Primary Testicular Lymphoma with Central Nervous System Relapse Was Successfully Treated by a Chemo-Free Regimen: A Case Report and Literature Review

Figures & data

Figure 1 Imaging features of the patient’s lymphoma. (A) Ultrasonography demonstrates a focal area of hypoechogenicity with hypervascularity in the left testis. (B and C) Post-orchiectomy PET/CT shows an FDG-avid lesion (green arrow) in the right testis. (D) PET/CT-based CR was achieved after first-line immunochemotherapy. (E and F) At the first follow-up examination, MRI horizontal and frontal views show a new lesion (red arrow) involving right basal ganglia and pons. (G and H) MRI horizontal and frontal views show that the new lesion disappeared after the first cycle of chemo-free treatment.

Figure 2 Immunohistochemical features of the patient’s tumor. The lymphoma cells were positive for CD20, CD79a, Mum-1 (dim), BCL-6, BCL-2, and C-MYC, and negative for CD10. Ki-67 proliferation index was about 90%. Original manifestation 400×.

Figure 3 Treatment timelines of the patient.

Table 1 Reported PTL Studies

Study	N	Year	Limited Stage	Treatment (% or n)	OS (Time)	PFS (Time)	Incidence of CNS Relapse (Time)	Other Sites Commonly Involved at Relapse (n or %)
Zucca^Citation4	373	1968–1998	79%	Anthracycline-based CT (68%), ITC (18%), RT (36%), Orc (95%), HD-MTX (8%)	48% (5-y) 27% (10-y)	48% (5-y) 33% (10-y)	19% (5-y) 34% (10-y)	Contralateral testis (31), bone, skin, bone marrow, lung, soft tissue
Zouhair^Citation10	36	1980–1999	83.3%	CHOP (29), Orc (35), ITC (17), RT (20)	47% (5-y)	66% (5-y)	22.2% (median 42 ms)	NA
Hasselblom^Citation11	35	1985–2000	91.4%	CHOP-like (28), ITC (17), RT (12), Orc (34)	3.9 ys (median)	NA	17.1% (median 45 ms)	Contralateral testis (1)
Linassiera^Citation12	16	1988–1998	100%	Anthracycline-based CT (all), Orc (all), RT (14), RT to brain (9), ITC (all)	65% (median 73.5 ms)	70% (median 73.5 ms, DFS)	6.3% (median 73.5 ms)	Contralateral testis (1)
Avilesb^Citation40	34	1993–1998	100%	CHOPB (all), Orc (all), HD-MTX (33), RT (all)	30% (5-y)	NA	0 (median 74 ms)	Lung (7), bone marrow (2)
Mazloom^Citation13	75	1977– 2008	62%	Orc (70), Doxorubicin-based CT (37), R-CHOP (22), ITC (30), RT (72)	53% (5-y) (15.4% before 1977; 86.6% after 2000)	46% (5-y) (15.4% before 1977; 59.3% after 2000)	12.9% (5-y)	Lymph nodes (8), contralateral testis (5), soft tissue (5), bone or bone marrow (3)
Avilesc^Citation14	38	2000–2005	100%	R-CHOP14 (all), HD-MTX (33), RT (all)	66% (5-y)	70% (5-y, EFS)	0 (median, 64.8 ms)	Lung (3), stomach (2), disseminated (5)
Cao^Citation15	32	1985–2009	93.8%	CHOP-like ± R (27), Orc (all), ITC (7), RT (8)	72.9% (5-y) 68.3% (10-y)	57.4% (5-y) 47.8% (10-y)	21.7% (median 48.9 ms)	Contralateral testis (4), nasopharynx (2)
Vitolod^Citation16	53	2001–2006	100%	R-CHOP (all), Orc (all), ITC (50), RT (47)	85% (5-y)	82% (5-y)	6% (5-y)	Pleura, skin, lymph nodes
Twa^Citation35	82	1981–2008	65%	CHOP (like) ± R (68), RT or Orc (59)	NA	NA	20% (5-y)	NA
Xu^Citation2	1169	1973–2013	68.6%	Systemic therapies were unknown, Orc (all), RT (34.9%)	CSS: 44%–70.4% (different periods) (5-y)	NA	NA	NA
Pollari^Citation41	74	1983–2013	64%	Anthracycline-base CT ± R (60), ITC (7), intravenous CNS prevention (34), RT (12)	56% (5-y)	53% (5-y)	NA	NA
Kim^Citation18	12	2000–2012	83.3%	CHOP ± R (all), Orc (13), RT (12), ITC (0)	89% (3-y)	81% (3-y)	7.1% (median 39 ms)	Contralateral testis and bone marrow (1), skin (1)
Deng^Citation3	280	1993–2014	77%	Orc (87%), CHOP (like) (91%), R (64%), ITC (34%), RT (39%)	58% (5-y) 68% (CT with R) 34% (CT without R)	46% (5-y) 56% (CT with R) 36% (CT without R)	15% (5-y) 21% (10-y)	Contralateral testis (9), skin and/or soft tissue (6)
Kridel^Citation19	134	1982–2015	62%	CHOP±R (all), ITC (12), RT (92), Orc (133)	60% (with R, 5-y) 54% (without R, 5-y)	51% (with R) 44% (without R)	25% (5-y)	NA
Mannisto^Citation25	189	1987–2013	63%	RT (47%), ITC (24%), R (63%), CT (NA), Orc (NA)	60% (5-y)	52% (5-y)	10% (median 80 ms)	NA
Zhou^Citation20	37	2009–2014	56%	CHOP ± R (36), ITC (18), RT (10), Orc (all)	57% (3-y)	NA	20% (3-y)	Contralateral testis (3)
Jovanovic^Citation21	21	2002–2016	66%	R-CHOP (all), ITC (10), RT (9)	4 ys (median)	NA	NA	NA
Ma^Citation5	22	1993–2017	68.1%	CHOP-like ± R (19), Orc (20), ITC (12), RT (8)	57.6% (5-y)	46.7% (5-y)	9% (median 30 ms)	Nodal (18.2%), Contralateral testis (13.6%),
Liu^Citation22	32	2010–2018	62.5%	R-CHOP (all), Orc (30), ITC (all), RT (19)	92% (3-y)	79% (3-y)	9.4% (median 31.5 ms)	NA
Zhu^Citation36	30	2006–2017	66.7%	Anthracycline-base CT ± R (23), Orc (all), RT (11), ITC (18)	NA	NA	3.3% (median 23.5 ms)	Contralateral testis (3.3%)
Chen^Citation23	28	2008–2018	68%	CHOP± R (12), Orc (26), RT (5), ITC (8)	53.4 (5-y)	35.4% (5-y)	NA	NA
Wang^Citation33	90	2007–2018	NA	CHOP± R (all), RT (12)	NA	NA	NA	NA
Caumont^Citation24	1897	2006–2016	73.1% (SOC group) 63.6% (non-SOC group)	SOC group (891) Non-SOC group (1006)	74.1% (5-y, SOC group) 51.2% (5-y, non-SOC group)	NA	NA	NA

Note: ^a,b,c,dProspective studies.

Abbreviations: OS, overall survival; PFS, progression-free survival; CNS, central nervous system; CT, chemotherapy; ITC, intrathecal chemotherapy; RT, radiotherapy; Orc, orchiectomy; HD-MTX, high-dose methotrexate; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; ms, months; y, year; ys, years; NA, not available; DFS, disease-free survival; EFS, event-free survival; CSS, cause specific survival; R, rituximab; SOC, standard of care including orchiectomy, chemotherapy, and radiotherapy.

Table 2 Important Molecular Aberrations in PTL

Study	N	MYD88 Mutation (%)	CD79B Mutation (%)	PDL Rearrangement (%)	PDL Gain or Amplification (%)	BCL6 Rearrangement (%)	BCL2 Rearrangement (%)	MYC Rearrangement (%)	Double Expressor
Twa^Citation35	82	67 (32/48)	NA	8 (6/76)	35.5 (27/76)	23 (17/75)	7 (5/75)	7 (6/73)	18 (15/82)
Kraan^Citation31	37	68 (25/37)	18.9 (7/37)	–	–	16.2 (6/37)	0 (0/37)	5.4 (2/37)	–
Menter^Citation34	45	–	–	–	–	48 (15/29)	4 (1/27)	6 (2/33)	15.1(5/33)
Oishi^Citation9	17	82 (14/17)	–	–	–	–	–	–	–
Chapuy^Citation32	49	78 (38/49)	49 (22/45)	4 (2/50)	54 (26/50)	–	–	–	–
Jovanovic^Citation21	21	–	–	–	–	–	7.1 (1/14)	7.1 (1/14)	21.4 (3/14)
Chen^Citation43	30	60 (18/30)	43.3 (13/30)	–	–	–	–	–	–
Wang^Citation33	90	75.6 (68/90)	–	–	–	–	–	–	–
Bernasconi^Citation44	16	–	–	–	–	43 (6/15)	12.5 (2/16)	20 (3/15)	–

Table 3 Prognostic Factors for PTL

Parameter	Prognostic Factor	Reference
OS or PFS	Advanced stage	[^Citation2–5,Citation10,Citation11,Citation13,Citation23,Citation25, ^Citation43]
	Higher IPI score	[^Citation4,Citation11,Citation15,Citation19,Citation23,Citation25,Citation43]
	Older age	[^Citation2,Citation4,Citation10,Citation12,Citation25]
	Non-SOC treatment	[^Citation3,Citation10,Citation24]
	Non-rituximab-containing CT	[^Citation2,Citation3,Citation19]
	PS >1	[^Citation4,Citation15,Citation25]
	B symptoms	[^Citation4,Citation5,Citation13]
	More than one extranodal sites involved	[^Citation4,Citation5,Citation25]
	Without contralateral testis RT	[^Citation2,Citation4,Citation25]
	Non-anthracycline-based CT	[^Citation3,Citation4]
	Treatment era	[^Citation2,Citation13]
	Elevated LDH level	[^Citation13,Citation25]
	CNS involvement	[^Citation15]
	Without ITC	[^Citation3]
	Without intravenous CNS-targeted CT	[^Citation25]
	Low PD-L1^+CD68^+ macrophage and PD-1^+ lymphocyte contents	[^Citation41]
	Lower amount of tumor-infiltrating CD4^+ and CD8^+ T cells	[^Citation42]
	CXCR4 and/or pCXCR4 expression	[^Citation34]
	B1XR1 mutation	[^Citation23]
	TBL1XR1 mutation	[^Citation33]
CNS relapse	Kidney/adrenal involvement	[^Citation15,Citation19]
	BCL6 or PDL rearrangement	[^Citation35]
	Advanced stage	[^Citation19]
	Elevated LDH level	[^Citation25]
	More than one extranodal sites involved	[^Citation25]
	Without ITC	[^Citation11]

Abbreviations: OS, overall survival; IPI, international prognostic index; SOC, standard of care (SOC) including orchiectomy, chemotherapy, radiotherapy, and preventive CNS-targeted treatment; CT, chemotherapy; PS, performance status; RT, radiotherapy; LDH, lactate dehydrogenase; CNS, central nervous system; ITC, intrathecal chemotherapy.

Zucca E, Conconi A, Mughal TI, et al. Patterns of outcome and prognostic factors in primary large-cell lymphoma of the testis in a survey by the International Extranodal Lymphoma Study Group. J Clin Oncol. 2003;21(1):20–27. doi:10.1200/JCO.2003.11.14112506165

 PubMed Web of Science ®Google Scholar

Zouhair A, Weber D, Belkacemi Y, et al. Outcome and patterns of failure in testicular lymphoma: a multicenter Rare Cancer Network study. Int J Radiat Oncol Biol Phys. 2002;52(3):652–656. doi:10.1016/s0360-3016(01)02647-511849786

 PubMed Web of Science ®Google Scholar

Hasselblom S, Ridell B, Wedel H, Norrby K, Sender Baum M, Ekman T. Testicular lymphoma–a retrospective, population-based, clinical and immunohistochemical study. Acta Oncol. 2004;43(8):758–765. doi:10.1080/0284186041000285115764222

 PubMed Web of Science ®Google Scholar

Linassier C, Desablens B, Lefrancq T, et al. Stage I-IIE primary non-Hodgkin’s lymphoma of the testis: results of a prospective trial by the GOELAMS Study Group. Clin Lymphoma. 2002;3(3):167–172. doi:10.3816/clm.2002.n.02312521394

 PubMedGoogle Scholar

Aviles A, Neri N, Huerta-Guzman J, Perez F, Fernandez R. Testicular lymphoma: organ-specific treatment did not improve outcome. Oncology. 2004;67(3–4):211–214. doi:10.1159/00008131915557780

 PubMed Web of Science ®Google Scholar

Mazloom A, Fowler N, Medeiros LJ, Iyengar P, Horace P, Dabaja BS. Outcome of patients with diffuse large B-cell lymphoma of the testis by era of treatment: the M. D. Anderson Cancer Center experience. Leuk Lymphoma. 2010;51(7):1217–1224. doi:10.3109/1042819100379335820443676

 PubMed Web of Science ®Google Scholar

Aviles A, Nambo MJ, Cleto S, Neri N, Huerta-Guzman J. Rituximab and dose-dense chemotherapy in primary testicular lymphoma. Clin Lymphoma Myeloma. 2009;9(5):386–389. doi:10.3816/CLM.2009.n.07519858059

 PubMedGoogle Scholar

Cao B, Ji DM, Zhou XY, et al. A clinical analysis of primary testicular diffuse large B-cell lymphoma in China. Hematology. 2011;16(5):291–297. doi:10.1179/102453311X1308564468022121902893

 PubMed Web of Science ®Google Scholar

Vitolo U, Chiappella A, Ferreri AJ, et al. First-line treatment for primary testicular diffuse large B-cell lymphoma with rituximab-CHOP, CNS prophylaxis, and contralateral testis irradiation: final results of an international Phase II trial. J Clin Oncol. 2011;29(20):2766–2772. doi:10.1200/JCO.2010.31.418721646602

 PubMed Web of Science ®Google Scholar

Twa DDW, Lee DG, Tan KL, et al. Genomic predictors of central nervous system relapse in primary testicular diffuse large B-cell lymphoma. Blood. 2021;137(9):1256–1259. doi:10.1182/blood.202000633832967007

 PubMed Web of Science ®Google Scholar

Xu H, Yao F. Primary testicular lymphoma: a SEER analysis of 1,169 cases. Oncol Lett. 2019;17(3):3113–3124. doi:10.3892/ol.2019.995330867741

 PubMed Web of Science ®Google Scholar

Pollari M, Bruck O, Pellinen T, et al. PD-L1(+) tumor-associated macrophages and PD-1(+) tumor-infiltrating lymphocytes predict survival in primary testicular lymphoma. Haematologica. 2018;103(11):1908–1914. doi:10.3324/haematol.2018.19719430026337

 PubMed Web of Science ®Google Scholar

Kim J, Yoon DH, Park I, et al. Treatment of primary testicular diffuse large B cell lymphoma without prophylactic intrathecal chemotherapy: a single center experience. Blood Res. 2014;49(3):170–176. doi:10.5045/br.2014.49.3.17025325036

 PubMedGoogle Scholar

Deng L, Xu-Monette ZY, Loghavi S, et al. Primary testicular diffuse large B-cell lymphoma displays distinct clinical and biological features for treatment failure in rituximab era: a report from the International PTL Consortium. Leukemia. 2016;30(2):361–372. doi:10.1038/leu.2015.23726308769

 PubMed Web of Science ®Google Scholar

Kridel R, Telio D, Villa D, et al. Diffuse large B-cell lymphoma with testicular involvement: outcome and risk of CNS relapse in the rituximab era. Br J Haematol. 2017;176(2):210–221. doi:10.1111/bjh.1439227739058

 PubMed Web of Science ®Google Scholar

Mannisto S, Vahamurto P, Pollari M, et al. Intravenous but not intrathecal central nervous system-directed chemotherapy improves survival in patients with testicular diffuse large B-cell lymphoma. Eur J Cancer. 2019;115:27–36. doi:10.1016/j.ejca.2019.04.00431082690

 PubMed Web of Science ®Google Scholar

Zhou, Bao C, Ye X, et al. Clinical and histological features of primary testicular diffuse large B-cell lymphoma: a single center experience in China. Oncotarget. 2017;8(68):112384–112389. doi:10.18632/oncotarget.1973629348832

 PubMedGoogle Scholar

Jovanovic MP, Mihaljevic B, Jovanovic P, et al. Clinicopathological and fluorescence in situ hibridisation analysis of primary testicular diffuse large B-cell lymphoma: a single-centre case series. Pol J Pathol. 2018;69(2):136–142. doi:10.5114/pjp.2018.7669730351860

 PubMed Web of Science ®Google Scholar

Ma RZ, Tian L, Tao LY, et al. The survival and prognostic factors of primary testicular lymphoma: two-decade single-center experience. Asian J Androl. 2018;20(6):615–620. doi:10.4103/aja.aja_73_1830246707

 PubMed Web of Science ®Google Scholar

Liu YZ, Luo P, Liu C, et al. Prognostic significance of LDH ratio in serum/cerebral spinal fluid of patients with primary testicular diffuse large B-cell lymphoma. Onco Targets Ther. 2019;12:10469–10475. doi:10.2147/OTT.S22874631819527

 PubMed Web of Science ®Google Scholar

Zhu D, Zhu J, Yu W, et al. Expression of programmed cell death-ligand 1 in primary testicular diffuse large B cell lymphoma: a retrospective study. Oncol Lett. 2019;18(3):2670–2676. doi:10.3892/ol.2019.1059531452749

 PubMed Web of Science ®Google Scholar

Chen B, Cao DH, Lai L, et al. Adult primary testicular lymphoma: clinical features and survival in a series of patients treated at a high-volume institution in China. BMC Cancer. 2020;20(1):220. doi:10.1186/s12885-020-6711-032171265

 PubMed Web of Science ®Google Scholar

Wang X, Xu X, Cai W, et al. TBL1XR1 mutation predicts poor outcome in primary testicular diffuse large B-cell lymphoma patients. Biomark Res. 2020;8:10. doi:10.1186/s40364-020-00189-132322395

 PubMed Web of Science ®Google Scholar

Caumont F, Porter C, DeBerg H, Burns J, Frankel J, Flores JP. Combined chemotherapy and radiotherapy improves survival in 1897 testicular Lymphoma patients from a contemporary cohort. Urol Oncol. 2020;38(7):641e1–641e8. doi:10.1016/j.urolonc.2020.02.027

 Web of Science ®Google Scholar

Kraan W, van Keimpema M, Horlings HM, et al. High prevalence of oncogenic MYD88 and CD79B mutations in primary testicular diffuse large B-cell lymphoma. Leukemia. 2014;28(3):719–720. doi:10.1038/leu.2013.34824253023

 PubMed Web of Science ®Google Scholar

Menter T, Ernst M, Drachneris J, et al. Phenotype profiling of primary testicular diffuse large B-cell lymphomas. Hematol Oncol. 2014;32(2):72–81. doi:10.1002/hon.209023949965

 PubMed Web of Science ®Google Scholar

Oishi N, Kondo T, Nakazawa T, et al. High prevalence of the MYD88 mutation in testicular lymphoma: immunohistochemical and genetic analyses. Pathol Int. 2015;65(10):528–535. doi:10.1111/pin.1233626388135

 PubMed Web of Science ®Google Scholar

Chapuy B, Roemer MG, Stewart C, et al. Targetable genetic features of primary testicular and primary central nervous system lymphomas. Blood. 2016;127(7):869–881. doi:10.1182/blood-2015-10-67323626702065

 PubMed Web of Science ®Google Scholar

Chen YP, Ke LF, Lu JP, et al. Prevalence and clinical significance of oncogenic CD79B and MYD88 mutations in primary testicular diffuse large b-cell lymphoma: a retrospective study in China. Onco Targets Ther. 2019;12:10165–10175. doi:10.2147/OTT.S22218932063711

 PubMed Web of Science ®Google Scholar

Bernasconi B, Uccella S, Martin V, et al. Gene translocations in testicular lymphomas. Leuk Lymphoma. 2014;55(6):1410–1412. doi:10.3109/10428194.2013.83405523952247

 PubMed Web of Science ®Google Scholar

Leivonen SK, Pollari M, Bruck O, et al. T-cell inflamed tumor microenvironment predicts favorable prognosis in primary testicular lymphoma. Haematologica. 2019;104(2):338–346. doi:10.3324/haematol.2018.20010530237271

 PubMed Web of Science ®Google Scholar