocytes (CD68 positive, Fig. 1j). No aberrant loss of T-
cell markers including CD2, CD3, CD5, CD7, and CD43
was seen (Fig. 1ef). There were scattered CD30-positive
blasts (Fig. 1k). However, most cells showed strong expres-
sion of CD99 (Fig. 1l) and a high proliferation index of
90 % as assessed by Ki-67 immunostaining (Fig. 1). These
atypical features prompted the local pathologist to make a
diagnosis of T-cell lymphoma, probably of lymphoblastic
type. Upon expert review, additional immunohistochemistry
showed no expression of TdT, CD34, CD10, or CD117.
EpsteinBarr virus-encoded RNA was not detected by in
situ hybridization. The polymerase chain reaction using the
Biomed-2 T-cell receptor beta and gamma primers showed
reproducible polyclonal smears.
The lymph node culture was negative for BCG but grew
Gemella morbillorum, a streptococcus-like anaerobic bacte-
rium rarely associated with disease in humans. EBV and
CMV serology were negative. These overall findings were
interpreted as BCG lymphadenitis with reactive hyperim-
mune PVR. The baby received antibiotic therapy. The ultra-
sound and whole-body MRI scans performed after 2 months
showed no evidence of lymphadenopathy or organomegaly.
Eight months after the event, the child remains well, with no
signs of disease.
Discussion
This case of unusual hyperimmune PVR and ectopic BCG
lymphadenitis highlights several problems which have
caused substantial concerns for both clinicians and patholo-
gists. As a consequence of the atypical clinical and particu-
larly pathological findings, a malignant diagnosis was
seriously entertained.
While the literature data on the clinical and pathological
appearances of PVRs are scanty, the information available is
useful in preventing diagnostic errors [4,5]. Studies of
peripheral lymphadenopathy in children highlight the clini-
cal features which point to a high likelihood of underlying
malignancy. These include lymphadenopathy of more than
2 cm, more than 4 weeks in duration, supraclavicular in-
volvement, and abnormal laboratory and radiological find-
ings [2,6]. For pathologists, the difficulty in interpreting the
histology of PVRs partly stems from the fact that they are
quite rare. Most are managed empirically by clinicians and
pathologists who exceptionally rarely see biopsies from
these patients [1]. In most cases, PVRs involve the injection
site [1]. Lymphadenopathy is relatively uncommon. A vari-
ety of histologically brisk and sometimes blastic hyperim-
mune reactions are usually associated with small pox,
measles, and tetanus vaccines [7,8].
BCG lymphadenitis in very young patients is also uncom-
mon with an incidence estimated at 431 cases per 10,000
602 Virchows Arch (2012) 461:601605
Author's personal copy
vaccinated subjects under the age of 1 year. There is signifi-
cant geographical variation pointing to varied susceptibility of
different populations [9]. It usually takes 26 weeks after
vaccination to develop and, in 95 % of cases, presents itself
as ipsilateral, mostly axillary lymphadenopathy. Notably, in
the remaining 5 % of cases, lymphadenopathy develops in
Fig. 1 Histological features. aLymph node with effaced architecture
and a large necrotic area. bSerpiginous granulomas with peripheral
palisading of histiocytes. cDiffuse infiltrate of medium-sized and large
lymphoid blasts with mitotic activity. dCD20 shows no evidence of
any B-cell infiltrate. eCD3 highlights a diffuse proliferation of T cells.
fCD3 outlines a range of cell sizes including medium-sized and large
blasts. gCD4 highlights few positive cells; the cells showing weak
expression of CD4 are histiocytes. hThe T-cell infiltrate is restricted to
expression of CD8. iMost cells are positive for TIA1. jLarge numbers
of CD68-positive histiocytes are present. kThere are scattered CD30-
positive blasts. lMost of the T cells are positive for CD99. H & E,
original magnification: a,d,e×10, b× 40, c× 400, fl× 200
Virchows Arch (2012) 461:601605 603
Author's personal copy
areas outside the lymphatic drainage of the inoculation site
and may involve the inguinal nodes, as in our case [10,11].
The risks for BCG lymphadenitis are associated with the dose,
strain of vaccine, vigor of application, age, underlying immu-
nosuppression, and HIV infection [1]. The clinical aspect is
important, and typically there are no significant systemic
symptoms. BCG is isolated in two thirds of cases, and sapro-
phytic and anaerobic flora of different types is often detected
[12]. Likewise, acid-fast bacilli are not universally identified
by special stains, and diagnosis should not rely on their
histological identification [4]. G. morbillorum,asseeninour
case, rarely causes clinical symptoms. The typical histological
appearances of BCG lymphadenitis may not differ from cases
of tuberculous lymphadenitis. In addition, abundant suppura-
tion associated with granulomatous inflammation is also seen
[4]. There is a background T-cell infiltrate composed of small
lymphocytes. In our case, the diffuse proliferation of atypical
lymphoid blasts with effacement of the lymph node architec-
ture, as well as the clinical presentation with massive lymph-
adenopathy in an unusual site, prompted the pathologist to
consider a diagnosis of lymphoma. Our patient was immuno-
competent, with no history of HIV infection.
In our case, the baby also received hepatitis B vaccine
concurrently with the BCG. Most PVRs associated with the
hepatitis B vaccine are confined to the injection site. They
are rare and result in cutaneous lymphoid hyperplasia of B-
cell phenotype or a polyclonal proliferation of B-cell and T-
cell subsets [3,13]. It is thus unlikely that the extent of
blastic T-cell reaction would have been associated specifi-
cally to the hepatitis B vaccine. It is possible that the co-
administration and the adjuvant effect of both vaccines
together played the key role in eliciting a blastic T-cell
proliferation. The additional complicating feature in this
case was the expression of CD99. Within the T-cell lineage,
this is frequently associated with lymphoblastic lymphoma/
leukemia [14]. However, it may not be widely appreciated
that CD99 is expressed on all T cells, but the level of
expression depends on the level of maturation and also cell
subset. Most studies of CD99 expression in T cells have
assessed it by means of flow cytometry. As it is much less
sensitive, low levels of expression may not be identifiable
by immunohistochemistry on tissue samples. Not only nor-
mal CD4+ memory T cells abundantly express CD99, but
also CD8+ cells, in particular those with a cytotoxic pheno-
type [15,16]. This can potentially result in erroneous inter-
pretation of the nature of the lymphoid proliferation as
neoplastic [17]. As T-lymphoblastic leukemia was consid-
ered in this case in the differential diagnosis, while sponta-
neous remission has been reported in the literature, this is
exceptionally rare in adults and even more so in children
[18,19]. In addition, the activated cytotoxic phenotype of
this T-cell lymphoproliferation would be highly unusual in
acute lymphoblastic leukemia.
In summary, the clinical context is of paramount impor-
tance for accurate interpretation of the pathological features.
In conjunction with PVRs, both pathologists and clinicians
should be aware of the uncommon features such as massive
lymphadenopathy outside the lymphatic drainage areas of
the injection site and extensive blastic, hyperimmune T-cell
reaction. Familiarity with reactive T-cell phenotypes includ-
ing the expression of CD99 is also important. Even with the
atypical site of presentation of this PVR, the biopsy and
concerns it raised could have been avoided altogether as the
spectrum of clinical features commonly associated with
malignancy was absent. In the context of exuberant and
atypical PVR, it would be prudent to look for evidence of
underlying immunodeficiency.
Conflict of interest The authors declare no conflicts of interest.
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