1. GENERAL INFORMATION
Non-Hodgkin’s lymphoma of the testis (PTL) is an uncommon disease. It accounts for about 9% of testicular neoplasms. Despite this low overall incidence, however, it is the most common testicular malignancy in the elderly. PTL has a rather high incidence of bilateral involvement and a propensity for extranodal spread to the skin, subcutaneous tissue, CNS, lung, and Waldeyer’s ring. Diffuse large B-cell lymphoma is the most common histotype in primary forms, while in secondary involvement of testis, other aggressive histologies, especially Burkitt’s lymphoma, are prevalent. Although excellent results with doxorubicin-containing chemotherapy followed or not by radiotherapy have been achieved in limited disease, patients with advanced disease have a severe prognosis, and an elevated number of aggressive relapses have been observed in patients with stage I-II disease. CNS and residual testicle are often involved in relapsed patients (Tondini 1999; Zucca 1997).
PTL is a rare diseases that represents 1% to 2% of all non-Hodgkin’s lymphomas, with an estimated incidence of 0.26/100,000 per year (Duncan 1980). The first case was reported by Malassez in 1877. PTLs account for no more than 5% of all testicular malignancies, however they represent the most frequent testicular cancer in men older than 50 years of age (Zucca 1997). PTL is a typically disease of elderly, 85% of PTLs are diagnosed in men over 60 years of age.
1.3 Risk factors
There are not well-documented predisposing causes for primary testicular lymphoma (PTL). Anecdotal reports associated with trauma, chronic orquitis, cryptorchidism, or filariasis exist (Osman 1969; Sussman 1977; Talerman 1977). To date, no case-control studies proving their etiologic significance have been published.
2. PATHOLOGY AND BIOLOGY
Histologically, 80% to 90% of PTLs are diffuse large-cell type (DLCL) with B cell phenotype, but isolated cases of other histological subtypes have been described such as Burkitt and burkitt’s-like types in 10-20% of cases, mainly in HIV+ patients. Rarely T-cell or follicular lymphomas have been reported (Ferry 1994; Lambrechts 1995; Moertel 1995). Monoclonal lymphoid cells have been shown in controlateral testis in PTL patients, suggesting that bilateral testicular involvement is a pattern of a disease of the same origin (Leite 2000).
The vast majority of NHLs primarily involving the testis shows a B-immunophenotype, with rare reports of T-cell nature (Ferry 1994; Freeman 1972). Immunophenotype depends on histotype.
2.3 Molecular features
Peculiar molecular features have been described in PTL such as somatic hypermutation of immunoglobulin heavy-chain gene, indicating a possible antigen-driven stimulation, analogous to what is seen in extranodal marginal zone lymphoma (Hyland 1998).
3.1 Clinical presentations
Primary testicular lymphomas (PTL) present in adult patients, with a median age in the sixth decade. The most common clinical presentation is a unilateral painless scrotal swelling, sometimes with sharp scrotal pain. Systemic conventional symptoms such as fever, night sweats, weight loss are usually present only in advanced stage in 25% to 41% of patients (Doll 1986; Moller 1994; Shahab 1999). Less frequently, abdominal pain and ascites can be seen in patients with enlarged retroperitoneal lymph nodes (Sampat 1974). Hydrocele is observed in 43% of cases, requiring ultrasound of the testis to detect the parenchymal mass. On physical examination there is usually a monolateral nontender firm mass. Bilateral testicular involvement may be synchronous at diagnosis or, more frequently, asynchronous during the course of the disease. Bilateral involvement has been described up to 35% of patients (Moller 1994; Shahab 1999). Lymphoma is the most common bilateral tumor of the testis, with an overall incidence between 20% and 50% of cases (Ahmad 1994; Poulsen 1991). Lymphomatous mass has a sonographic appearance of a focal hypoechoic mass without a definable capsule or diffuse enlargement and decreased echogenicity of the entire testis that contrasts with the hyperechoic aspect of normal testis. Locally, PTL can infiltrate epididymus, spermatic cord and scrotal skin. PTL has a propensity to disseminate systematically to several extranodal sites including the controlateral testis, central nervous system (CNS 6% – 16%), skin (0% – 35%), Waldeyer’s ring (5%), lung, pleura and soft tissue. Involvement of Waldeyer’s ring is enigmatic. This may be because of a common embryonic origin, since both the testis and the oropharynx and nasopharynx are derived from the endoderm. Involvement of these sites may occur either concurrently or subsequently during the course of the disease. These data explain the high rate of relapses, the majority of them occurring in extranodal sites. The same pattern can be observed subsequently during the course of disease in patients with PTL.
3.2 Diagnostic criteria
For pathological diagnosis orchiectomy is the method of choice to obtain tissue better than fine needle ultrasound guided biopsy. Orchiectomy not only provides a better histological definition but it also removes the main tumour mass allowing a good local tumour control (Salem 1994). Moreover orchiectomy also removes a potential sanctuary site, as the blood-testis barrier makes testis tumors inaccessible to systemic chemotherapy (Doll 1986). Ultrasound is the initial investigation of choice. For pathological diagnosis orchiectomy is the method of choice of obtaining tissue better than fine needle ultrasound guided biopsy. Lymphomatous mass has a sonographic appearance of a focal hypoechoic mass without a definable capsule or diffuse enlargement and decreased echogenicity of the entire testis that contrasts with the hyperechoic aspect of normal testis. Testicular lymphoma may involve testicle only, but also structures within the scrotum and regional retroperitoneal lymph nodes. Locally, PTL can infiltrate epididymus, spermatic cord and scrotal skin. The definitive diagnosis is only histological. The large majority of cases are of diffuse large B-cell histology, Rarely lymphoblastic, follicular or T-cell lymphomas have been reported. Testis lymphoma is rare, however, is still the most common testis tumor in men older than 50 years of age. The rarity of non-germ cell testis tumors can jeopardize their correct diagnosis and is an important reason for the failure to recognize them reliably, especially in young patients. Diagnostic errors in this setting, though small in number, can be clinically tragic because treatment and prognosis are very different from the germ cell tumors. Testicular lymphoma in most cases should be easily distinguishable from germ cell cancer on morphologic grounds. However, the differential diagnosis with seminoma in some cases may not be straightforward; immunohistochemistry is very helpful in this setting.
3.3 Additional useful tests
Immunohistochemistry can solve problems in the differential diagnosis with germ cell tumors. The utility of especial techniques of molecular biology is conditioned by the histological nature of the lymphoma.
4.1 Staging procedures
Ultrasound is the initial investigation of choice. For pathological diagnosis orchiectomy is the method of choice of obtaining tissue better than fine needle ultrasound guided biopsy. Orchiectomy not only provides a better histological definition but it also removes the main tumour mass allowing a good local tumour control (Salem 1994). Staging procedures in PTL are similar to those applied in nodal lymphomas with some peculiar features. A thorough evaluation to determine the extent of lymphomatous involvement should be made, focusing specially to the central nervous system, controlateral testis, skin and Waldeyer’s ring. Complete staging work-up for primary testicular lymphoma (PTL) is the same that routinely used for other NHL. It includes an accurate physical examination, complete hematological and biochemical exams, total-body computerized tomography, gastrointestinal tract examination, and bone marrow aspirate and biopsy. Some particular sites of disease frequently involved by PTL, that is CNS, skin, Waldeyer’s ring, and the contralateral testis, require especial diagnostic procedures: CSF examination for malignant cells and screening ultrasound of the contralateral testis are advisable. The presence of pulmonary masses or pleural effusions should be histologically verified. Bone marrow assessment should follow the general statements for all NHL. CSF flow cytometry has been recently showed to detect occult CNS disease in aggressive B-cell lymphomas (Hegde 2005) and PET scan may increase accuracy in lymphoma staging (Spaepen 2001). Such new staging procedures may be worthwhile to be incorporated into staging work-up of PTL, but so far only anecdotal reports exist on the use of PET in PTL (Romics 1999).
4.2 Staging system
The standard staging system used for primary testicular lymphomas (PTL) is the same as that proposed for Hodgkin’s disease at the Ann Arbor Conference in 1971 (Carbone 1971). This system is currently used for all non-Hodgkin’s lymphomas, even if other staging systems are used in some extranodal lymphomas with particular biological behavior. Localized stages I and II account for 70-80% of the patients (50-60% stage I and 20-30% stage II). Stage III is very rare (3-5%), whereas the precise incidence of stage IV is not easy to assess. A stage IV PTL is virtually undistinguishable from a nodal advanced stage lymphoma with a testicular involvement. The rate of testicular involvement in advanced stage DLCL is 10-18% and 10-29% in Burkitt’s lymphoma. In order to separate these two entities, a PTL is usually defined if the testicular mass is the primary site of the disease or the main site of involvement. PTLs are staged according to Ann Arbor criteria with few modifications:
Stage IE: involvement of the testis mono or bilateral
Stage IIE: mono or bilateral testicular involvement with loco regional lymph nodes (iliac and/or lomboaortic).
Advanced stage III/IV: mono or bilateral testicular involvement with involvement of distant lymph nodes and/or extranodal sites (Zucca 2003).
4.3 Molecular analysis of minimal residual disease
No reliable molecular markers are available for monitoring of minimal residual disease in stage I-II primary testicular lymphomas.
4.4 Restaging procedures
Restaging should include all diagnostic procedures positive at time of diagnosis and initial staging. CSF examination for malignant cells, screening ultrasound of the contralateral testis and Waldeyer’s ring examination are advisable even in cases with initial negative result.
5.1 Natural history
Primary testicular lymphomas (PTL) are very aggressive malignancies, most patients with limited disease relapse in spite of initial complete remission (Crellin 1993; Duncan 1980; Fickers 1991; Liang 1990; Moertel 1995). The pattern of relapse depends on the first-line treatment. Although occasionally long-term survival may be achieved with orchiectomy alone, the majority of the patients have relapsed within two years suggesting that widespread microscopic disease is present at diagnosis (Ciatto 1979). Almost all patients irradiated to the retroperitoneum relapse with disseminated disease. PTL behaves aggressively with a poor outcome. Five year survival ranged from 16% to 50% and median survival has been reported of only 12-24 months according to the different series of patients (Moller 1994; Salem 1994). Most relapses occur within the first two years of follow-up, but late relapses have been also reported (Ikeda 1986). In most cases relapses occurred in extranodal sites such as: CNS, skin, lung, pleura, soft tissue, Waldeyer’ring (Zietman 1996; Fonseca 2000). One of the peculiar feature of PTL is a controlateral testis relapse occurring in 5-35% of the patients (Shahab 1999). Moreover CNS relapses are definitely more common than in other aggressive lymphomas and they have been reported up to 30% of the patients within 1-2 years from diagnosis. However occasionally late relapse have also been described, sometimes as CNS relapse alone (Touroutoglou 1995; Tondini 1999). CNS failures may occur both in brain parenchyma and in meninges. In a large retrospective series of 373 patients reported by IELSG, the commonest sites of relapse were: CNS (5 and 10-years risk of CNS relapse 20% and 35%) and controlateral testis (15% at 3 years, 40% at 15 years) occurring in patients not receiving prophylactic scrotal radiotherapy (Zucca 2003). In the final phase of disease infiltration of any organ may occur, and a leukemic phase has also been reported (Liang 1990). Five-year relapse rate in patients with limited disease treated with orchiectomy and chemotherapy, followed or not by radiotherapy, oscillates between 42% and 66% (Ostronoff 1995; Touroutoglou 1995). Disseminated lymphomas involving the testis (stage IV disease) show a very aggressive behavior with more than 90% of relapse rate and a 5-year survival of 20% – 25%. Patterns of relapse and dissemination are similar to those described for patients with limited disease (Tondini 1999; Zucca 2003).
5.2 Prognostic factors
Prognostic indicators for primary testicular lymphoma reported by some studies were as follows: age, performance status, systemic symptoms, tumor burden higher than 9 cm, spermatic cord involvement, LDH ratio, histologic grade, vascular invasion, degree of sclerosis, and stage of disease(Fickers 1991; Paladugu 1980; Shahab 1999; Sussman 1977). In the large study by of the International Extranodal Lymphoma Study Group (IELSG), clinical features significantly associated with a longer overall survival in multivariate analysis were: low/low-intermediate IPI score, no B symptoms, anthracyclines containing regimens, prophylactic scrotal radiotherapy (Zucca 2003).
6.1 Treatment of limited disease (stage I-II)
Standard treatment for patients with PTL has not been yet established (Shahab 1999). Orchiectomy not only provides histological tissue for diagnosis but it also removes a potential sanctuary site, as the blood-testis barrier makes testicular tumours inaccessible to systemic chemotherapy. Although occasionally long-term survival may be achieved with orchiectomy alone, surgery should not be considered as the exclusive treatment even in patients with stage-I disease. In fact, most of these patients treated with surgery alone experience relapse within two years, suggesting that widespread microscopic disease is present at diagnosis in PTL (Ciatto 1979). Thus, orchiectomy followed by complementary anthracycline-containing chemotherapy is a widely accepted option as suitable for individual clinical use on a type 3 level of evidence. The use of anthracycline-based chemotherapy has been associated with a 5-yr survival of 30% – 75% (Tondini 1999; Crellin 1993; Liang 1990; Touroutoglou 1995; Connors 1998). Nevertheless, there appears to be a continuous relapse pattern with no clear evidence of plateau in the survival curve. Although it is not possible to individuate the most efficacious chemotherapy regimen due to the limited number of patients in the reported series and the lack of randomised trials, doxorubicin-containing regimens have been associated with an improvement in the relapse-free survival compared with orchiectomy ¡À radiotherapy. However, the advantage on survival time varied greatly among the different series published so far. The most common chemotherapy regimen used was standard CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) in the most recent studies and less frequently CHOP-like regimens such as MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, bleomycin, and prednisone) (Tondini 1999) or VCAP (vindesine, doxorubicin, cyclophosphamide, and prednisone) (Linassier 2002). As in nodal DLBCL, the addition of rituximab to CHOP chemotherapy may be useful in PTL as suggested by preliminary data of the recently reported IELSG #10 trial (Vitolo 2006). In this study, 49 patients with stage I-II PTL were treated with 6 ¨C 8 cycles of CHOP and rituximab and complete prophylaxis with intrathecal methotrexate and scrotal radiotherapy ¡À loco-regional radiotherapy for stage II. The preliminary results suggest an improvement in the outcome with a 3-year OS and 3-year PFS of 87% and 84%, no contralateral testis relapses and 2.5% actuarial risk of CNS relapse at three years (Vitolo 2006). In a preliminary study conducted by IELSG and MDACC, 27 patients were treated with the same regimen (CHOP + intrathecal methotrexate and crotal radiotherapy ¡À loco-regional radiotherapy for stage II) but without rituximab. The 5-year PFS and OS were78% and 66%, respectively, without an apparent plateau. There were no testicular relapses and the actuarial risk of CNS relapse was still high 16% (Sarris 2006). It is difficult to assess from these studies if the addition of rituximab may prevent CNS relapses. The differences in results may be merely due to different follow-up time or to a true reduced risk of systemic relapse in rituximab treated patients that might prevent CNS recurrences. On the other hand, as demonstrated by Feugier et al. in a randomized trial on 399 patients with DLBCL comparing R-CHOP versus CHOP chemotherapy regimen (Feugier 2004), the addition of rituximab did not reduce the risk of CNS dissemination at relapse. In fact, CNS dissemination rate was 5.4% and 4.5% (p= 0.68) for patients treated with R-CHOP and CHOP, respectively. Effectively, there are several doubts about the capacity of rituximab to cross the whole blood-brain barrier and, as consequence, to prevent CNS dissemination. Larger studies with a more mature follow-up will show the role of rituximab in PTL treatment. Routine CNS prophylaxis is recommended in PTL patients of any stage since the high rate of CNS recurrence. The best strategy to prevent CNS relapse is still a matter of debate. The value of prophylactic intrathecal chemotherapy is controversial because CNS relapses occur more frequently in brain parenchyma than in meninges and also in patients who had received intrathecal chemotherapy (Zucca 2003; Fonseca 2000). Perhaps, the use of drugs with a higher CNS bioavailability, like methotrexate or cytarabine administered at high doses, could reduce the incidence of this dismal complication. This type of chemotherapy could however be associated with severe toxic side effects in elderly patients, such as PTL usually are. Radiation therapy can be used, as prophylactic therapy, to prevent relapse in the regional lymph nodes or in the controlateral testis in patients with stage-IE disease or to treat lymphomatous lesions, mostly retroperitoneal lymphadenopathies, in patients with stage-IIE disease. Patients should be treated on linear accelerator with energies ¡Ý6MV and by anterior and posterior equally weighted fields, both fields being treated daily 5 days per week. The Clinical Target Volume in involved field (IF) irradiation for stage-II disease should include the entire involved nodal region and may include an adjacent nodal region. Minimum IF, for patients with limited para-aortic lymph node involvement only, should include the cm wide field. Maximum IF should include inverted ¡°Y¡± or ¡°dog leg¡± field and include para-aortic lymph node region and bilateral pelvic lymph nodes. For patients receiving pelvic irradiation, the inferior border should be at the superior border of the obturator foramen in patients with inguinal lymph node involvement, and 5 cm below the involved inguinal lymph nodes in patients with inguinal lymph node involvement. Left renal hilar lymph nodes must be included in patients with left testicular presentation. Both kidneys should be located by planning CT and appropriate blocks should be used to prevent including more than 25% of renal parenchyma in the para-aortic field. IF radiation dose in patients with stage-II disease depends of the response to primary chemotherapy: 30 35 Gy (conventional fractionation) for patients who achieved complete remission and 35 45 Gy for patients who did not. The indication for radiation therapy as exclusive treatment after orchidectomy should be kept for patients with clinical contraindications to systemic treatment. Almost all patients with stage IE or IIE irradiated to the retroperitoneum experience systemic dissemination, with a very few cases of in-field relapses. Prophylactic irradiation (25-30 Gy; standard fractionation) prevents relapses in the contralateral testis, with excellent tolerability (Duncan 1980; Crellin 1993; Fickers 1991; Connors 1998; Pectasides 2000). The Clinical Target Volume in scrotal irradiation should be defined clinically by palpation. The contralateral testis should be treated with the direct anterior beam with electron beam 9 to 12 MV or direct anterior Cobalt field or 6MV field bolus should be placed for patient who are treated with 6MG linear accelerator. Care should be taken to avoid unnecessary radiation to the perineum or the legs. Other uses of radiation therapy could be related to the control of CNS disease. With the current evidence, CNS prophylactic irradiation was not addressed in reported literature while the irradiation of CNS lesions from PTL should follow the general rules for other aggressive lymphomas with CNS involvement at relapse. In conclusion, PTL patients with limited disease should be managed with primary orchidectomy followed by R-CHOP treatment, CNS prophylaxis (high-dose methotrexate +/- intrathecal chemotherapy) and prophylactic scrotal radiotherapy. In patients with stage-IIE disease, irradiation of involved lymph nodes is advisable.
6.2 Treatment of advanced disease (stage III-IV)
These patients should be treated according to the guidelines for the treatment of advanced stage nodal Diffuse large B-Cell lymphoma. Standard therapeutic option for patients with stage III-IV disease is conventional-dose anthracycline-containing chemotherapy with Rituximab with the addition of prophylactic scrotal radiotherapy and intrathecal chemotherapy. The addition of intermediate-high dose methotrexate might improve CNS prophylaxis, especially in the younger patients but this has never been formally demonstrated (Seymour 2001). High-dose chemotherapy supported by stem cell transplantation may be an investigational option in these patients.
6.3 Treatment of relapsed or refractory disease
Standard therapeutic option for patients with stage relapsed disease has not been yet defined. Therapeutic guidelines should be the same as for for other aggressive NHL. High-dose chemotherapy with autologous stem cell rescue is the treatment of choiche in patients less than 60 years with chemosensitive relapse. In any way, therapeutic decision should be strongly influenced by age, performance status and clinical conditions of patients. Many of these patients are elderly, have a large tumor burden, poor performance status, excessive weight loss, and multiorgan dysfunction.
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Dr. Andrés Ferreri (Associate Editor)
San Raffaele Scientific Institute – Milan, Italy
Dr. Umberto Vitolo (Author)
Azienda Ospedaliera S.Giovanni Battista (Molinette)
Prof. Emanuele Zucca (Reviewer)
Oncology Institute of Southern Switzerland – Bellinzona, Switzerland