Patients were identified by searching the Asan Medical Center NHL registry databases for PTL. Between November 2000 and June 2012, 14 patients were newly diagnosed as having DLBCL as a form of PTL. We retrospectively reviewed the computerized medical records of these patients. The institutional review board of Asan Medical Center approved this study (IRB No. 2013-0528).

Diagnosis was based on the morphological and immunohistochemical examination of testicular biopsy samples. Histopathological classification was based on the World Health Organization (WHO) criteria for NHL [11]. PTL was diagnosed, if the testicles were the primary site of the disease or at least the main site of involvement, with either no or only minor nodal involvement [12]. The patients had no prior therapy for lymphoma before diagnosis.

Staging evaluation for each patient included physical examination; computed tomography (CT) scans of the neck, thorax, abdomen, and pelvis; bilateral bone marrow aspiration and biopsy; lumbar puncture; and positron emission tomography-computed tomography (PET-CT). Patients were staged according to the Ann Arbor staging classification. The international prognostic index (IPI) was assessed as previously described [13].

We assessed therapeutic response using the Revised Response Criteria for Lymphoma [14]. History taking, physical examination, and routine follow-up contrast enhanced neck, chest, and abdominopelvic CT, and PET-CT were performed every 3 months for the first 2 years, every 6 months for the next 3 years, and yearly thereafter or whenever clinically indicated after achieving a complete response (CR).

Overall survival (OS) was calculated from the date of diagnosis until the time of death as a result of any cause, or the date of the last follow-up for surviving patients. Progression-free survival (PFS) was calculated from the date of diagnosis to progression of disease or death as a result of any cause. If patients had not progressed or died, PFS was censored at the time of last follow-up. Both OS and PFS curves were plotted using the Kaplan-Meier method. The log-rank test was used to compare survival rates between groups of patients divided according to clinical characteristics. Statistical analyses were performed using the Statistical Package for Social Sciences version 20.0 (SPSS, Chicago, IL).

All of the patients initially presented with painless testicular swelling. The median age at diagnosis was 57 years (range, 41-79 years). The left testicle was involved in 2 patients (14.3%), the right testicle in 11 patients (78.6%), and both testicles in 1 patient (7.1%). All patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 1. Nine patients (64.3%) had stage I, 1 patient (7.1%) had stage II, and the other 4 patients (28.6%) had stage IV disease. The 4 patients with stage IV disease had extranodal involvement of the bone (N=1), bone marrow (N=1), lung (N=1), and Waldeyer's ring + bone + bone marrow + adrenal gland (N=1). The IPI score was 0-1 (low risk group) in 6 patients (42.9%), 2 (low-intermediate risk group) in 6 patients, and 3 (high-intermediate risk group) in 2 patients (14.3%). No patient had B symptoms. The serum lactate dehydrogenase (LDH) level was elevated in 6 patients. Patient characteristics are summarized in Table 1, and individual characteristics are listed in Table 2.

Thirteen patients (92.9%) underwent orchiectomy as an initial diagnostic and therapeutic procedure. All patients underwent chemotherapy, consisting of either R-CHOP (N=12, 85.7%) or CHOP (N=2, 14.3%) before introduction of rituximab. Prophylactic radiotherapy was administered to the contralateral testis once daily with 5 fractions per week for 12 of the 14 patients with unilateral testicular involvement. The median radiation dose was 3,200 cGy (range, 2,400-3,600 cGy) in 17.6 fractions (range, 12-20 fractions). The remaining 2 patients did not receive prophylactic radiotherapy; one of these patients initially presented with extensive disease (stage IV) and the other was aged 79 years with stage II disease. None of the patients underwent intrathecal prophylaxis, and only one patient with stage IV disease received therapeutic intrathecal methotrexate, after relapse at the leptomeninges was confirmed.

In total, 9 patients with stage I disease and 3 with stage IV disease underwent trimodal treatments comprising orchiectomy, CHOP±R chemotherapy and prophylactic radiotherapy to the contralateral testis. One patient with stage II disease underwent bimodal treatment involving orchiectomy and CHOP chemotherapy, but not prophylactic radiotherapy at the discretion of the treating physician. The remaining patient with stage IV disease received R-CHOP chemotherapy only. Initial treatments are summarized in Table 1 and individual treatment modalities are listed in Table 2.

All patients achieved a CR after completion of first-line chemotherapy. The median duration of follow-up in the surviving patients was 39 months (range, 10-139 months). Lymphoma recurred in 4 patients (28.6%). One patient with stage II disease at diagnosis, who was not administered prophylactic radiotherapy to the contralateral testis, experienced a relapse at multiple sites including the bone marrow, contralateral testis, epididymis, nasopharynx, and both the cervical and intra-abdominal lymph nodes. He died of sepsis after the first cycle of second-line chemotherapy (DHAP, dexamethasone, cytarabine, and cisplatin). Another patient with stage IV disease at diagnosis, who was given R-CHOP chemotherapy only, experienced relapse at the spinal nerve roots and leptomeninges 27 months after initially achieving a CR. He was then administered intrathecal methotrexate, and high-dose methotrexate/cytarabine chemotherapy, although refractory disease persisted. The other 2 patients with stage I disease at diagnosis, who underwent orchiectomy+R-CHOP chemotherapy+prophylactic radiotherapy to the contralateral testis, suffered from relapses, one in the left cervical lymph nodes and the other in the skin of the left upper arm. One patient with relapse at the cervical lymph node achieved a second CR after 6 cycles of ESHAP chemotherapy (etoposide, methylprednisolone, cytarabine, and cisplatin). The other patient underwent excision biopsy for the skin involvement. Although the tumor showed regression after excision, he experienced relapse in the skin of the thigh and stomach 5 months after excision. He showed progressive disease despite the administration of ESHAP chemotherapy and autologous stem cell transplantation, and he died of progressive disease. The treatment responses and outcomes of individual patients are listed in Table 2, and a flowchart summarizing the treatment of all patients is shown in Fig. 1.

The median PFS was 3.8 years, with a 3-year PFS rate of 81%. No median OS had been reached at the time of reporting, but the 3-year OS rate was 89% (Fig. 2). In univariate analysis, none of the patient characteristics-including an older age (≥60 years old), bilateral testicular involvement, left testicular involvement, advanced stage, extranodal involvement other than testis, a high-intermediate or high risk IPI, elevated LDH level, and prophylactic radiotherapy-were found to be significantly associated with PFS and/or OS (Table 3). The ECOG PS was 1 for all patients, and was therefore not analyzed. Multivariate analysis was not performed due to the small sample size and number of events.