Pediatric Infradiaphragmatic Hodgkin’s lymphoma: a unique identity
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Key findings
• Infra-diaphragmatic localization should be considered as a high-risk factor in stage I/II Hodgkin’s lymphoma.
What is known and what is new?
• Stage I/II is considered as early stage in Hodgkin’s lymphoma and treated without consideration to site across the diaphragm in pediatric group of patients.
• However, when we did analysis of rare type of stage I/II infra-diaphragmatic Hodgkin’s lymphoma. We found that it has distinctive biological features and much lower outcome than supra-diaphragmatic type in pediatric group patients.
What is the implication, and what should change now?
• So further studies should be carried to understand the underlying biological features responsible for such poor outcome meanwhile further intensification of chemotherapy might be beneficial especially for those who had slow response in interim positron emission tomography/computed tomography.
Introduction
Pure infra-diaphragmatic Hodgkin’s lymphoma (IDHL) presents with distinct clinicopathologic characteristics. Primary IDHL comprises merely 3% of all pediatric cases (1). Whether patients with pure infra-diaphragmatic localization have a worse prognosis than those with stage I/II supra-diaphragmatic disease remains controversial (2,3). Important questions regarding prognostic factors and optimal treatment of pure IDHL still remain unanswered, because most studies have included limited numbers of patients and/or treated with different modalities suggesting that the unfavorable profile of IDHL site is responsible for poor outcome of such group (1,4-6).
Aim of work: Evaluating the clinicopathologic features, prognostic factors and outcome of pediatric patients with IDHL diagnosed and treated at Children Cancer Hospital 57357 of Egypt.
Methods
This retrospective study included all patients with histologically confirmed stage I/II pure IDHL including clinical presentation, initial lab work and radiological findings, response to initial treatment and their outcome in comparison with supra-diaphragmatic HL (SDHL) stage I/II in the pediatric oncology department, Children Cancer Hospital, Egypt (CCHG 57357), during the period from July 2007 to December 2020. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional research board committee of Children Cancer Hospital 57357 of Egypt (No. 9/2023) with no need for informed consent as it is retrospective study. Primary therapy: all patients with classical HL received 4 to 6 courses of ABVD regimen according to their risk (7) as first-line treatment, each cycle was administered as follows: vinblastine, 6 mg/m2, IV on days 1 and 15; bleomycin 10 international unit/m2 IV on days 1 and 15; doxorubicin, 25 mg/m2 IV on days 1 and 15, and dacarbazine (DTIC), 375 mg/m2 IV on days 1 and 15. While those diagnosed as nodular lymphocytic predominant Hodgkin’s lymphoma (NLPHL) were 12 cases, 4 received ABVD (according to applied protocol during 2007–2014) and 3 of them received R-CHOP and five patients underwent surgical excision and put under follow up. Radiotherapy: for delineation of the affected group of lymph nodes, computed tomography (CT) images obtained before any intervention were reviewed to determine the radiation involved field volume. The involved field should be outlined on the simulation study and considered as the clinical target volume (CTV) encompassing all initially involved lymph nodes before the administration of chemotherapy. Yet, normal structures such as kidneys, liver, and muscles that were clearly uninvolved should be excluded from the CTV based on clinical judgment. CTV to planning target volume (PTV) margins were added according to the department policy. The dose to the involved field and the surrounding normal organs were calculated using three-dimensional or intensity-modulated radiotherapy through Monaco treatment planning system. The radiotherapy dose is 1,980 cGy given in 11 fractions (180 cGy per fraction). Bulky tumors received an extra dose (boost) of 540–1,080 cGy according to the bulk of the disease and its location.
Inclusion criteria
This study includes all patients (less than 18 years old) with pathologically confirmed HL with complete work up. Those with infra-diaphragmatic localization only either stage I, or stage II.
Exclusion criteria
- Stage III/IV HL.
- Patients with no available data (missing medical records, laboratories and /or radiological diagnostics data).
- Stages I/II supra-diaphragmatic site at presentation.
- Staging procedures: all patients were staged according to the Ann Arbor system and underwent fluorodeoxyglucose positron emission tomography (FDG-PET) scan for all patients, and bilateral bone marrow biopsies (BMB) when indicated (stage IIB).
- PET/CT images were revaluated by radiologist and nuclear medicine physician, blinded to the original results of patient’s outcome.
- B symptoms: fevers to more than 101 °F (38.3 °C), drenching night sweats, or unexplained weight loss of more than 10% of body mass over 6 months (8).
- Tumor bulk: a single nodal mass in contrast or multiple smaller node of 10 cm or ≥1/3 of thoracic diameter at any level of thoracic vertebra as determined by CT (8).
- Relapse free survival (RFS) calculated from the date of diagnosis to the date of last follow-up or to date of relapse, failure to achieve complete remission (CR) or second malignancy.
- Overall survival (OS) was measured from the date of diagnosis to the date of last follow-up or to the date of death from any cause.
- Statistical analysis: descriptive analysis for the patients’ demographics will be done as medians/means + standard deviation for quantitative variables, although site and bone marrow by only frequencies/percentages for qualitative variables. The outcome will be evaluated by calculating OS and RFS using Kaplan-Meier on SPSS PROGRAM. Given a significance level of 0.05.
Results
From total 991 pediatric patients diagnosed as staged I/II HL, over a period of 13 years, there were 35 IDHL patients making incidence of IDHL in our hospital 3.5% of total cases diagnosed as stage I/II HL, age at presentation was ranged from 4.3 to 17.8 years with median age of diagnosis was ten years, male to female ratio 2.5:1, stage II disease was the most common (26/35) accounting to 74.8% of the studied group, B symptoms were evident in 12 patients only. Regarding pathological type: NLPHL accounted for 34.3% of cases (12/35) while most prevalent histological type was classical HL (CHL) of mixed cellularity (MC) type in 37.1%, by comparing this with pathological types of SDHL we found that NLPHL diagnosed in 6.3% of cases while the most prevalent histological type in CHL was nodular sclerosis (NS) accounting for 49.1% with statistical P<0.001 of different prevalence of pathological type according to diaphragmatic site. Patients’ characteristic at initial evaluation illustrated in Table 1.
Table 1
Patient characteristic | With infra-diaphragmatic disease (n=35) | With supra-diaphragmatic disease (n=956) | P |
---|---|---|---|
Age, years, median (range) | 10.1 (4.3–17.8) | 8.8 (1.6–18) | 0.90 |
Gender | 0.90 | ||
Female | 10 (28.6%) | 268 (28%) | |
Male | 25 (71.4%) | 688 (72%) | |
Stage | 0.06 | ||
1A | 8 (22.9%) | 262 (27.4%) | |
1B | 1 (2.9%) | 34 (3.6%) | |
2A | 15 (42.9%) | 518 (54.2%) | |
2B | 11 (31.4%) | 142 (14.9%) | |
B symptoms** | 0.01 | ||
No | 23 (65.7%) | 780 (81.6%) | |
Yes | 12 (34.3%) | 176 (18.4%) | |
Pathological subtype** | <0.001 | ||
Mixed cellularity | 13 (37.1%) | 403 (42.2%) | |
NLPHL | 12 (34.3%) | 60 (6.3%) | |
Nodular lymphocyte rich | 2 (5.7%) | 24 (2.5%) | |
Nodular sclerosis | 8 (22.9%) | 469 (49.1%) | |
Radiotherapy | 0.09 | ||
No | 14 (40%) | 259 (27.1%) | |
Yes | 21 (60%) | 697 (72.9%) | |
Event (relapse & secondary malignancy) | 0.001 | ||
Yes | 7 (20%) | 60 (6.3%) | |
No | 28 (80%) | 896 (93.7%) |
**, secondary malignancy. NLPHL, nodular lymphocytic predominant Hodgkin’s lymphoma.
Erythrocyte sedimentation rate (ESR) was available in 80% of patients; 57% of them ESR was <30 but there no significant correlation between either with OS or RFS and ESR at cut off 30 in infra-diaphragmatic patients.
The incidence of Event either relapse or secondary malignancy in the studied group was higher than supra-diaphragmatic (20% versus 6.3%) respectively with statistical significance (P=0.001).
However, our infra-diaphragmatic cohort had higher incidence of B symptoms than supra-diaphragmatic cohort with statistically significant P=0.01 yet correlation of OS and RFS according to presence of it is not significant in infra-diaphragmatic cohort in contrast to supra-diaphragmatic cohort where occurrence of B symptoms affects OS only P=0.02 (Table 2).
Table 2
Variables | Site | OS | RFS | |||
---|---|---|---|---|---|---|
5 years | P value | 5 years | P value | |||
B symptoms | Infra-diaphragmatic | 0.30 | 0.91 | |||
Positive | 78.8% | 68.8% | ||||
Negative | 93.8% | 79.6% | ||||
Supra-diaphragmatic | 0.02 | 0.16 | ||||
Positive | 95.9% | 88.9% | ||||
Negative | 98.7% | 93.5% | ||||
Radiotherapy | Infra-diaphragmatic | 0.26 | 0.46 | |||
Received | 83.2% | 77% | ||||
Not received | 100% | 72% | ||||
Supra-diaphragmatic | <0.001 | 0.007 | ||||
Received | 99.4% | 93.6% | ||||
Not received | 92.9% | 90% |
OS, overall survival; RFS, relapse-free survival.
We did correlation of OS with stage of disease in infra-diaphragmatic cohort and found lower OS of stage II than stage I (84.6% versus 100%) respectively but with no statistical significance (P=0.35) in contrary, RFS was lower in stage I than stage II (57.1% versus 79.8%) respectively also with no statistical significance (P=0.14).
The 60% of our patients (21/35) had received radiotherapy, nineteen of them were CHL and only two patients were NLPHL however correlation of OS and RFS between patient who received and those who didn’t was not significant.
In our study, radiotherapy affect OS and RFS only in supra-diaphragmatic cases where the cases who received radiotherapy had better OS and RFS (99.4% and 93.6%) at 5 years in comparison to cases of supra-diaphragmatic who did not receive (92.9% and 90%) at 5 years respectively with statistically highly significant P<0.001 for OS, P=0.007 for RFS (Table 2).
In the infra-diaphragmatic cohort: thirty patients treated with chemotherapy and did interim PET/CT post 2nd cycle of chemotherapy, correlation of OS with interim PET/CT was statistically significant being 100% for cases with negative PET/CT versus 25% for cases who had positive PET/CT (P<0.001) (Figure 1; Table 3). Correlation of interim PET/CT response with RFS was also significant where cases with negative PET/CT had RFS of 93.8% versus 25% for positive PET/CT patient at 5 years (P<0.001) (Figure 1; Table 3).
![Click on image to zoom](http://cdn.amegroups.cn/journals/ales/files/journals/30/articles/10018/public/10018-PB6-2039-R1.jpg/w300)
Table 3
Variables | Negative interim PET/CT | Positive interim PET/CT | Total number | P value |
---|---|---|---|---|
Number | 26 | 4 | 30 | – |
At 5 years | ||||
Number of deaths | 0 | 3 | 3 (100%) | – |
OS | 100% | 25% | <0.001 | |
Number of relapses | 1 | 3 | 4 (100%) | – |
RFS | 93.8% | 25% | <0.001 |
IDHL, infra-diaphragmatic Hodgkin’s lymphoma; PET/CT, positron emission tomography/computed tomography; OS, overall survival; RFS, relapse-free survival.
Correlation of RFS with pathological type revealed that cases with NLPHL had lower RFS versus CHL being 48.6% versus 89.7% at five years with statistical significance (P=0.01) (Figure S1); however, OS correlation between the same group was not significant (88.1% for CHL versus 88.9% for NLPHL at 5 years, P=0.94) (demography, treatment and outcome of cases of NLPHL illustrated in Table S1).
OS of whole studied group was 87.8% (Figure S2) while the RFS was 76.2% at 5 years (Figure S2).
Correlation of the OS and RFS was statistically significant according to diaphragmatic site where cases of stage I/II IDHL had significant lower OS and RFS (87.8% and 76.2% for infra-diaphragmatic stages I/II versus 98.2% OS and 93% RFS at 5 years for SDHL) (P value for OS was 0.01) (P value for RFS was <0.001) (Figure 2).
![Click on image to zoom](http://cdn.amegroups.cn/journals/ales/files/journals/30/articles/10018/public/10018-PB7-1705-R1.jpg/w300)
We did further sub-analysis of HL according to diaphragmatic site based on pathological type and when we compared outcome of NLPHL across diaphragm; we found significant difference in both OS and RFS where cases of supra-diaphragmatic had OS 100% vs. 88.9% for infra-diaphragmatic cases at 5 years (P=0.03) also RFS was 85.5% for supra-diaphragmatic NLPHL versus 48.6% for infra-diaphragmatic cases at 5 years (P=0.007). we did not find the same statistical difference in OS and RFS in other types (MC or NS) however both had lower OS and RFS in infra-diaphragmatic patients (Table 4).
Table 4
Pathological type | OS | RFS | |||
---|---|---|---|---|---|
5 years | P value | 5 years | P value | ||
MC | 0.2 | 0.46 | |||
Infra-diaphragm | 90% | 90% | |||
Supra-diaphragm | 98.3% | 95% | |||
NS | 0.16 | 0.67 | |||
Infra-diaphragm | 83.3% | 87.5% | |||
Supra-diaphragm | 97.7% | 92.7% | |||
NLPHL | 0.03 | 0.007 | |||
Infra-diaphragm | 88.3% | 48.6% | |||
Supra-diaphragm | 97.7% | 85.5% |
OS, overall survival; RFS, relapse-free survival; MC, mixed cellularity; NS, nodular sclerosis; NLPHL, nodular lymphocytic predominant Hodgkin’s lymphoma.
Discussion
HL confined below the diaphragm is rare, making it difficult to analyze results and to design therapeutic schedules. This type of presentation accounts for 5% up to 13% of HL cases at stages I and II (2).
The impact of infra-diaphragmatic site on prognosis had controversial results in early-stage HL. We performed a retrospective analysis that included a total of 991 patients with HL stages I, or II from one center (The CCHE 57357), we distinguished 35 cases who had isolated infra-diaphragmatic disease which made our incidence close to literature (3.5%).
IDHL exhibits distinctive characteristics when compared to supra-diaphragmatic disease such as older age, multiple involved sites, increased frequency of lymphocyte predominant histology, and a reduced frequency of NS variants (9).
Patients’ characteristics in our cohort demonstrated this specificity in the landscape of HL. IDHL patients were more frequently males (71.4%) with older age than SDHL (median age at diagnosis: 10.1 vs. 8.8 years). This discrepancy in both age and gender across diaphragm were mentioned in a big series in 2006 (2) where they compared the initial characteristics of SDHL patients with those of IDHL. NLPHL account for 34.3% of our cohort (12/35) while most prevalent histological type was HL of MC type in 37.1%. Interestingly in the study done by Iannitto et al. 1997 in adults, revealed higher incidence of infra-diaphragmatic site 10% of cases (31/282), they had the same results in form of male predominance, older age at presentation, distinct pathological type (MC). They also reported lower OS in IDHL than SDHL with statistical P value. however, when age was adjusted below 40 years, OS was the same for both sites, so they concluded that negative prognosis was rather due to age than to site of presentation (10). Together with our study we suggest that the incidence of infra-diaphragmatic presentation might increase with age.
Rossi et al. who retrospectively studied clinical and biological features of adult IDHL, collected 65 IDHL patients staged by PET/CT over a period of ten years. Their cohort is a larger than in our study with male predominance (72%) that is supporting our observation regarding increase incidence with age and male predominance however their results differ in histological type where NS was predominant than MC type of CHL (65% vs. 22%) while NLPHL accounted for 9% of the cases in PET/CT staged IDHL cohort (11).
PET/CT is better diagnostic tool in both sensitivity and accuracy than CT alone for identifying HL localization, in particular extra-nodal involvement, and has been recommended for staging HL patients since 2007 (Cheson 2007) (12,13). Furthermore to assess response to treatment in lymphoma (14). Moreover, some authors suggest that lymph nodes size is not a sensitive indicator of disease involvement (15,16). So tumor extension could be under-staged by CT rendering advanced disease underestimated. Role of PET/CT was emphasized by Rossi et al. who did comparative analysis between CT staged versus PET/CT staged IDHL and found that outcomes in PET-staged IDHL patients were superior than those in CT-staged patients. They claimed that CT-staged IDHL might be under staged and so under treated.
As initial PET/CT was done as baseline investigation for every patient so accurate staging of all involved nodal structures were accomplished resulting in precise separation between IDHL and SDHL. We also found that 74.3% of whole IDHL cases were stage II, this result is similar to that mentioned in literature and reported multiple involved sites at initial presentation (9). The same result was reported by Rossi et al. who found 74% of PET/CT staged IDHL cases were stage II (11).
Patients diagnosed as classic HL in our study received ABVD protocol (4–6 cycles according to protocol) (7) and 60% of whole studied group had received involved field radiotherapy (IFRT) after finishing chemotherapy, but correlation of OS and RFS between patient who received and those who didn’t, was not significant in contrast to SDHL where radiotherapy has effect in outcome both in OS and RFS in our study; negative interim PET/CT had a strong prognostic factor in both OS and RFS in IDHL cohort where the cases of negative PET/CT had better OS and RFS (100% and 93.8%) at 5 years while cases of positive interim PE/CT had dismal prognosis (25% at 5 years for OS and RFS). So intensifying treatment for those who had poor response after 2 courses of chemotherapy may improve their outcome. Correlation of OS with stage of disease revealed lower OS of stage II than stage I (84.6% vs. 100%) respectively however P value is not statistically significant: 0.356 which may be attributed to small number of patients having stage I.
We noted higher incidence of events in the studied group (IDHL) in comparison to supra-diaphragmatic group (20% versus 6.3%) with statistical significant P=0.001. With a minimum follow up period of 25 months and a maximum of 13 years (a median follow up period was 40.3 months), 7 out 35 patients progressed and relapsed (20%).
Three of our patients died: 2 patients from second malignancies [one case developed Burkitt leukemia ALL L3 and the other developed acute myeloid leukemia (AML)] and one patient from unknown cause.
When we did comparative analysis of outcome across the diaphragm we concluded that: infra-diaphragmatic localization had significant lower OS and RFS (87.8% and 76.2%) than supra-diaphragmatic site which had OS, RFS of 98.2%, 93% at 5 years (P value for OS was 0.016; P value for RFS was <0.001) (Figure 2), as mentioned by Sasse et al., 2018 (17) who had the same observation also they suggest that combined modality treatment may counterbalance the adverse outcome of IDHL.
When we compare our patients’ characteristics across diaphragm with study published by Sasse et al., we found that we have near the same results as the incidence of B symptoms were more evident in IDHL group with significant P value in our cohort while in Sasse et al. (17) cohort only fever and weight loss were more evident in IDHL however both results confirm significant difference in pathological types distributions across diaphragm with an inverse association with the NS subtype with higher incidence of NLPHL and MC type of HL in infra-diaphragmatic group which confirm distinction of infra-diaphragmatic localization.
The prognostic value of infra-diaphragmatic localization in lymphoma has been studied by Abdulla et al. who reported that cases of diffuse large B-cell lymphoma with abdominal lymph node involvement having inferior survival than patient without however this study was including more advanced disease stage (stage III–IV) than our cohort (17).
In an attempting to find out underlying factor for such poorer prognosis we did further analysis of outcome between cases of CHL and NLPHL in infra-diaphragmatic cohort.
The children with NLPHL had a much worse survival than those with Classic HL (RFS was 48.6% versus 89.7% at 5 years with significant statistical (P=0.013). but with no statistical difference on OS between both group but when we compared NLPHL across diaphragm we found statistical lower both OS and RFS in infra-diaphragmatic group than supra-diaphragmatic NLPHL which confirm the role of tumor localization across diaphragm.
In summary, there is no statistical significance in multivariate analysis in our study explain such poorer outcome and the only independent prognostic factor was interim PET/CT response that emphasize the need of intensified treatment for IDHL especially for those having residual viable disease detected by interim PET/CT.
Although, this analysis has restrictions that it is a retrospective study, which might confine the weight of the results, yet its advantage from other studies, is the dependence on PET/CT in staging accuracy and 1st study got benefit from analysis of interim PET/CT in this identity group, as well as its standard protocol, large cohort and only in pediatric age group.
Conclusions
Although IDHL cases do not carry high risk features still this category of the patients has lower OS and RFS in comparison to patients who were supra-diaphragmatic at initial presentation making infra-diaphragmatic site by itself a bad prognostic factor.
Recommendation
Based on previous findings we suggest that IDHL has different biological features which mandate intensifying treatment especially for those who are slow responders as they had dismal outcome. Further studies should be taken for better understanding of biological features of IDHL.
Acknowledgments
We are extremely grateful to all patients and their families.
Funding: None.
Footnote
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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aol.amegroups.com/article/view/10.21037/aol-23-26/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional research board committee of children cancer hospital 57357 of Egypt (No. 9/2023) with no need for informed consent as it is retrospective study.
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Cite this article as: Ezzeldeen N, Moussa E, El Wakeel M, Mehesen M, Khorshed E, Elnashar A, Abdelkerim S, Zaghloul MS, Hamoda A. Pediatric Infradiaphragmatic Hodgkin’s lymphoma: a unique identity. Ann Lymphoma 2024;8:3.