Discussion
The median age (11 years) and location of common LN involvement (head
and neck) in our patients is comparable to previous studies. The male
predominance of cases was not as dramatic as other case series, which
have found a nearly 2:1 ratio. 2,8 Compared to the
prior single-center review of PTGC from Shaikh, et al (2013), our
patients underwent fewer recurrent lymph node biopsies (5% versus
52%).2 The larger sample size and longer duration of
follow-up for the current report suggest that repeated biopsies are less
common than previously reported.
The percent of patients with preceding or concurrent diagnosis of
lymphoma was similar to that previously found (10% versus 14%) in the
Shaikh, et al study (2013).2 Our study reiterates the
reported association of PTGC with lymphoma;5 however,
it does not argue against the more likely view that PTGC is a vigorous
reactive process. Antecedence or concurrence with lymphoma can also be
said of established reactive processes such as follicular hyperplasia,
which is concurrently identified in virtually all LNs with PTGC. An
interesting histopathologic study by Chang, et al (2003) suggested that
follicular hyperplasia and PTGC constitute an evolutionary spectrum in
resolution of lymphoid hyperplasia with sequential ingression of T-cells
followed by mantle B-cells.9 More recently, Gars, et
al (2020) employed a multitude of immunohistochemical stains to study
the immunoarchitecture of lymphoid follicles and pointed out that PTGC
is a conceivable stage in the life cycle of a reactive germinal
center.10 It is notable that no patient with PTGC in
our cohort went on to develop a new malignancy within the time frame of
follow-up. Our hospital system allowed for the treatment of patients
until the age of 21 years during the time of this study, and all 26 of
the patients who would have “graduated” from pediatric care by 2020
had been diagnosed a minimum of 7 years prior to the end of the
inclusion period.
Fewer patients at our center had immune-mediated conditions associated
with PTGC compared to the prior review (5% versus 24% in Shaikh et al,
study). ALPS, CVID, Castleman disease, systemic lupus erythematosus
(SLE), and autoimmune cytopenias have all been previously described in
patients with PTGC.2,11,12 Two of the patients in our
cohort had increased double-negative T-cells on LN flow cytometry, but
neither patient had confirmatory testing for ALPS within our center, and
one had a pre-existing diagnosis of CVID. Our patient with Evans
syndrome (immune-mediated anemia and thrombocytopenia) who developed
PTGC had previously been evaluated for ALPS but did not have increased
double-negative T-cells; due to persistent bulky lymphadenopathy and
development of neutropenia, repeat flow cytometry and FAS gene mutation
analysis were sent, both of which returned negative. He was noted to
have low IgM and elevated IgG, with increased transitional B cells in
his immune cell subsets (CD21 low, CD19 high), concerning for a
developing immunologic defect, but unfortunately was lost to follow-up.
Only one of the patients in our study presented with fever. This patient
did not have evidence of infection on physical exam or by extensive
laboratory evaluation, although she did have evidence of systemic
inflammation as demonstrated by elevated ESR and CRP values. PTGC has
been reported in patients with HIV and upper respiratory tract
infections; infection screening is recommended based on exposure
history.13
Our review adds to the literature about the diagnostic evaluation and
referral patterns for pediatric patients with PTGC. Of our 57 patients,
only nine were seen by a PHO specialist prior to biopsy; one was seen by
an infectious disease specialist prior to biopsy. The rest were
diagnosed after referral to a pediatric otolaryngologist or general
surgeon at our pediatric hospital. All nine patients seen by PHO had a
follow-up visit to discuss biopsy results, while 12 patients were
referred to PHO for follow-up after biopsies resulted. These 21 patients
all had some subset of laboratory evaluations sent, as described above,
and were followed for anywhere from 1 week to 5 years after initial
biopsy. Although most of these 21 patients only had one visit with PHO,
patients who had prior or concurrent history of lymphoma were followed
for longer, and one patient whose brother had a history of relapsed CHL
was followed for over 2.5 years. Of the 36 patients who did not see PHO
at all, only 9 (25%) had any blood tests sent. These 36 patients did
not have in-person follow-up with any of our children’s hospital
providers, and if counseling occurred on the telephone regarding the
potential for recurrence, increased risk of lymphoma, and association
with autoimmune or lymphoproliferative conditions, this was not
documented in our EMR.
Given the association of PTGC with lymphoma and lymphoproliferative
conditions, we propose that a PHO specialist should see and examine
patients diagnosed with PTGC at least once following their diagnostic
biopsy, if they have not yet been involved in their care. Given that
laboratory evaluations may not be performed by the provider performing
the biopsy, a PHO specialist would have the expertise to draw labs
tailored to the patient’s presentation and counsel patients and families
on close monitoring. Yan, et al (2022) proposed standardized Tier 1
investigations recommended for all patients with isolated
PTGC.13 Additional visits to PHO may be necessary
depending on recurrence of lymphadenopathy, abnormal lab values, family
history, and patient needs.