Patterns of Disease in Early Stage Favorable Hodgkins Lymphoma
Authors: Tharmaseelan Hishan , Jablonski Janina , Bühnen Ina , Rosenbrock Johannes , Bröckelmann Paul J. , Ferdinandus Justin , Borchmann Peter 
Published: December 2024

Background:
Early stage favorable Hodgkin's Lymphoma (HL) is a curable disease. Current standard of care (SOC) consists of a combined modality treatment with a 5-year PFS of 93.4%. Previous works have shown that the location of lymph node involvement (supra- vs. infradiaphragmatic) in early stage HL (Sasse et al., JCO 2018), has an influence on outcome. Compared to early stage unfavorable/ advanced stage HL there are no established risk factors.
Objective:
The aim was to describe distribution patterns of early-stage favorable HL and identify their associations with specific baseline characteristics and/or outcome.
Methods:
A total of N=3816 patients from the ITT Cohort of the German Hodgkin Study Group early stage favorable HL trials HD10, 13 and 16 were analyzed. Based on the clinical staging records the lymph node regions (e.g. cervical left or supraclavicular right) were identified. These lymph nodes were assigned to the areas A/B: right/left cervical/periclavicular/neck; C: hilar/mediastinal; D/E: right/left axillary; F: upper abdominal (celiac/splenic hilum/liver hilum); G: lower abdominal (paraaortic/mesenteric); H/I: right/left iliac; K/L: right/left inguinal/femoral.
The frequencies of lymph node involvement patterns were calculated. Following, the ten most frequent combinations of areas were analyzed. Baseline characteristics, including IPS variables (sex, age, gender, B-symptoms, lymphocytes, thrombocytes, erythrocytes, and albumine), were compared by applying chi-squared/unpaired t-test. In addition, the progression-free survival (PFS) of the subset of patients with a treatment according to the current SOC (combined modality treatment, 2 x ABVD + 20 Gy ISRT) (n=867), was compared by applying a log-rank test.
Results:
The analysis identified 31 patterns in the cohort of which 60% had a lymph node involvement in more than one area. From the cohort, pattern B+C (21.1%), B (19.2%), A+B (18.1%), A (17.3%), A+C (5.6%), B+E (4%), C (3.2%), A+D (2.8%), H+K (n=93, 2.5%), I+L (n=79, 2.1%) were the ten most frequent ones.
Isolated unilateral cervical/periclavicular/neck lymph node infiltration (Pattern A or B) was associated with older patients and male sex (A vs. others: [Age (mean): 44.0 vs. 39.0 (p&lt;0.001) | Sex: 70.1% vs. 57.5% male (p&lt;0.001)]; B vs. others: [Age (mean): 42.7 vs. 39.2 (p&lt;0.001) | Sex: 68.0% vs. 57.7% male (p&lt;0.001)]). A bilateral infiltration of cervical/neck and hilar/mediastinal lymph node areas (Pattern A+B) was also associated with male Sex, but no significant differences in Age were observed [Age (mean): 39.8 vs. 39.7 | Sex: 68.0% vs. 57.7% male (p&lt;0.001)].
Pattern B+C/A+C (unilateral cervical/neck and hilar/mediastinal lymph nodes) tended to be present in younger patients and women compared to other patterns (B+C vs. others: [Age (mean): 33.1 vs. 41.2 (p&lt;0.001) | Sex: 59.7% vs. 36.6% female (p&lt;0.001)]; A+C vs. others: [Age (mean): 33.4 vs. 40.8 (p&lt;0.001) | Sex: 59.3% vs. 37.7% female (p&lt;0.001)]). Isolated hilar/mediastinal involvement (Pattern C) was associated with female sex (C vs. others: [Sex: 65.3% vs. 39.8% female (p&lt;0.001)]).
A combined unilateral involvement of right/left cervical/periclavicular/neck and axillary lymph nodes was associated with sex (A+D vs. others: [Sex: 77.9% vs. 58.9% male (p&lt;0.001)]) on the right side. The left side showed a similar tendency (B+E vs. other: [Sex: 65.5% vs. 59.1% male]), but had no statistical significance. A combined involvement of unilateral right/left iliac and inguinal/femoral (I+L vs. others / H+K vs. others) lymph nodes showed no significant association with sex or other variables.
In all patterns, no significant difference in PFS in the SOC cohort was observed. There was no clinically significant difference in baseline serum IPS-variables between any of these patterns.
Conclusion:
There are distinct lymph node infiltration patterns of early stage favorable HL associated with sex and age. While some patterns are more frequent in younger patients and women, others are more frequent in older patients and men. Despite associations with age and sex, the patterns did not result in significant differences of progression free survival. These results provide the foundation for further pattern analysis harnessing the power of big data to identify disease trajectories in HL patients from all stages.