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.