Summary of studies included in incidence analysis
| Study . | Year . | Author . | Reference . | Study period . | n∗ . | Median age, y (range) . | Staging criteria . | E-Lesion location (n) . | Staging tools . | Incidence of E-lesions by stage . | Treatment (E/total, % with E-lesion) . | Impact of E-lesions on prognosis, notable covariates . | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| I . | II . | III . | ||||||||||||
| 1 | 1977 | Mill et al | 55 | 1968-1972 | 116 | nd | Ann Arbor | nd | CXR w/wo chest tomog, IVP, L/S, LAG, BMBx, lap (58%). | IA: 0% (0/23) | IIA: 4% (2/51) | IIIA: 4% (1/24) | RT (IFRT, EFRT, TNI) vs CMT | There were more relapses in E-lesion group (statistical significance, nd). |
| IB: 0% (0/2) | IIB: 19% (3/16) | na | ||||||||||||
| 2 | 1977 | Levi et al | 22† | 1968-1976 | 111 | (9-60) | Ann Arbor | Lung only (12), lung + other (2), thyroid (2), and subcutaneous (1) | CXR w/wo chest tomog (4%); EBx (8); lap (100%). | IA: 0% (0/9) | IIA: 12% (6/50) | IIIA: 18% (7/40) | Randomized: cobalt EFRT alone (16%, 11/67) vs CMT: LFRT followed by 3-6× MOPP (16%, 7/44) | E-lesions were associated with significantly more relapses, shorter remission duration, and worse OS in EFRT-only group but not in CMT group. Strong association between lung E-lesions, moderate to large mediastinal masses, and subsequent marginal recurrences. |
| na | IIB: 42% (5/12) | na | ||||||||||||
| 1982 | Wiernik and Slawson | 23‡ | 1966-1981 | 177 (62 unique) | nd | Ann Arbor | Majority pulmonary involvement by direct extension from MMT | Chest tomog; lap (100%). | I-III: 33/177 (19%) | Randomized to EFRT alone (19%, 20/106) vs CMT: RT and 6× MOPP (18%, 13/71) | ||||
| 3 | 1982 | Hoppe et al | 25‡ | 1968-1978 | 230 | nd | Ann Arbor | Lung (28), pleura (2), bone (6), pericardium (13), soft tissue (5), and myocardium (1) | CXR (90%); LAG, lap (100%). | I/II: 17% (40/230) | na | Randomized per H1, H2, H4, R1, K1, S1, S2, and S3: EFRT alone (8%, 9 of 109) vs CMT (26%, 8/121): IFRT (I-IIA), STNI (I-IIA, IIAE), or TLI (I-IIB, IIBE) then MOP(P) or PAVe | E-lesions were not a significant factor for OS or FFR within treatment groups. | |
| 1986 | Crnkovich et al | 26† | 1968-1982 | 126 | 26 | Ann Arbor | Lung (31), pericardium (14), pleura (11), bone (5), and other (6) | CXR, BMBx, LAG; most chest tomog/CT, lap (94%) | na | IIB: 33% (41/126) | na | TLI (18%, 13/73,); 18 pts CMT (53%, 28/53) most MOPP or PAVe | E-lesions were not a significant factor for 10-year OS and FFR between treatment groups. | |
| 4 | 1984 | Zagars and Rubin | 56 | 1969-1981 | 91 | 25 | Ann Arbor | Lung, pleura, pericardium, and thoracic wall | CXR, w/wo chest tomog/CT, LAG, w/wo lap with splenectomy | IA: nd | IIA:12% (6/51) | na | All RT (TNI or STNI), 8% CMT | E-lesions associated with significantly more relapses in stage IIA treated with RT alone. In 2 cases, mediastinal masses may have driven poor prognosis. In a small portion with CMT, E-lesions did not show negative prognostic implication. |
| 5 | 1985 | Zittoun et al | 34 | 1976-1981 | 335 | (15-74) | Ann Arbor | Mediastinal involvement | CXR, chest tomog, LAG, BMBx | I, II, and IIIA: 6% (20/335) | All CMT: 3×/6× MOPP and randomized to EFRT (4%, 7/166) vs IFRT (8%, 13/169) | Patients with stage IIE disease had significantly worse 5-year DFS than defined low-risk groups. | ||
| 6 | 1985 | Leslie et al | 35 | 1969-1980 | 307 | (3 to > 40) | Ann Arbor | Lung (13), pericard (5), chest wall (3), and other (4) | CXR w/wo chest tomog/CT, LAG, lap with splenectomy (100%) | IA-IIB supradiaphragmatic: 8% (25/307) | na | IA, IIA: RT alone; IB & IIB: RT alone or CMT with MOPP; RT mostly MPA | When analyzed by mediastinal size, E-lesions did not influence FFR or OS. Among patients with E-stage disease, 11 of 25 had B-symptoms and 13 of 25 had bulk disease. | |
| 7 | 1989 | Loeffler et al | 28†,§ | 1983-1988 | 89 | 28 (15-56) | Ann Arbor | Mostly massive lung involvement | CXR, abd CT & U/S, BMBx, SS; lap or liver bx/BMBx/LAG; optional: chest CT, L/S, skeletal XR | IA: 0% (0/1) | IIA: 28% (8 of 29); IIB: 24% (5/21) | IIIA: 8% (3/38) | Per HD1: (I-III with LMT, E-stage, and/or MSI): All CMT with 2× ABVD/COPP and EFRT or TNI; bulk RT boost; stage IIIA TNI | E-lesions had no prognostic significance for CR rate, FFTF, OS, or FFP. Six of the patients with stage IIAE disease and 5 of the patients with stage IIBE disease also had MLT. |
| 1997 | Loeffler et al | 27‡,§ | HD1: 1984-1988 | HD1 147 | (15-60) | Ann Arbor | nd | CXR, chest CT, abd CT and U of S, BMBx, liver biopsy, NM BS; optional studies: L/S, LAG, skeletal XR (lap recommended in HD1, but not HD5) | HD1, I-IIIA + risk factors: 41% (31/147) | Per HD1 & HD5: (I-III with LMT, E-stage, and/or MSI): all CMT with 2× ABVD/COPP and EFRT or TNI; bulk RT boost | Despite E-lesions not routinely irradiated (lung pleura), there were 100% local CR and no relapses after chemotherapy (median follow-up, 6.5 y). | |||
| HD5: 1988--1993 | HD5 111 | 31 (16-62) | HD5, I-IIIA + risk factors: 27% (30/111) | |||||||||||
| 8 | 1989 | Leopold et al | 36§ | 1969-1984 | 92 | (9-50) | Ann Arbor | nd | CXR, abd CT or LAG, BMBx, lap and splenectomy (74%, TG 1 and 2) | CS IA-IIB with LMA --> PS IA-IIIB: 29% (27/92) | TG 1: RT only with MPA, TNI, or whole-lung RT (17%, 6/38); TG 2&3: CMT with MOPP and IFRT, MRT, MPA, or TNI (39%, 21/54) | E-lesions had no significant effect on 12-year relapse rate or survival within treatment groups. | ||
| 9 | 1992 | Oberlin et al | 32 | 1982-1988 | 217 (IV, 21) | 10 (2-18) | Ann Arbor | Pleura (4), pericardium and pleura (1), thoracic wall (2), and lung (3). | CXR w/wo chest CT, LAG, BMBx | I-III: 5% (10/217) | TG1: ABVD only, TG2-4: CMT with ABVD w/wo MOPP, IF-RT w/wo LSF | Four patients with E-lesions (40%) had local relapses, (statistical significance, nd). Two of these had bulky disease. | ||
| 10 | 1999 | Shah et al | 37 | 1970-1995 | 106 | 14 (3-22) | Ann Arbor | nd | CXR, CT C (61%) or CT A (78%) or CT P (73%), L/S (60%), LAG (50%), NM BS (34%), NI (84%), lap (60%), w/wo BMBx | Supradiaphagmatic I/II: 3% (3/106) | na | RT, IFRT, mantle only, TNI, STNI | E-lesions had no significant influence on relapse rate, OS, or EFS. | |
| 11 | 2000 | Franklin et al | 18§ | 1988-1994 | 712 | (15-75) | Ann Arbor | nd | nd | I-IIIA: 12% (85 of 712) | Per HD5: CMT with COPP/ABVD or COPP/ABV/IMEP, followed by EFRT, bulk RT boost | Patients with E-lesions, especially IIBE and IIIE, had a poor prognosis at 5 years. E-lesions were a significant poor prognostic factor beyond IPS. | ||
| na | IIB-IIIA: 5% (35/712) | |||||||||||||
| 2002 | Sieber et al | 29‡,§ | 1988-1993 | 973 | 31 (16-74) | Ann Arbor | nd | CXR, CT C/A/P, BMBx, liver bx | I, II, and IIIA: 12% (113/973) | 7-year FFTF and CR rate significantly worse in both treatment arms. | ||||
| 12 | 2001 | Ruhl et al | 33 | 1995-2000 | 730 (IV, 100) | 14 (maximum 18) | Cotswolds revision of Ann Arbor | Pleura, pericardium, and anterior thoracic wall | CXR, chest CT, abd CT/MRI; US th/ abd/ LN; w/wo neck CT/MRI, NM BS, BMBx, lap/liver bx | 0% (0/58) | IIA: 27% (100/365) | IIIA: 33% (25/75) | Per GPOH-HD 95: all 2× OEPA/OPPA, w/wo 2× or 4× COPP; response-adapted IFRT | E-lesions were a significant risk factor for both progressive disease and relapse. |
| na | IIB: 53% (66/125) | IIIB: 27%(25/91) | ||||||||||||
| 13 | 2002 | Dieckmann et al | 15 | 1990-1995 | 518 (IV, 60), precentral review | 12 (2-17) | Ann Arbor | Pericardium, lung, chest wall, and pleura. | CXR, CT C/A/P, U/S (neck, axilla, abd, pelvis), w/wo lap, w/wo BMBx | IA: 1% (1/98); IB: 0% (0/7) | IIA: 9% (20/218); IIB: 18% (14/78) | IIIA: 12% (7/59); IIIB: 15% (9 of 58) | Per GPOH-HD-90: TG1 (I/IIA) 2× OPPA (females) or OEPA (males); TG2 (IIB/IIIA/IE/IIEA); 4× OPPA (females) or OEPA (males); TG3 (IIIB/IV/IIEB/IIIE) 6× OPPA (females) or OEPA (males); all groups received local RT to initially involved areas (25 Gy TG 1&2; 20 Gy TG3; w/wo 5-10 Gy boost) | nia |
| 494 (IV, 84), postcentral review | IA: 0% (0/89); IB: 0% (0/5) | IIA: 15% (33/214); IIB: 37% (29/78) | IIIA: 24% (13/55); IIIB: 21% (11/53) | |||||||||||
| 14 | 2003 | Glimelius et al | 38 | 1985-1994 | 99 | 33 (17-59) | Ann Arbor | nd | CXR, CT C/A/P, abd US, BMBx | na | IIB: 11% (11/99) | na | CT 6-8× MOPP/ABVD, RT | Not significant in 10-year DFS and HL-specific survival |
| 15 | 2003 | Hodgson et al | 39 | 1981-1996 | 324 | 29 (15-78) | Ann Arbor | Lung or chest wall. | Chest CT | I-II: 12% of (40/324) lung invasion | na | All CMT | 5-year OS: no significant effect | |
| I-II: 7% (22/324) of chest-wall invasion | Chest wall significantly worse; 5-year CSS and DFS: lung extension no significant effect | |||||||||||||
| 16 | 2004 | Hudson et al | 40§ | 1993-2000 | 115 (IV, 44) | 15 (2-19) | Ann Arbor | nd | CXR, CT with contrast neck/C/A/P (or MRI for A/P) | I-II with risk factors or III: 10% (11/115) | na | E-lesions were not distinguished from stage IV disease with analysis regarding extranodal involvement. | ||
| 17 | 2004 | Vassilakopoulos et al | 41 | 1980-2001 | 367 | 30 (14-82) | Ann Arbor | nd | CXR, CT C/A/P, LAG, BMBx | IA & IIA: 5% (20/367) | na | MOPP (8%, 5/65) or E(A)BVD (5%, 15/302) then RT (89% IFRT) | In A(E)BVD subgroup (but not all patients), E disease was an independent predictor of poorer 10-year FFS. E disease status did not impact 10-year OS. | |
| 18 | 2005 | Gisselbrecht et al | 42 | nd | 1156 | 30 (14-69) | Cotswolds revision of Ann Arbor | nd | nd | I-II: 8% (91/1156) | na | Per H8 (36/518) 3-6× MOPP/ABV, then IFRT or STNI; per H9 (55/638): CMT with 6× EBVP, 4-6× ABVD, or 4× BEACOPP, then IFRT | E-lesions associated with significantly worse OS at 42 months. Authors hypothesize E disease may be surrogate for bulky mediastinal disease | |
| 19 | 2007 | Gallamini et al | 43 | 2001-2006 | 216 (IV, 44) | 32 (14-72) | Cotswolds revision of Ann Arbor | nd | CXR, CT C/A/P, LAG, FDG-PET | 6% (4 of 67) | 10% (7/70) | 24% (19/79) | na | E-lesions were not distinguished from stage IV disease with analysis regarding extranodal involvement. |
| 20 | 2011 | Wirth et al | 48 | 1999-2001 | 148 | 33 (18-75) | Cotswolds revision of Ann Arbor | nd | CT, BMBx | I-II: 3% (5/148) | na | 3-4× ABVD, IFRT | Significant factor for worse OS and FFS at 5 years | |
| 21 | 2012 | Gobbi et al | 49§ | nd | 129 | 34 (20-48) | Cotswolds revision of Ann Arbor | nd | CT with contrast neck/C/A/P | IA, IB, IIA + risk factors: 8% (10/129) | IIB, III, and IV taken together in analysis | 4-6× ABVD, IFRT | For early, unfavorable disease, presence of E-lesions was the only statistically important predictor of early treatment failure beyond relative tumor burden. | |
| 22 | 2013 | Song et al | 50 | 2006-2011 | 127 | 42 (18-78) | Cotswolds revision of Ann Arbor | nd | CT neck/C/A/P, BMBx, FDG-PET/CT | I-II: 24% (30/127) | na | 4-6× ABVD and IF-RT or 6 ABVD | E-lesion not a significant factor for PFS nor OS at 45 months. | |
| 23 | 2014 | Laskar et al | 44§ | 2000-2008 | 151 | 20 (3-70) | Cotswolds revision of Ann Arbor | nd | CT | IA: 0% (0/38) | IIA: 3% (3/96) | na | 4-6× ABVD and IFRT | E-lesions were a significant factor for worse 10-year PFS and OS among patients with early unfavorable disease. |
| IB: 0% (0/13) | IIB: 0% (0/4) | na | ||||||||||||
| 24 | 2018 | Gaudio et al | 46 | 2006-2017 | 384 (IV w/ bone involvement, 27/32; 85%). | 36 (15-83) | Ann Arbor | E-lesion vs stage IV sites nd | CXR, CT-CAP, FDG-PET/CT–total body, unilateral BMBx | I/II w/ bone involvement: 3% (1/32) | III w/ bone involvement: 12% (4/32) | ABVD w/wo RT | E-lesions were not distinguished from stage IV disease with analysis regarding extralymphatic involvement. | |
| 25 | 2018 | Gaudio et al | 45 | 2006-2016 | Stage I-II: 235 (III/IV, 106) | 36 (15-83) | Ann Arbor | E-lesion vs stage IV sites nd | CXR, CT-CAP, FDG-PET/CT–total body, unilateral BMBx | I/II: 3% (7/235) | III/VI | ABVD w/wo IFRT | E-lesions were not distinguished from stage IV disease with analysis regarding extralymphatic involvement. | |
| 26 | 2019 | Casasnovas et al | 47§| | 2011-2014 | 823 | 30 (16-30) | Ann Arbor | nd | CXR; PET/CT head/neck/C/A/P; BMA | na | IIB: 11% (10/87) | na | Per AHL2011: 6× eBEACOPP vs 2× eBEACOPP then PET-driven BEACOPP and/or ABVD | nia |
| 27 | 2020 | Myint et al | 51 | 2005-2014 | 293 | 40 (18-85) | Ann Arbor | nd | nd | IA/IIA: 1% (2/293) | na | Chemotherapy alone vs CMT | E-lesion inclusion in multivariate survival modeling is not explicitly stated. | |
| 130 | 35 (18-88) | IB/IIB: 3% (4/130) | ||||||||||||
| 28 | 2021 | Picardi et al | 52 | 2017-2019 | 60 | 40 (18-70) | Ann Arbor classification with Lugano modification | nd | Same-day FDG- PET/CT, followed by FDG-PET/unenhanced MRI C/A/P; BMBx, U/S | 0% (0/8) | 1% (2/22) | na | 2-6× ABVD and IFRT (I/II) or residual mass RT | nia |
| 29 | 2021 | Kumar et al | 53§ | 2013-2019 | 117 | 32 (18-59) | Ann Arbor | Pericardial, chest wall, and sternum | PET | na | TG 1&2, II: 25% (15/59) | na | Brentiximab-vedotin + AVD ×4 cycles w/wo RT (TG 1&2 ISRT, TG3 CVRT) | No clear impact of E-lesions; 1 of 7 patients with primary refractory/relapsed disease had stage IIBXE disease. All patients had risk factors, with TG 2-4 (86% overall) having bulky (>7 cm) disease. |
| TG 3&4, I-II : 16% (9/56) | ||||||||||||||
| 30 | 2022 | Mauz-Korholz et al | 30 | 2007-2013 | TG2&3: 793 (IV, 494) | 14 (IQR, 12-16) | Cotswolds revision of Ann Arbor | nd | CT with contrast neck/C/A/P (or MRI neck/A/P), FDG-PET | na | IIA: 97% (93/96) | IIIA: 16% (30/187) | Per EuroNet-PHL-C1: TG1: OEPA ×2; TG2: OEPA ×2 --> COPP or COPDAC ×2; TG3: OEPA ×2 --> COPP or COPDAC ×4; early response assessment-based w/wo IFRT w/wo residual RT boost | nia |
| na | IIB: 37% (114/308) | IIIB: 27% (54/202) | ||||||||||||
| 2023 | Mauz-Korholz et al | 31 | TG1: 713 | 14 (IQR, 12-16) | IA: 0% (0/40) | IIA:<1% (1/666) | IIIA: 0% (0/1) | |||||||
| IB: 0% (0/5) | IIB: 0% (0/1) | x | ||||||||||||
| 31 | 2021 | Borchmann et al | 54§ | 2012-2017 | 1096 | 31 (18-60) | Ann Arbor | nd | PET-CT | I-II with risk factor: 8% (89/1096) | na | Per HD17: 2× eBEACOPP + 2× ABVD; IFRT or PET-guided INRT | nia | |
| Study . | Year . | Author . | Reference . | Study period . | n∗ . | Median age, y (range) . | Staging criteria . | E-Lesion location (n) . | Staging tools . | Incidence of E-lesions by stage . | Treatment (E/total, % with E-lesion) . | Impact of E-lesions on prognosis, notable covariates . | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| I . | II . | III . | ||||||||||||
| 1 | 1977 | Mill et al | 55 | 1968-1972 | 116 | nd | Ann Arbor | nd | CXR w/wo chest tomog, IVP, L/S, LAG, BMBx, lap (58%). | IA: 0% (0/23) | IIA: 4% (2/51) | IIIA: 4% (1/24) | RT (IFRT, EFRT, TNI) vs CMT | There were more relapses in E-lesion group (statistical significance, nd). |
| IB: 0% (0/2) | IIB: 19% (3/16) | na | ||||||||||||
| 2 | 1977 | Levi et al | 22† | 1968-1976 | 111 | (9-60) | Ann Arbor | Lung only (12), lung + other (2), thyroid (2), and subcutaneous (1) | CXR w/wo chest tomog (4%); EBx (8); lap (100%). | IA: 0% (0/9) | IIA: 12% (6/50) | IIIA: 18% (7/40) | Randomized: cobalt EFRT alone (16%, 11/67) vs CMT: LFRT followed by 3-6× MOPP (16%, 7/44) | E-lesions were associated with significantly more relapses, shorter remission duration, and worse OS in EFRT-only group but not in CMT group. Strong association between lung E-lesions, moderate to large mediastinal masses, and subsequent marginal recurrences. |
| na | IIB: 42% (5/12) | na | ||||||||||||
| 1982 | Wiernik and Slawson | 23‡ | 1966-1981 | 177 (62 unique) | nd | Ann Arbor | Majority pulmonary involvement by direct extension from MMT | Chest tomog; lap (100%). | I-III: 33/177 (19%) | Randomized to EFRT alone (19%, 20/106) vs CMT: RT and 6× MOPP (18%, 13/71) | ||||
| 3 | 1982 | Hoppe et al | 25‡ | 1968-1978 | 230 | nd | Ann Arbor | Lung (28), pleura (2), bone (6), pericardium (13), soft tissue (5), and myocardium (1) | CXR (90%); LAG, lap (100%). | I/II: 17% (40/230) | na | Randomized per H1, H2, H4, R1, K1, S1, S2, and S3: EFRT alone (8%, 9 of 109) vs CMT (26%, 8/121): IFRT (I-IIA), STNI (I-IIA, IIAE), or TLI (I-IIB, IIBE) then MOP(P) or PAVe | E-lesions were not a significant factor for OS or FFR within treatment groups. | |
| 1986 | Crnkovich et al | 26† | 1968-1982 | 126 | 26 | Ann Arbor | Lung (31), pericardium (14), pleura (11), bone (5), and other (6) | CXR, BMBx, LAG; most chest tomog/CT, lap (94%) | na | IIB: 33% (41/126) | na | TLI (18%, 13/73,); 18 pts CMT (53%, 28/53) most MOPP or PAVe | E-lesions were not a significant factor for 10-year OS and FFR between treatment groups. | |
| 4 | 1984 | Zagars and Rubin | 56 | 1969-1981 | 91 | 25 | Ann Arbor | Lung, pleura, pericardium, and thoracic wall | CXR, w/wo chest tomog/CT, LAG, w/wo lap with splenectomy | IA: nd | IIA:12% (6/51) | na | All RT (TNI or STNI), 8% CMT | E-lesions associated with significantly more relapses in stage IIA treated with RT alone. In 2 cases, mediastinal masses may have driven poor prognosis. In a small portion with CMT, E-lesions did not show negative prognostic implication. |
| 5 | 1985 | Zittoun et al | 34 | 1976-1981 | 335 | (15-74) | Ann Arbor | Mediastinal involvement | CXR, chest tomog, LAG, BMBx | I, II, and IIIA: 6% (20/335) | All CMT: 3×/6× MOPP and randomized to EFRT (4%, 7/166) vs IFRT (8%, 13/169) | Patients with stage IIE disease had significantly worse 5-year DFS than defined low-risk groups. | ||
| 6 | 1985 | Leslie et al | 35 | 1969-1980 | 307 | (3 to > 40) | Ann Arbor | Lung (13), pericard (5), chest wall (3), and other (4) | CXR w/wo chest tomog/CT, LAG, lap with splenectomy (100%) | IA-IIB supradiaphragmatic: 8% (25/307) | na | IA, IIA: RT alone; IB & IIB: RT alone or CMT with MOPP; RT mostly MPA | When analyzed by mediastinal size, E-lesions did not influence FFR or OS. Among patients with E-stage disease, 11 of 25 had B-symptoms and 13 of 25 had bulk disease. | |
| 7 | 1989 | Loeffler et al | 28†,§ | 1983-1988 | 89 | 28 (15-56) | Ann Arbor | Mostly massive lung involvement | CXR, abd CT & U/S, BMBx, SS; lap or liver bx/BMBx/LAG; optional: chest CT, L/S, skeletal XR | IA: 0% (0/1) | IIA: 28% (8 of 29); IIB: 24% (5/21) | IIIA: 8% (3/38) | Per HD1: (I-III with LMT, E-stage, and/or MSI): All CMT with 2× ABVD/COPP and EFRT or TNI; bulk RT boost; stage IIIA TNI | E-lesions had no prognostic significance for CR rate, FFTF, OS, or FFP. Six of the patients with stage IIAE disease and 5 of the patients with stage IIBE disease also had MLT. |
| 1997 | Loeffler et al | 27‡,§ | HD1: 1984-1988 | HD1 147 | (15-60) | Ann Arbor | nd | CXR, chest CT, abd CT and U of S, BMBx, liver biopsy, NM BS; optional studies: L/S, LAG, skeletal XR (lap recommended in HD1, but not HD5) | HD1, I-IIIA + risk factors: 41% (31/147) | Per HD1 & HD5: (I-III with LMT, E-stage, and/or MSI): all CMT with 2× ABVD/COPP and EFRT or TNI; bulk RT boost | Despite E-lesions not routinely irradiated (lung pleura), there were 100% local CR and no relapses after chemotherapy (median follow-up, 6.5 y). | |||
| HD5: 1988--1993 | HD5 111 | 31 (16-62) | HD5, I-IIIA + risk factors: 27% (30/111) | |||||||||||
| 8 | 1989 | Leopold et al | 36§ | 1969-1984 | 92 | (9-50) | Ann Arbor | nd | CXR, abd CT or LAG, BMBx, lap and splenectomy (74%, TG 1 and 2) | CS IA-IIB with LMA --> PS IA-IIIB: 29% (27/92) | TG 1: RT only with MPA, TNI, or whole-lung RT (17%, 6/38); TG 2&3: CMT with MOPP and IFRT, MRT, MPA, or TNI (39%, 21/54) | E-lesions had no significant effect on 12-year relapse rate or survival within treatment groups. | ||
| 9 | 1992 | Oberlin et al | 32 | 1982-1988 | 217 (IV, 21) | 10 (2-18) | Ann Arbor | Pleura (4), pericardium and pleura (1), thoracic wall (2), and lung (3). | CXR w/wo chest CT, LAG, BMBx | I-III: 5% (10/217) | TG1: ABVD only, TG2-4: CMT with ABVD w/wo MOPP, IF-RT w/wo LSF | Four patients with E-lesions (40%) had local relapses, (statistical significance, nd). Two of these had bulky disease. | ||
| 10 | 1999 | Shah et al | 37 | 1970-1995 | 106 | 14 (3-22) | Ann Arbor | nd | CXR, CT C (61%) or CT A (78%) or CT P (73%), L/S (60%), LAG (50%), NM BS (34%), NI (84%), lap (60%), w/wo BMBx | Supradiaphagmatic I/II: 3% (3/106) | na | RT, IFRT, mantle only, TNI, STNI | E-lesions had no significant influence on relapse rate, OS, or EFS. | |
| 11 | 2000 | Franklin et al | 18§ | 1988-1994 | 712 | (15-75) | Ann Arbor | nd | nd | I-IIIA: 12% (85 of 712) | Per HD5: CMT with COPP/ABVD or COPP/ABV/IMEP, followed by EFRT, bulk RT boost | Patients with E-lesions, especially IIBE and IIIE, had a poor prognosis at 5 years. E-lesions were a significant poor prognostic factor beyond IPS. | ||
| na | IIB-IIIA: 5% (35/712) | |||||||||||||
| 2002 | Sieber et al | 29‡,§ | 1988-1993 | 973 | 31 (16-74) | Ann Arbor | nd | CXR, CT C/A/P, BMBx, liver bx | I, II, and IIIA: 12% (113/973) | 7-year FFTF and CR rate significantly worse in both treatment arms. | ||||
| 12 | 2001 | Ruhl et al | 33 | 1995-2000 | 730 (IV, 100) | 14 (maximum 18) | Cotswolds revision of Ann Arbor | Pleura, pericardium, and anterior thoracic wall | CXR, chest CT, abd CT/MRI; US th/ abd/ LN; w/wo neck CT/MRI, NM BS, BMBx, lap/liver bx | 0% (0/58) | IIA: 27% (100/365) | IIIA: 33% (25/75) | Per GPOH-HD 95: all 2× OEPA/OPPA, w/wo 2× or 4× COPP; response-adapted IFRT | E-lesions were a significant risk factor for both progressive disease and relapse. |
| na | IIB: 53% (66/125) | IIIB: 27%(25/91) | ||||||||||||
| 13 | 2002 | Dieckmann et al | 15 | 1990-1995 | 518 (IV, 60), precentral review | 12 (2-17) | Ann Arbor | Pericardium, lung, chest wall, and pleura. | CXR, CT C/A/P, U/S (neck, axilla, abd, pelvis), w/wo lap, w/wo BMBx | IA: 1% (1/98); IB: 0% (0/7) | IIA: 9% (20/218); IIB: 18% (14/78) | IIIA: 12% (7/59); IIIB: 15% (9 of 58) | Per GPOH-HD-90: TG1 (I/IIA) 2× OPPA (females) or OEPA (males); TG2 (IIB/IIIA/IE/IIEA); 4× OPPA (females) or OEPA (males); TG3 (IIIB/IV/IIEB/IIIE) 6× OPPA (females) or OEPA (males); all groups received local RT to initially involved areas (25 Gy TG 1&2; 20 Gy TG3; w/wo 5-10 Gy boost) | nia |
| 494 (IV, 84), postcentral review | IA: 0% (0/89); IB: 0% (0/5) | IIA: 15% (33/214); IIB: 37% (29/78) | IIIA: 24% (13/55); IIIB: 21% (11/53) | |||||||||||
| 14 | 2003 | Glimelius et al | 38 | 1985-1994 | 99 | 33 (17-59) | Ann Arbor | nd | CXR, CT C/A/P, abd US, BMBx | na | IIB: 11% (11/99) | na | CT 6-8× MOPP/ABVD, RT | Not significant in 10-year DFS and HL-specific survival |
| 15 | 2003 | Hodgson et al | 39 | 1981-1996 | 324 | 29 (15-78) | Ann Arbor | Lung or chest wall. | Chest CT | I-II: 12% of (40/324) lung invasion | na | All CMT | 5-year OS: no significant effect | |
| I-II: 7% (22/324) of chest-wall invasion | Chest wall significantly worse; 5-year CSS and DFS: lung extension no significant effect | |||||||||||||
| 16 | 2004 | Hudson et al | 40§ | 1993-2000 | 115 (IV, 44) | 15 (2-19) | Ann Arbor | nd | CXR, CT with contrast neck/C/A/P (or MRI for A/P) | I-II with risk factors or III: 10% (11/115) | na | E-lesions were not distinguished from stage IV disease with analysis regarding extranodal involvement. | ||
| 17 | 2004 | Vassilakopoulos et al | 41 | 1980-2001 | 367 | 30 (14-82) | Ann Arbor | nd | CXR, CT C/A/P, LAG, BMBx | IA & IIA: 5% (20/367) | na | MOPP (8%, 5/65) or E(A)BVD (5%, 15/302) then RT (89% IFRT) | In A(E)BVD subgroup (but not all patients), E disease was an independent predictor of poorer 10-year FFS. E disease status did not impact 10-year OS. | |
| 18 | 2005 | Gisselbrecht et al | 42 | nd | 1156 | 30 (14-69) | Cotswolds revision of Ann Arbor | nd | nd | I-II: 8% (91/1156) | na | Per H8 (36/518) 3-6× MOPP/ABV, then IFRT or STNI; per H9 (55/638): CMT with 6× EBVP, 4-6× ABVD, or 4× BEACOPP, then IFRT | E-lesions associated with significantly worse OS at 42 months. Authors hypothesize E disease may be surrogate for bulky mediastinal disease | |
| 19 | 2007 | Gallamini et al | 43 | 2001-2006 | 216 (IV, 44) | 32 (14-72) | Cotswolds revision of Ann Arbor | nd | CXR, CT C/A/P, LAG, FDG-PET | 6% (4 of 67) | 10% (7/70) | 24% (19/79) | na | E-lesions were not distinguished from stage IV disease with analysis regarding extranodal involvement. |
| 20 | 2011 | Wirth et al | 48 | 1999-2001 | 148 | 33 (18-75) | Cotswolds revision of Ann Arbor | nd | CT, BMBx | I-II: 3% (5/148) | na | 3-4× ABVD, IFRT | Significant factor for worse OS and FFS at 5 years | |
| 21 | 2012 | Gobbi et al | 49§ | nd | 129 | 34 (20-48) | Cotswolds revision of Ann Arbor | nd | CT with contrast neck/C/A/P | IA, IB, IIA + risk factors: 8% (10/129) | IIB, III, and IV taken together in analysis | 4-6× ABVD, IFRT | For early, unfavorable disease, presence of E-lesions was the only statistically important predictor of early treatment failure beyond relative tumor burden. | |
| 22 | 2013 | Song et al | 50 | 2006-2011 | 127 | 42 (18-78) | Cotswolds revision of Ann Arbor | nd | CT neck/C/A/P, BMBx, FDG-PET/CT | I-II: 24% (30/127) | na | 4-6× ABVD and IF-RT or 6 ABVD | E-lesion not a significant factor for PFS nor OS at 45 months. | |
| 23 | 2014 | Laskar et al | 44§ | 2000-2008 | 151 | 20 (3-70) | Cotswolds revision of Ann Arbor | nd | CT | IA: 0% (0/38) | IIA: 3% (3/96) | na | 4-6× ABVD and IFRT | E-lesions were a significant factor for worse 10-year PFS and OS among patients with early unfavorable disease. |
| IB: 0% (0/13) | IIB: 0% (0/4) | na | ||||||||||||
| 24 | 2018 | Gaudio et al | 46 | 2006-2017 | 384 (IV w/ bone involvement, 27/32; 85%). | 36 (15-83) | Ann Arbor | E-lesion vs stage IV sites nd | CXR, CT-CAP, FDG-PET/CT–total body, unilateral BMBx | I/II w/ bone involvement: 3% (1/32) | III w/ bone involvement: 12% (4/32) | ABVD w/wo RT | E-lesions were not distinguished from stage IV disease with analysis regarding extralymphatic involvement. | |
| 25 | 2018 | Gaudio et al | 45 | 2006-2016 | Stage I-II: 235 (III/IV, 106) | 36 (15-83) | Ann Arbor | E-lesion vs stage IV sites nd | CXR, CT-CAP, FDG-PET/CT–total body, unilateral BMBx | I/II: 3% (7/235) | III/VI | ABVD w/wo IFRT | E-lesions were not distinguished from stage IV disease with analysis regarding extralymphatic involvement. | |
| 26 | 2019 | Casasnovas et al | 47§| | 2011-2014 | 823 | 30 (16-30) | Ann Arbor | nd | CXR; PET/CT head/neck/C/A/P; BMA | na | IIB: 11% (10/87) | na | Per AHL2011: 6× eBEACOPP vs 2× eBEACOPP then PET-driven BEACOPP and/or ABVD | nia |
| 27 | 2020 | Myint et al | 51 | 2005-2014 | 293 | 40 (18-85) | Ann Arbor | nd | nd | IA/IIA: 1% (2/293) | na | Chemotherapy alone vs CMT | E-lesion inclusion in multivariate survival modeling is not explicitly stated. | |
| 130 | 35 (18-88) | IB/IIB: 3% (4/130) | ||||||||||||
| 28 | 2021 | Picardi et al | 52 | 2017-2019 | 60 | 40 (18-70) | Ann Arbor classification with Lugano modification | nd | Same-day FDG- PET/CT, followed by FDG-PET/unenhanced MRI C/A/P; BMBx, U/S | 0% (0/8) | 1% (2/22) | na | 2-6× ABVD and IFRT (I/II) or residual mass RT | nia |
| 29 | 2021 | Kumar et al | 53§ | 2013-2019 | 117 | 32 (18-59) | Ann Arbor | Pericardial, chest wall, and sternum | PET | na | TG 1&2, II: 25% (15/59) | na | Brentiximab-vedotin + AVD ×4 cycles w/wo RT (TG 1&2 ISRT, TG3 CVRT) | No clear impact of E-lesions; 1 of 7 patients with primary refractory/relapsed disease had stage IIBXE disease. All patients had risk factors, with TG 2-4 (86% overall) having bulky (>7 cm) disease. |
| TG 3&4, I-II : 16% (9/56) | ||||||||||||||
| 30 | 2022 | Mauz-Korholz et al | 30 | 2007-2013 | TG2&3: 793 (IV, 494) | 14 (IQR, 12-16) | Cotswolds revision of Ann Arbor | nd | CT with contrast neck/C/A/P (or MRI neck/A/P), FDG-PET | na | IIA: 97% (93/96) | IIIA: 16% (30/187) | Per EuroNet-PHL-C1: TG1: OEPA ×2; TG2: OEPA ×2 --> COPP or COPDAC ×2; TG3: OEPA ×2 --> COPP or COPDAC ×4; early response assessment-based w/wo IFRT w/wo residual RT boost | nia |
| na | IIB: 37% (114/308) | IIIB: 27% (54/202) | ||||||||||||
| 2023 | Mauz-Korholz et al | 31 | TG1: 713 | 14 (IQR, 12-16) | IA: 0% (0/40) | IIA:<1% (1/666) | IIIA: 0% (0/1) | |||||||
| IB: 0% (0/5) | IIB: 0% (0/1) | x | ||||||||||||
| 31 | 2021 | Borchmann et al | 54§ | 2012-2017 | 1096 | 31 (18-60) | Ann Arbor | nd | PET-CT | I-II with risk factor: 8% (89/1096) | na | Per HD17: 2× eBEACOPP + 2× ABVD; IFRT or PET-guided INRT | nia | |
abd, abdomen; ABVD, adriamycin/bleomycin/vinblastine/dacarbazine; BMA, bone marrow aspirate; BMBx, bone marrow biopsy; Bx, biopsy; C/A/P, chest/abdomen/pelvis; CMT, combined modality therapy; COPP, cyclophosphamide, oncovin, prednison, procabazin; COPDAC, cyclophosphamide, oncovin, prednison, dacarbazin; CR, complete remission; CS, clinical stage; CT, computed tomography; CVRT, consolidation-volume radiotherapy; CXR, chest X-ray; DFS, disease-free survival; eBEACOPP, escalated dose etoposide/cyclophosphamide/doxorubicin and regular doses bleomycin/vincristine/procarbazine/prednisone; EBx, E-lesion biopsy; EFRT, extended field radiotherapy; EFS, event-free survival; FDG, fluorodeoxyglucose, FFP, failure free progression; FFR, freedom from first relapse; FFS, freedom from progression; FFTF, freedom from treatment failure; HD, Hodgkin disease; IFRT, involved field radiotherapy; ISRT, involved site radiotherapy; IPS, international prognostic score; IQR, interquartile range; IVP, intravenous pyelogram; LAG, bipedal lymphangiography; lap, staging laparotomy; LFRT, limited field radiotherapy; LMA, large mediastinal adenopathy; LMT, large mediastinal mass; LN, lymph nodes; L/S, liver/spleen scintiscan; LSF, lumbo-splenic field radiotherapy; MMT, massive mediastinal tumor; MOPP, mustargen/oncovin/procarbazine/prednisone; MPA, mantle and para-aortic splenic pedicle radiotherapy; MRT, mantle radiation therapy; MSI, massive spleen involvement; n, number of cases; na, not applicable; nd, not defined; nia, not included in analysis; NM BS, nuclear medicine bone scan; OEPA, oncovin, etoposide, prednison, anthracyclin (doxorubicin); OPPA, oncovin, procarbazin, prednison, anthracyclin (doxorubicin); PAVe, procarbazine/l-phenylalamine mustard/vinblastine; PFS, progression-free survival; PS, pathologic stage; Ref, reference; RT, radiotherapy; SS, skeletal scan; STNI, subtotal nodal irradiation; TG, treatment group; th, thorax; TLI, total lymphoid irradiation; TNI, total nodal irradiation; tomog, tomography; U/S, ultrasound; x, times; XR, X-ray; and w/wo, with or without.
Patients with stage IV HL were excluded in this number.
Because there were overlapping study populations, these data were used for stage-specific incidence calculation.
Because there were overlapping study populations, these data were used for overall incidence calculation.
This study used elevated risk–based criteria for inclusion.