Table of Contents  

Venyo: Primary and metastatic lymphoma of the testis – a review of the literature

Introduction

Primary lymphoma of the testis accounts for approximately 1% of all lymphomas and up to about 5% of all tumours of the testis. The majority (about 90%) of lymphomas of the testis are diffuse large B-cell lymphomas (DLBCLs) of non-germinal centre type, and they predominantly occur in men who are over 60 years of age. Primary follicular lymphoma of the testis is rare and it occurs mainly in boys and young adult men. Other types of lymphoma, although rare, can occur in the testis. The various types of lymphoma that are found in the testis are either primary lymphomas or metastatic lymphomas. Other tumours and inflammatory conditions may mimic lymphoma of the testis; therefore, the correct diagnosis of the lymphoma of the testis and the cell type is required through careful histological examination. Whether a lymphoma is a localized primary, advanced or metastatic lymphoma determines the approach taken to management. In developed countries, oncologists collaboratively, through a multidisciplinary team approach, discuss the approach to management of lymphomas of the testis. Unfortunately, in some developing countries – where there may not be a full complement of oncologists in some of the remote areas of such countries – management of lymphomas of the testis may be carried out without involvement of the oncologist. The ensuing review of the literature of lymphoma of the testis is divided into four parts: (1) a general overview, (2) a summary of the features of DLBCL, (3) a summary of the salient features of follicular lymphoma of the testis, and (4) miscellaneous narrations from some reported cases of lymphoma of the testis.

Methods

Various online databases were used to search for literature on lymphoma of the testis. The key words that were used include ‘primary lymphoma of the testis’, ‘metastatic lymphoma of the testis’ and ‘secondary lymphoma of the testis’. Seventy-five references on case reports, case series, review papers and other documentations were used to write the review of the literature on lymphoma of the testis, including on the presentation, clinical findings, investigations, management and outcome of the disease.

Literature review

Overview

General

Lymphoma of the testis is classified as having either primary or secondary involvement by malignant clonal lymphocytes.1 The most common type of lymphoma of the testis is DLBCL.1 Other types of lymphoma that involve the testis include anaplastic lymphoma, Burkitt’s lymphoma, Hodgkin’s lymphoma, peripheral T-cell lymphoma and follicular lymphoma.

Epidemiology

Lymphoma of the testis accounts for approximately 5% of testicular malignancies.1 It is the most common malignant testicular neoplasm in men over 60 years of age, but it can occur at any age. The mean age of patients afflicted by lymphoma of the testis is 67 years, but the age at which it can occur ranges from 16 to 91 years.2

Clinical features

Patients with lymphoma of the testis tend to present with a painless testicular mass.1 In lymphoma of the testis, bilateral testicular involvement occurs in up to 35% of cases, and the lymphoma quite often spreads to the central nervous system (CNS).1

Radiological features – ultrasound scan findings

In lymphoma of the testis, using grey-scale and colour Doppler ultrasound scanning, various appearances of the testis can be seen, including diffuse infiltration and enlargement of the testis with associated hypervascularity (increased vascularity) and also multifocal areas of hypoechoic, solid and hypervascular nodules (nodules with increased vascularity within the testes).3

The role of positron emission tomography/computerized tomography in diagnosis and assessment

According to Cronin et al.4:

  • On the whole, there are no specific markers available that are capable of diagnosing malignancy of lymphocytes; the diagnosis is based upon a combination of (1) morphological characteristics (of lymph nodes, blood and bone marrow), (2) immunophenotyping of the aforementioned specimens and (3) molecular and cytogenetic data of the specimens. Many lymphomas exhibit characteristic morphological features upon examination, and excision biopsy is preferable to core biopsy and fine-needle aspiration of lymph node specimens to obtain information on structural detail of diagnostic value.

  • In situations when there is a lack of palpable lymphadenopathy, computerized tomography (CT) or positron emission tomography (PET)/CT can be used to localize suitable sites to obtain biopsy specimens. PET/CT does have the advantage over CT of depicting sites of lymphoma that are both accessible and metabolically active and, thus, it is most likely to yield a true positive result,5 but CT is the most commonly utilized and most readily available modality for the staging of lymphoma. Nevertheless, CT has limitations in that (1) the recognition of lymph node involvement is based solely upon size and (2) the detection of bone marrow and extranodal tissue involvement may be limited.

Some authors6,7 have indicated that (1) PET/CT detects nodal sites of lymphoma involvement with greater accuracy than CT, (2) PET/CT has greater sensitivity for sites of extranodal involvement than CT and has been found to improve baseline staging in comparison with conventional CT alone and (3) PET/CT findings have the capability of indicating the overall activity of lymphoma, which correlates with patients’ serum levels of lactate dehydrogenase (LDH; a prognostic predictor).

PET/CT has a role to play in the assessment of treatment response, and some studies8,9 have illustrated the prognostic value of PET/CT during and after chemotherapy for the identification of patients in whom further intensive therapy is required.

Macroscopic characteristics

Macroscopic inspection tends to reveal a white/tan/pink fleshy tumour, which resembles lymphoma, and quite often there is evidence of extratesticular involvement.1

Microscopic characteristics

Microscopic examination tends to reveal splaying apart; nevertheless, there is often relative sparing of the tubules by the lymphoma cells.1 The malignant cells are usually pleomorphic and non-cohesive, with nuclei that tend to be large and irregular with prominent nucleoli. There may be evidence of vascular invasion and sclerosis of the seminiferous tubules, and there is often no evidence of intratubular germ cell neoplasia or follicular large cell lymphoma.

Immunohistochemical staining characteristics – positive staining

Lymphomas of the testis tend to stain positively for leucocyte common antigen (LCA/CD45).1 The other immunohistochemical staining characteristics depend upon the subtype of the lymphoma of the testis.1

Immunohistochemical staining characteristics – negative staining

Lymphomas of the testis stain negatively for placental alkaline phosphatase (PLAP)1 and SALL4.1

Differential diagnoses

The differential diagnoses of lymphoma of the testis include chronic orchitis, which tends to cause patchy heterogeneous infiltrates,1 myeloid sarcoma or granulocytic sarcoma,1 classic subtype of seminoma1 and spermatocytic subtype of seminoma.1

Treatment

Lymphoma of the testis is treated by orchiectomy and chemotherapy.1

Prognosis

Primary unilateral lymphomas of the testis have a better prognosis (5-year survival of 60%) than disseminated disease/other stages (5-year survival of 17%).1

Summary of the features of the most common primary lymphoma of the testis – primary diffuse large B-cell lymphoma

General

Horne and Adeniran10 reported that primary DLBCL of the testis is most often seen in older patients, and the disease tends to present as a testicular mass involving one testis.

Microscopic examination of the testis usually reveals the following features: diffuse infiltration of lymphocytes between intact seminiferous tubules, evidence of spermatogenic arrest, interstitial fibrosis, and hyalinization of tubules. Immunohistochemistry of the tumours is usually positive for B-cell markers. The disease is treated by orchiectomy and combination chemotherapy, but very few patients enjoy prolonged disease-free survival. In recent times, radiotherapy to the contralateral testis has been undertaken in an attempt to reduce the incidence of recurrence in the contralateral testis, and intrathecal chemotherapy has also been used in the hope of reducing CNS recurrence. However, recurrences still occur.

Clinical presentation of primary diffuse large B-cell lymphoma

Various clinical presentations of the disease have been reported by a number of authors, as follows:

  • The disease is most often found in adults, with the median age in the sixth decade, and as a unilateral, painless testicular enlargement that progresses rapidly.10

  • The testicular mass may have been present for weeks, months or a number of years before the initial presentation.10,11

  • Between 25% and 40% of patients report systemic symptoms including fever, night sweats, anorexia and weight loss.1013

  • Local examination of the testis and scrotum may reveal tumour extension to the epididymis, spermatic cord and scrotal skin and, on occasion, the patient may have scrotal pain.10,13

  • Of the patients with DLBCL, 40% are reported to have presented with hydrocele.10,13

  • Involvement of both testes has been reported.10,14

Staging

Staging of the tumour has been categorized based on the Ann Arbor staging system (I, III, III and IV), which has been added to the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 7th edition.10,15

Laboratory tests

It has been suggested that determining serum LDH levels could be beneficial to the assessment of tumour volume and to the assessment of the response to treatment, as serum LDH levels had been found to be correlated with tumour aggressiveness; on the other hand, serum levels of other tumour markers such as serum beta-human chorionic gonadotropin and alpha-fetoprotein are rarely elevated.10,13

Macroscopic characteristics

The features of the tumour on gross examination have been described by a number of authors, as follows:

  • The tumour tends to vary in size, but is usually large. Examination of cut sections of the testis reveals a fleshy to firm mass, which is often lobulated and can be a variety of colours (cream, tan, pale yellow).10,16

  • The tumour tends to be homogeneous and to replace the testis in a diffuse manner.10

  • Areas of bleeding and necrosis may be seen. The tumour may extend to involve the epididymis, spermatic cord or adjacent soft tissues, and this may be evident on gross examination.10,14,17

Microscopic characteristics

Horne and Adeniran10 summarized the features of the tumour on microscopic examination as follows:

  • Microscopic examination shows sheets of discohesive cells that have infiltrated diffusely and have often penetrated diffusely into tissue spaces, resulting in the production of wide separation of the normal structures, but without usually leading to complete destruction of the basic architecture (Figure 1A).10

  • The seminiferous tubules may be preserved, atrophic or completely obliterated. Spermatogenic arrest, interstitial fibrosis and hyalinization are also often seen.10

  • The cells of the lymphoma frequently also penetrate the reticulin fibres that encompass the tubules, resulting in the production of a loose, open network of peritubular fibres.10

  • In some cases, there may be evidence of destruction of the tubular walls and invasion of the lumen.10,17,18

  • The tumour cells are usually described as medium-sized to large lymphoid cells with oval to round, vesicular nuclei with fine chromatin.10

  • Multiple small, membrane-bound nucleoli are frequent. The cytoplasm tends to be scanty and amphophilic to basophilic (Figure 1B).10

  • Areas of the tumour may have larger cells with more cytoplasm, which at times appear cohesive. These larger cells tend to have distinct nucleoli, which mimic undifferentiated carcinoma.10,19

FIGURE 1

Interface between tumour and non-neoplastic testis. (A) Diffuse intertubular infiltration by tumour cells with sparing of the seminiferous tubules (right). (B) Discohesive tumour cells showing irregular nuclear foldings and granular chromatin. The larger cells possess distinct nucleoli, with moderate pale cytoplasm. Haematoxylin and eosin stain, original magnification ×40 (A) and ×400 (B). Reproduced from Horne MJ, Adeniran AJ. Primary diffuse large B-cell lymphoma of the testis. Arch Pathol Lab Med 2011; 135(10):1363–7,10 with permission from Archives of Pathology & Laboratory Medicine. Copyright 2011 College of American Pathologists.

9-2-1-fig1a.jpg9-2-1-fig1b.jpg

Immunohistochemical staining characteristics

Horne and Adeniran10 summarized the immunohistochemistry of lymphoma of the testis as follows:

  • Primary DLBCL of the testis expresses a number of pan-B-cell markers, including CD19, CD20 (Figure 2A), CD22 and CD79a, but the tumour tends to lack one or more of these.10,19

  • Cytoplasmic immunoglobulin is found in 50–75% of cases and the presence of cytoplasmic immunoglobulin does not correlate with the expression of plasma cell markers such as CD38 and CD138, as these markers are rarely co-expressed in CD20-positive cells.10,19,20

Tagawa et al.21 reported that the tumour cells express CD5 in approximately 10% of cases.

Berglund et al.22 stated that DLBCL is constituted by at least two prognostic entities, depending upon its resemblance to either a normal germinal centre or activated B cells, by the use of global gene expression profiling. They also stated that the expression patterns of BCL-6, CD10 and IRF-4, which is also known as MUM1, had been suggested as alternative means for the identification of the germinal and non-germinal centre (activated B-cell like) groups. Berglund et al.22 evaluated the immunohistochemistry expression patterns of CD10, BCL-6, IRF-4 and BCL-2 in 161 DLBCL patients and reported that patients who had the germinal centre phenotype were more likely to survive than patients with the non-germinal centre phenotype. Furthermore, they also found that, with regard to prognosis, positive staining of the tumours for BCL-6 and CD10 was predictive of superior survival, but expression of IRF-4 alone was not associated with prognosis. In addition, expression of BCL-2 was associated with worse event-free survival and overall survival; a multivariate analysis of the results showed that a high international prognostic index score (3–5), non-germ cell phenotype and BCL-2 expression constituted independent adverse prognostic factors. The authors formed the opinion based upon the aforementioned findings that it is important to determine the germinal or non-germinal centre phenotype in patients with DLBCL for prognostication.

Some authors10,20,23 have found that CD5-positive tumours can be differentiated from the blastoid variant of mantle cell lymphoma by the absence of cyclin D1 expression; CD10 expression was found in 30–60% of cases; the expression of transitional marker MUM1 is observed in 35–65% of cases (see Figure 2B); and nuclear expression of BCL-6 has been reported in 60–90% of cases.

Miller et al.24 stated that the Ki-67 staining proliferative index in the tumours tends to be high and usually more than 40%10 (see Figure 2C).

FIGURE 2

Immunohistochemical staining of primary testicular DLBCL. (A) The neoplastic infiltrate shows strong expression of CD20. (B) The lymphocyte cells express MUM1. (C) The proliferative activity labelled by Ki-67 is high. Original magnification ×200 (A and B) and ×100 (C). Reproduced from Horne MJ, Adeniran AJ. Primary diffuse large B-cell lymphoma of the testis. Arch Pathol Lab Med 2011; 135(10):1363–7,10 with permission from Archives of Pathology & Laboratory Medicine. Copyright 2011 College of American Pathologists.

9-2-1-fig2a.jpg9-2-1-fig2b.jpg9-2-1-fig2c.jpg

Flow cytometry and gene rearrangement/translocation studies

According to Horne and Adeniran,10 DLBCL can be further subclassified, using gene expression arrays, into germinal centre B-cell-like DLBCL and non-germinal centre B-cell-like DLBCL, the latter including activated B-cell-like DLBCL. It is possible to use CD10, BCL6 and MUM1 to distinguish between subtypes as an aid to diagnosis.25,26

Molecular characteristics

According to Horne and Adeniran10:

  • Cytogenetic studies, fluorescence in situ hybridization (FISH) and array comparative genomic in situ hybridization have demonstrated that genetic alterations in DLBCL of the testis are quite often complex abnormalities, including translocations, trisomies, amplifications and deletions, and that the more commonly observed abnormalities include 3q27 abnormalities and 6q deletions.

  • Even though deletion of 6q has been considered a secondary chromosomal abnormality, in a number of cases a primary pathological role has been postulated based on the finding that this deletion has occurred as the only cytogenetic abnormality.27

  • Some studies have found that 6q deletions are more frequent in tumours that have an activated B-cell-like gene expression profile than in tumours with a germinal centre B-cell-like gene expression profile.28,29

  • DLBCL structural alterations have been identified. There is no correlation between BCL-2 rearrangement and BCL-2 protein expression, as almost half of DLBCL cases with BCL-2 rearrangement have no or weak BCL-2 protein expression and about 40% of DLBCL cases with high BCL-2 protein expression do not have detectable rearrangement. An explanation for the discrepancy could be mutations in the open reading frame of the translocated BCL-2 gene.30,31

  • Nevertheless, not much is known about the specific frequency of this particular translocation in DLBCL.

Treatment

The treatment of lymphoma of the testis may be divided into (1) treatment of limited disease (stages I and II) and (2) treatment of advanced stage III and IV disease.10

As regards (1), the treatment of limited disease:10

  • There is no consensus regarding the standard treatment for limited disease.10

  • Tumour specimens for macroscopic, microscopic, immunohistochemistry and other types of pathological examination are obtained by transinguinal radical orchiectomy, and histological examination of the cord structures can indicate whether or not cord structures are involved.10

  • For a long time, until recently, CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) was the standard chemotherapeutic regimen.10

  • Other forms of intensive CHOP-like chemotherapy, such as MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, bleomycin, prednisolone and vindesine), have been utilized to treat localized disease in an attempt to improve prognosis;32,33 however, their use has not been proven to provide additional benefits to patients.

  • Coiffier34 reported that the addition of the chimeric anti-CD20 monoclonal antibody rituximab to the CHOP regimen markedly increased progression-free and overall survival.

  • CNS relapse of lymphoma of the testis remains a major problem; thus, routine CNS prophylaxis should be recommended. However, the best way to achieve this remains controversial, as CNS relapses have been found to occur more frequently in brain parenchyma than in the meninges and CNS relapses have occurred in patients who have received intrathecal chemotherapy.10,12,35

  • Radiotherapy can be used prophylactically to prevent relapse either in the regional lymph nodes or in the contralateral testis, or to treat lymphomatous lesions such as retroperitoneal lymph nodes.12

As regards (2), the treatment of advanced disease:10

  • The therapeutic approach to the management of advanced disease is dependent on the guidelines for the treatment of advanced-stage nodal DLBCL.10

  • In patients with stage III or IV disease, the standard therapeutic approach is conventional anthracycline-containing chemotherapy plus rituximab with the addition of prophylactic scrotal radiotherapy and intrathecal chemotherapy.10,12

  • In the case of patients with relapsed disease, a consensus on the standard therapeutic regimen has not yet been reached.10,12

  • Among patients with relapsed advanced disease, the management decision is influenced by the patient’s age, performance status and previous treatment.10,12

Outcome

Diffuse large B-cell lymphoma is a very aggressive malignancy associated with a poor prognosis.10 Despite the initial complete remission, the majority of patients – even those with stage I or II disease – tend to experience relapses.12 It has also been reported that most DLBCL relapses occur within the first 2 years of follow-up.10 The International Extranodal Lymphoma Study Group found 5- and 10-year overall survival rates of 48% and 27%, respectively.35

Some authors11,36 have reported a number factors affecting prognosis, including the patient’s age, the patient’s performance status, the presence of systemic symptoms, tumour greater than 9 cm in diameter, spermatic cord involvement, serum LDH level, histological grade, vascular invasion, the degree of sclerosis and the stage of the disease.10

Differential diagnoses

The differential diagnoses of primary DLBCL of the testis include10:

  • germ cell tumours such as classic seminoma, spermatic seminoma and embryonal carcinoma10 (Figure 3 – this figure shows characteristics of seminoma to compare with Figures 1 and 2);

  • granulomatous and viral orchitis10 (Figure 4 – this figure shows characteristics of viral orchitis).

To help differentiate DLBCL from other differential diagnoses, immunohistochemical staining can be used, which quite often finds that testicular lymphomas are positive for CD45 and CD20 but are negative for OCT3/4 and placental alkaline phosphatase.10,37

FIGURE 3

Seminoma showing diffuse arrangement of pale to clear cells with distinct cell membranes in association with a prominent inflammatory infiltrate. Haematoxylin and eosin stain, original magnification ×400. Reproduced from Horne MJ, Adeniran AJ. Primary diffuse large B-cell lymphoma of the testis. Arch Pathol Lab Med 2011; 135(10):1363–7,10 with permission from Archives of Pathology & Laboratory Medicine. Copyright 2011 College of American Pathologists.

9-2-1-fig3.jpg
FIGURE 4

Orchitis. (A) Granulomatous orchitis showing prominent intratubular granulomatous reaction associated with lymphocytic infiltrate. (B) Viral-type orchitis showing patchy intratubular and interstitial lymphocyte infiltrate. Haematoxylin and eosin stain, original magnification ×400. Reproduced from Horne MJ, Adeniran AJ. Primary diffuse large B-cell lymphoma of the testis. Arch Pathol Lab Med 2011; 135(10):1363–7,10 with permission from Archives of Pathology & Laboratory Medicine. Copyright 2011 College of American Pathologists.

9-2-1-fig4a.jpg9-2-1-fig4b.jpg

Summary of the features of follicular lymphoma of the testis

Primary follicular lymphoma of the testis is rare and it occurs predominantly in boys and young adults.38 It usually presents as a unilateral testicular swelling/enlargement.38 Macroscopic examination of primary follicular lymphoma of the testis usually reveals a firm white/tan tumour and there may be macroscopic evidence of involvement of the epididymis. Microscopic examination of the testicular tumour usually reveals lymphomatous infiltrate, which may permeate or replace the testicular and epididymal structures.38 The architecture of the tumour tends to be variable and can range from vaguely nodular to well-formed small neoplastic follicles. Foci of DLBCL may also be seen.

Immunohistochemical staining of follicular lymphoma of the testis revealed the following:

  • negative staining for BCL-2 in four out of four tumours (positive staining in zero out of four cases) and in 11 out of 11 other cases (positive staining in 0 out of 11 cases), which corresponds with the lack of a t(14;18) translocation;38

  • positive staining for CD20 in four out of four cases;38

  • positive staining for CD10 in four out of four cases and in five out of eight other cases;38

  • staining of dendritic follicular cells within the neoplastic follicles;38

  • positive staining for BCL-6 in four out of four cases and in eight out of nine other cases;38

  • expression in 40–80% of cells for Ki-67;38

  • positive staining for p53 in one out of four cases and in zero out of seven other cases.38

Polymerase chain reaction and fluorescence in situ hybridization studies

Polymerase chain reaction (PCR) and FISH studies in follicular lymphoma of the testis for t(14;18)IgH/BCL-2 rearrangement gave negative results in four out of four cases (positive in zero out of four cases) and in seven out of seven cases (positive in zero out of seven cases).38

Differential diagnosis

A differential diagnosis of follicular lymphoma of the testis is DLBCL, as the foci of diffuse large B-cells may be found in follicular lymphoma; however, the diagnosis should be obvious based upon the aforementioned characteristics of follicular lymphoma.38

Management

The management of primary follicular lymphomaof the testis includes orchiectomy and chemotherapy.38

Outcome

The prognosis following chemotherapy of primary follicular lymphoma of the testis is good, and it would appear that there is no propensity to spread widely as is seen in DLBCL.38

Miscellaneous narrations and discussions from some reported cases

Tondini et al.32 reported the clinical outcome of 29 patients (median age of 61 years) with testicular DLBCL treated with conventional-dose systemic chemotherapy. Sixteen of the patients had limited-stage disease (Ann Arbor stage I/II) and 13 patients had a testicular mass and distant metastasis (Ann Arbor stage IV). The patients were categorized based upon the International Prognostic Index. After a median follow-up of 82 months, disease had progressed in 22 patients and a further 22 patients had died. The actuarial median time to treatment failure and overall survival were, respectively, 44 months and 41 months for those patients who had limited-stage disease and 9 and 16 months for the patients who had advanced-stage disease. Initial treatment failed in eight of the patients, and 14 patients, who initially experienced remission, had relapsed after a median disease-free time of 17 months (range 6–98 months). The median survival time after progression of the lymphoma was 5 months (range 0–22 months). Of the 22 patients who experienced treatment failure, in nine (41%) the initial site of relapse was either the CNS or the contralateral testis; the remainder developed relapse in multiple extranodal sites. Tondini et al.32 concluded that the poor prognosis of patients with DLBCL necessitates more effective treatment strategies, such as high-dose chemotherapy programmes for younger patients or chemotherapy regimens that are specifically designed for patients who are not suitable for high-dose treatment, with the aim of providing control of both systemic disease and disease of the CNS and contralateral testis.

The potential benefit of radiotherapy to the contralateral testis needs to be taken into consideration in the planning of treatment.

Lu et al.39 reported on a 6-year-old boy who had undergone right radical orchiectomy for a follicular large cell lymphoma with diffuse areas that were confined to the testis and epididymis. Immunohistochemistry showed that the neoplastic cells were positive for CD10, CD20, CD79a and BCL-6; staining for CD21 accentuated networks of dendritic reticulum cells in the nodules. The tumour cells were negative for BCL-2, p53 and T-cell antigens. There was no evidence of the t(14;18) translocation detected by PCR (Figure 5AD and Table 1 illustrate the microscopic and immunohistochemical characteristics in this case). According to Lu et al.,39 five cases of primary follicular lymphoma of the testis in childhood have been reported previously.

The pathogenesis of follicular lymphoma of the testis in children is different from that in adults.

FIGURE 5

(A) The follicular growth pattern is most apparent in the tunica albuginea (haematoxylin and eosin stain, original magnification ×200). (B) The nodules are composed predominantly of large non-cleaved cells with occasional large cleaved cells (haematoxylin and eosin stain, original magnification ×400). (C) Staining for CD21 demonstrates well-organized clusters of dendritic reticulum cells and accentuates areas of follicular differentiation (immunohistochemical stain, original magnification ×200). (D) Antibody to BL-6 protein stains the nuclei of the neoplastic cells (immunohistochemical stain, original magnification ×400). Reproduced from Lu D, Medeiros LJ, Eskenazi AE, Abruzzo LV. Primary follicular large-cell lymphoma of the testis in a child. Arch Pathol Lab Med 2001; 126(4):551–4,39 with permission from Archives of Pathology & Laboratory Medicine. Copyright 2001 College of American Pathologists.

9-2-1-fig5a.jpg9-2-1-fig5b.jpg9-2-1-fig5c.jpg9-2-1-fig5d.jpg
TABLE 1

Primary follicular large cell lymphoma of the testis in childhood – some previous reported cases illustrated by Lu et al.39

Reference Age (years) Side Diagnosis Size (cm) Therapy Follow-up (months)
Moertel et al. (1995)40 8 Left F, L 2 OR NED, 14
Finn et al. (1999)41 3 Left F&D, L 2, 8 OR, CX NED, 18
3 Right F, L 2, 3 OR, CX NED, 18
10 Left F, L 4 OR, CX NED, 19
5 Right F, L 4 OR, CX NED, 24
Lu et al. (2001)39 6 Right F&D, L 3 OR, CX NED, 7

CX, chemotherapy; F, follicular; F&D, follicular and diffuse; L, large; NED, no evidence of disease; OR, orchiectomy.

Reproduced from Lu D, Medeiros LJ, Eskenazi AE, Abruzzo LV. Primary follicular large-cell lymphoma of the testis in a child. Arch Pathol Lab Med 2001; 126(4):551–4,39 with permission from Archives of Pathology & Laboratory Medicine. Copyright 2001 College of American Pathologists.

Vidyavathi et al.42 reported the case of a 50-year-old man who underwent fine-needle aspiration of a right inguinal lymph node mass, the histology of which had suggested lymphoma/seminoma. Following right orchiectomy, histological analysis of the tumour revealed non-Hodgkin’s lymphoma. Other tests excluded involvement of other organs by non-Hodgkin’s lymphoma. The authors concluded that primary testicular lymphoma typically presents as a unilateral testicular mass with occasional bilateral involvement. The tumour often spread to the rete testis, epididymis, the spermatic cord and, rarely, the tunica albuginea. At initial presentation and at relapse it is often found to have spread to extranodal sites such as the skin, CNS and Waldeyer’s ring. Less common metastatic sites include the lungs, liver, gastrointestinal system and nodal sites, especially the para-aortic lymph nodes. Testicular lymphoma that involves the inguinal lymph node is unusual. The clinical manifestation may mimic germ cell tumours.

Wang et al.43 reported on 13 patients who were treated for primary testicular lymphoma between 2001 and 2012 and found the following:

  • The average age at diagnosis was 62.3 ± 13.9 years.

  • All patients presented with painless testicular swelling.

  • DLBCL was the dominant histotype (69.2%).

  • All patients were treated by inguinal orchiectomy and chemotherapy and/or radiotherapy.

  • Complete follow-up data were available for 10 patients and the average follow-up duration was 28.4 ± 30.9 months.

  • Seven patients were categorized as having Ann Arbor stage I or II disease and three as having stage III or IV disease.

  • In eight patients hypo-echogenic and hypervascular signals in the testis were detected on ultrasound scanning.

  • Six patients experienced complete remission and four patients were still receiving chemotherapy during their last follow-up with no signs of relapse.

  • Of the 10 patients for whom follow-up records were complete, three had experienced relapses, which had occurred in the CNS, epiglottis and nasal cavity. The time to relapse in these cases was 2, 7 and 11 months, respectively.

  • The mean progression-free survival was 22.57 months (range 1.11–101.9 months).

Vural et al.44 reported on 12 patients who had primary testicular non-Hodgkin’s lymphoma. Patient age ranged from 29 to 78, years with a mean age of 47 years, and more than 80% of the patients were over 50. In the majority of the cases, orchiectomy was undertaken as a diagnostic and first-line treatment procedure. The major histological subtype was diffuse large B-cell non-Hodgkin’s lymphoma. In 7 of the 12 patients (58%), tumours were categorized as Ann Arbor stage I or II and in the remaining five patients (42%) as stage III or IV. All the patients underwent doxorubicin-based chemotherapy and achieved complete remission. Three of the patients in the group, who were the most recently treated, also underwent treatment that included rituximab and CNS prophylaxis with intrathecal combined chemotherapy containing methotrexate, cytarabine and dexamethasone. The relapse rate was 8% and the progression-free survival at 10 years was 88%. The duration of response ranged from 14 to 173 months (median 84 months). The median follow-up was 97.5 months. All of the patients were alive and in a state of remission.

Vural et al.44 concluded that systemic doxorubicin-based chemotherapy with or without prophylaxis for the contralateral testis and CNS seems to improve the outcome of primary testicular lymphoma.

Al-Abbadi et al.26 performed immunohistochemistry for CD10, BCL-6 and MUM1 on tumour tissue from 18 patients with primary testicular DLBCL and reported that 16 tumours (89%) were of the non-germinal centre B-cell-like type. Two (11%) were classified as germinal centre B-cell-like type, of which one had a CD1-positive, BCL-6-positive and MUM1-negative profile and the other, in a 38-year-old patient who was positive for human immunodeficiency virus (HIV), a CD10-negative, BCL-6-positive and MUM1-negative profile. All the cases expressed high proliferative activity (≥ 50% Ki-67 labelling). According to Al-Abbadi et al.,26 the commonest type of primary testicular lymphoma is DLBCL, which has a tendency to display aggressive clinical behaviour. DLBCL can be subclassified into two major prognostic categories –germinal centre B-cell-like type and non-germinal centre B-cell-like type – which can be distinguished on the basis of their immunohistochemical expression of CD10, BCL-6 and MUM1.

Al-Abbadi et al.26 concluded that the majority (89%) of primary testicular DLBCLs belong to the non-germinal centre B-cell-like subgroup and have high proliferative activity.

Guner et al.45 reported the case of a 47-year-old man with stage IIIE primary testicular large B-cell lymphoma of germinal centre B-cell-like type and involving both testes. He was treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) chemotherapy. Histological examination of the testicular mass revealed diffuse intratubular lymphomatous infiltration that was situated away from the spermatic cord, epididymis, efferent ducts and rete testis. Immunohistochemical examination of the tumour was positive for MUM1, BCL-2 and B-cell marker (CD20) and negative for TdT, CD3, CD5, BCL-1, CD10, BCL-6 and myeloperoxidase. Ki-67 proliferation accounted for 90% of neoplastic lymphoid infiltration. After chemotherapy, the patient underwent PET, the results of which were normal. He remained well and all his laboratory tests were normal. He was in complete remission. Because of reported higher rates of relapse in the contralateral testis (up to 50%),46 prophylactic radiotherapy of 30 Gy was administered to the contralateral testis and the CNS. According to Guner et al.,45 treatment of testicular lymphoma entails surgical excision, chemotherapy and radiotherapy, but accurate procedures had not been standardized at the time of publication of their paper. Factors associated with more favourable outcome include (1) younger patient age, (2) localized disease, (3) the presence of sclerosis at pathological analysis, (4) smaller tumour size, (5) lower histological tumour grade and (6) a lack of epididymal or spermatic cord involvement.

Petrescu et al.47 studied eight patients who underwent orchiectomy for lymphoma. All of the patients were categorized, using the Ann Arbor criteria, as having stage IE or IIID disease and they received a doxorubicin-based chemotherapy regimen [CHOP, methotrexate, CVP (cyclophosphamide, vincristine, prednisolone) and chlorambucil (Leukeran®, GlaxoSmithKline, London, UK)]. Histological examination revealed in all cases a proliferation of stroma with medium-sized monomorphic cells containing prominent nucleoli. Immunohistochemistry was performed for L26, alpha-fetoprotein, NK1, CD30 and cutaneous lymphocyte-associated antigen (CLA) and revealed positive staining for alpha-fetoprotein in the seminal tubes and negative staining in the tumour, positive staining for NK1 in small lymphocytes and negative staining in the tumour, L26 diffuse positivity in the tumour and CLA diffuse positivity in the tumour. The authors were able to follow up only four patients. They concluded that:

  • The diagnosis was of non-Hodgkin’s lymphoma in six cases and was secondary involvement of a haematopoietic malignancy (myeloid sarcoma and leukaemia) in two cases.

  • Lymphoma cases were categorized, using the Revised European American Lymphoma (REAL) classification, as small and large B-cell lymphoma.

  • Unfavourable evolution (one patient experienced relapse after 6 months and one died) demonstrates the aggressive evolution of primitive testicular lymphoma.

Pileri et al.48 reported on a 4-year-old boy who underwent left orchiectomy and right testis incisional biopsy for lymphoma. He received high-dose chemotherapy, which resulted in complete remission. At the last follow-up, 2 years and 4 months later, the patient was well and remained in complete remission.

Pileri et al.48 reported that the microscopic and immunohistochemistry features of the tumour were consistent with the diagnosis of primary lymphoma of the testis. The molecular analysis revealed monoclonal immunoglobulin heavy chain gene rearrangement and BCL-6 mutations in the absence of BCL-2 major breakpoint and BCL-2 minor cluster region rearrangements, p53 mutations and death-associated protein kinase gene hypermethylation. Pileri et al.48 concluded that these findings suggest that the pathogenesis of primary follicular lymphoma of the testis differs from that of adult follicular lymphoma and that this might explain its favourable course in spite of its aggressive histology.

Pileri et al.48 further stated that:

  • Follicular lymphoma is one of the most common lymphomas, occurring mainly in adults. Lymph node involvement is common and the tumour may transform into a DLBCL1,2

  • Three morphological grades are recognized.49,50 Grades I and II are indolent tumours that regularly carry the t(14;18) translocation with BCL-2 protein overexpression; grade III disease presents aggressively with a greater tendency to evolve into DLBCL and can show different chromosomal aberrations, with detectable BCL-2 mutations often lacking and BCL-2 protein expression found in only a minority of cases.4954

  • Paediatric tumours of the testis most frequently display germ cell derivation; gonadal stromal neoplasms, rhabdomyosarcomas, leukaemias and lymphomas are much rarer.55,56

  • Generally, lymphomas occur in the elderly, show aggressive histology and are associated with poor prognosis.57 Thus, the occurrence of a primary testicular lymphoma in a child is noteworthy per se5860 and it is particularly unusual for the lymphoma to be of the follicular type, as illustrated by the paucity of reports in the literature.3941

Haroon and Ahmed61 reported the case of a 40-year-old man who underwent biopsy of a right testicular lump, the histological characteristics of which were consistent with T-cell lymphoma. Immunohistochemical staining of the tumour cells showed positivity for T-cell markers CD3 and CD43. The tumour was also positive for CD56. The authors further reported that staining for pan-B-cell markers (CD20, CD4, CD8 and CD5) and the epithelial marker cytokeratin was negative. a test for the presence of Epstein–Barr virus (EBV) using EBV-latent membrane protein was also negative. Haroon and Ahmed61 concluded that testicular peripheral T-cell lymphomas are rare and aggressive cancers, to be differentiated clinically from seminoma and non-neoplastic conditions.

Demir et al.62 reported on a 73-year-old man who had undergone left radical orchiectomy for a stage IE non-Hodgkin’s DLBCL of the testis, based upon the Ann Arbor staging system. He received systemic R-CHOP chemotherapy. He also received prophylactic radiotherapy to the contralateral testis and CNS. He achieved complete remission and had been followed up for 3 months at the time of publication of the paper.

McDonald et al.63 reported on a 60-year-old man who had undergone left orchiectomy and insertion of a left ureteric stent for a suspected testicular tumour and left hydronephrosis because of enlarged para-aortic lymph nodes following initial antibiotic treatment for presumed epididymo-orchitis. Histological examination of the specimen revealed non-Hodgkin’s B-cell lymphoma. Immunohistochemical staining of the tumour revealed an atypical B-cell phenotype, which stained positive for CD5, CD20, bel-2, MUM1 2-microglobulin (focal and cytoplasmic). There was negative immunohistochemical staining for CD3, CD10, CD23 and p53. The proliferative fraction was 80–90%. The tumour was categorized, using the Ann Arbour classification for lymphomas, as stage IIEA. The patient was subsequently treated with eight cycles of R-CHOP chemotherapy and four cycles of intrathecal methotrexate and radiotherapy to the contralateral testis.

Surti and Ralls64 reported the case of a 45-year-old man who presented with a mass in the nasal cavity. The mass was surgically excised and histological examination of a specimen was consistent with a diagnosis of plasmablastic lymphoma (PBL). The patient subsequently underwent five courses of etoposide, vincristine, doxorubicin, cyclophosphamide and prednisolone chemotherapy, which was completed 6 months after excision of the mass. Ten months after completion of chemotherapy, the patient noticed a right testicular mass for which he underwent a right radical orchiectomy. Macroscopic examination of the tumour showed a tan/white mass on cross-section. Microscopic examination of the tumour showed PBL, which was identical to his nasal lesion. Three years after the initial presentation, the patient was diagnosed as having HIV infection and anti-retroviral therapy was instituted.

According to Surti and Ralls64:

  • PBL is a subset of acquired immune deficiency syndrome (AIDS)-related non-Hodgkin’s lymphoma that typically first presents in the oral cavity, although there are reports or cases in the skin, nasopharynx, stomach, stomach, lung and anus.65

  • PBL accounts for approximately 2.6% of all HIV-related lymphomas.66

  • In the original report describing PBL, 15 of the 16 oral cavity tumours were in HIV-infected individuals.67

  • PBL has morphological features of large B-cell lymphoma but expression of LCA and B-cell antigen CD20 is minimal or absent. In contrast, high levels of the plasma cell-associated markers VS38c and CD79a are seen. An association with EBV is thought to exist in up to 60% of cases.68

  • Schichman et al.69 described a case of PBL with disease that initially presented in the nasal sinus with recurrence in the testis and bones.

  • Although the ultrasonographic appearance of testicular plasmacytoma and large B-cell lymphoma had been documented previously, the ultrasonographic appearance of PBL of the testis has not been described.70

  • In contrast to testicular lymphoma, plasmacytoma of the testis is very rare, with a total of only 52 cases published between 1939 and 2002.71

  • Ultrasound scan findings of plasmacytoma are described as homogeneous or heterogeneous but primarily hypoechoic. Colour Doppler imaging shows hyperaemia mimicking testicular lymphoma or leukaemia.70

  • First described in 1997, PBL is a pathologically distinct entity with cells that show a blastoid structure but have acquired the antigen profile of plasma cells.

  • According to Häusermann et al.,72 PBL is a rare and relatively new entity that was originally described in HIV-infected individuals. This subset of EBV-related non-Hodgkin’s lymphomas is now regarded as a distinct clinicopathological category of AIDS-associated lymphomas occurring preferentially in the oral cavity and showing a poor prognosis.

  • Based upon the World Health Organization classification,73 these tumours are recognized as separate entities within the group of HIV-related lymphomas.

Tepperman et al.74 in 1982 reported a study of 16 patients who had non-Hodgkin’s lymphoma of the testis. Twelve of the patients had disease that was classified as local (stage IE or IIE). Eight patients had diffuse histiocytic lymphoma, six had diffuse poorly differentiated lymphocytic lymphoma, one had both lymphoma and seminoma and one patient had nodular poorly differentiated lymphocytic lymphoma.:

  • The overall median survival was 9.5 months.

  • Para-aortic nodal involvement was the factor that had the strongest prognostic influence on the management methods used.

  • The median survival without para-aortic nodal involvement was ≥ 57 months, but with para-aortic lymph node involvement it was 6 months (P = 0.002).

Taperman et al.74 asserted that there is a high probability of generalized disease if lymphoma can be detected in the para-aortic nodes. In the case of patients with stage IE or IIE disease, the preferred treatment is radical radiotherapy. For those with disseminated disease, the recommended management is chemotherapy, with radiotherapy reserved for symptomatic and bulky localized deposits.

Verma et al.75 reported the case of a 47-year-old man with HIV who presented right testicular swelling that was treated with radical right inguinal orchiectomy. The microscopic and immunohistochemical features of the testicular swelling supported the diagnosis of DLBCL. FISH did not reveal c-Myc translocation and cytogenetic studies were normal, findings that also supported the diagnosis of DLBCL rather than Burkitt’s lymphoma, despite the high proliferative index noted on Ki-67 staining. The patient was treated with the Hyper-CAVAD regimen76 with the addition of rituximab (R-Hyper-CVAD)77 and with prophylactic intrathecal chemotherapy. Because elevated serum levels of liver enzymes persisted, anti-retroviral treatment with efavirenz and abacavir/lamivudine was not started after the second cycle of chemotherapy, along with trimethoprim/sulphamethoxazole for Pneumocystis jiroveci prophylaxis. As a result of active hepatitis C, which interrupted further chemotherapy, his liver function test results worsened. He was readmitted with acute pancreatitis and sepsis, from which he died 7 months pursuant to his initial diagnosis.

Verma et al.75 concluded that:

  • Immunosuppressed patients have an increased risk of developing extranodal lymphoma, including testicular lymphoma.11

  • Immunocompromised patients tend to present at an early age (median age 37 years) with an aggressive histological tumour (centroblastic or immunoblastic DLBCL or Burkitt’s lymphoma) and a poor prognosis.11

  • Testicular involvement by DLBCL, in comparison with nodal lymphoma and extranodal lymphomas of other sites, is associated with an increased risk of bone marrow and CNS involvement.11

Lagrange et al.78 analysed 84 patients with primary non-Hodgkin’s lymphoma who were treated in French anti-cancer centres from 1969 to 1995. Their findings were as follows:

  • The median age of patients was 67 years (range 17–85 years).

  • In 42 patients, the disease was classified as stage I, in 19 patients as stage II and in 23 patients as stage III–IV.

  • DLBCL was diagnosed in 75% of cases.

  • The treatment included orchiectomy and radiotherapy and/or chemotherapy.

  • Complete remission was achieved in 72.6% of the overall patient population: 100%, 68% and 33% in patients with stage I, II and III–IV disease, respectively, two patients with stage II and one patient with stage IV disease.

  • Recurrence occurred in 32 patients. The most frequent site of recurrence was the CNS, which was affected in six patients presenting with stage I disease, two patients with stage II disease and one patient with stage IV disease.

  • The median overall survival was 32 months (95% confidence interval 19 to 43 months) for the entire population. With regard to patients with stage I, stage II and stage III–IV disease, at 2, 5 and 10 years, 55%, 36.7% and 19.2% were alive, respectively. Stage proved to be a significant factor in prognostication (P < 0.0001). Median survival was 52 months for those with stage I disease (95% confidence interval 36 to 82 months), 38 months for those with stage II disease (95% confidence interval 12–18 months) and 12 months for those with stage III–IV disease (95% confidence interval 12–18 months). Twenty-three per cent and 5% of the patients were found to be alive at 2 and 5 years, respectively.

  • Among patients who presented with stage I disease, no difference was found between those treated with combined surgery and chemotherapy and those who underwent surgery followed or not followed by radiotherapy.

Lagrange et al.78 made the following conclusions and recommendations:

  • Non-Hodgkin’s lymphoma of the testis carries a poor prognosis.

  • Systemic adjuvant chemotherapy should be studied further because of the high rates of recurrence.

  • These cases should be included in large cooperative prospective studies.

Mlika et al.46 reported the case of a 26-year-old man who presented with a painful right testicular swelling that was treated with right orchiectomy. Microscopic and immunohistochemistry examination of the lesion and radiological imaging findings established a diagnosis of stage I primary testicular large B-cell lymphoma of the germinal centre B-cell-like type. He was treated using chemotherapy but, at the time of publication of the paper, there was no information on the patient’s long-term outcome.

According to Mlika et al.46:

  • Testicular lymphoma was first reported by Malassez and Curling in 1866.44,79

  • Treatment modalities for primary lymphoma of the testis consist of surgical excision, chemotherapy and radiotherapy, but the accurate procedures have not been standardized.

  • Factors that have been linked to more favourable prognosis include younger patient age, localized disease, the presence of sclerosis at pathological analysis, smaller tumour size, lower histological tumour grade and a lack of epididymis or spermatic cord involvement.

Zouhair et al.80 undertook a retrospective multicentre study of 36 patients with Ann Arbor stage I (n = 21), II (n = 9), III (n = 3) or IV (n = 3) primary testicular lymphoma. All patients except one had undergone orchiectomy. Spermatic cord infiltration was found in nine patients. Twenty-nine patients (81%) had received chemotherapy. In the majority of cases, the chemotherapy regimen comprised cyclophosphamide, doxorubicin, vincristine and prednisolone. Of those treated, 17 patients had received intrathecal chemotherapy. External radiotherapy was delivered to the scrotum alone in 12 patients and to the testicular, iliac and para-aortic regions in eight patients. The median follow-up was 42 months and ranged from 6 to 138 months. Zouhair et al.80 reported the following results:

  • After a follow-up period ranging from 1 to 76 months (median 11 months), lymphoma progression was found in 14 patients and primarily targeted the CNS (n = 8).

  • Four of the 17 patients who received intrathecal chemotherapy experienced CNS relapse.

  • No testicular, iliac or para-aortic relapses occurred in patients who had received radiotherapy to these sites.

  • The 5-year overall, lymphoma-specific and disease-free survival rates were 47%, 66% and 43%, respectively.

  • The factors found to strongly influence a favourable outcome were early-stage and combined-modality treatments, according to univariate analysis.

  • Multivariate analysis revealed that the most favourable independent factors predicting outcome were younger age, early-stage disease and combined-modality treatment.

  • The CNS was the principal site of relapse and no lymphoma progression outside the CNS was observed in the irradiated volumes.

Zouhair et al.80 recommended that more effective CNS prophylaxis, including the use of combined modalities, should be prospectively studied to optimize the treatment of this uncommon extranodal form of lymphoma and improve patient outcomes.

According to Bacon et al.,38 primary lymphomas of the testis typically occur in patients who are older than 60 years. They are usually DLBCLs and are associated with frequent dissemination and a poor prognosis. Primary follicular lymphoma of the adult testis had not been characterized. However, a small number of stage IE primary lymphomas of the testis have been described in children. These tumours exhibited a lack of BCL-2 gene rearrangement and BCL-2 protein expression, and a good clinical outcome was achieved. Bacon et al.38 reported five cases of primary follicular lymphoma of the testis and epididymis in adults. They found the following:

  • The tumours presented as unilateral testicular masses 12–40 mm in diameter and were characterized histologically by small neoplastic follicles in a sclerotic background.

  • The neoplastic cells expressed CD10 and BCL-6, but not BCL-2, and lacked t(14;18)(q32;q21)IgH/BCL-2 and BCL-6 gene rearrangements.

  • Four of the affected patients were 35 years or younger and four presented with stage IEA disease.

  • The features were different from those of most adult nodal follicular lymphomas, but they were very similar to those of paediatric primary testicular follicular lymphomas.

  • Together, the paediatric and adult cases represented a discrete clinicopathological entity of t(14;18)(q32;q21)IgH/BCL-2-negative primary follicular lymphoma of the testis and epididymis, presenting as clinically indolent localized disease in young males and should be distinguished from the DLBCL more frequently seen in the testes of older adults.

Tralongo et al.81 reported a case of primary follicular non-Hodgkin’s lymphoma of the left epididymis in a 90-year-old man. Immunohistochemical studies demonstrated that the neoplastic cells strongly expressed CDD45RB, CD20, CD79a, BCL-6 and CD10, and BCL-2 immunostaining was negative. Molecular studies showed the presence of the monoclonal IgH gene rearrangement and IgH/BCL-2 rearrangement. The lymphoma was classified as low-grade follicular lymphoma, namely grade 1–2. The patient subsequently underwent radical orchiectomy, did not receive chemotherapy and, at the time of publication of the paper, was free from disease recurrence. Tralongo et al.81 concluded that:

  • The tumour is characterized by clinically indolent localized disease, a good clinical outcome, a lack of expression of the BCL-2 protein and the presence of the t(14;18)(q32;q21)IgH/BCL-2 translocation.

  • Although only a single case, this primary follicular lymphoma of epididymis with t(14;18) could represent either a variant of the previously reported t(14;18)-negative paratesticular follicular lymphoma or a distinct biological entity.

  • To report additional cases in the future would be helpful in resolving these questions.

Summary and conclusions

Primary lymphoma of the testis is rare. The commonest type of lymphoma of the testis is DLBCL, but a number of other types of primary and metastatic lymphomas of the testis also occur. DLBCL usually manifests as a painless unilateral mass in older men. Children can also develop lymphoma of the testis. Constitutional symptoms may be experienced by some patients. Treatment can be complex and depends upon patient characteristics. Orchiectomy is beneficial in providing histological confirmation of lymphoma and information on the specific type of lymphoma, as well as evidence of extratesticular involvement of cord structures. Adjuvant chemotherapy and radiotherapy are used in an attempt to avoid or reduce extranodal recurrence (the incidence of which is high, even in localized disease). Radiotherapy is used in the contralateral testis to avoid or reduce recurrence in the contralateral testis. Intrathecal chemotherapy is also used to reduce CNS recurrence, but despite this CNS recurrences do occur. There is no consensus on the best chemotherapy regimen. It is important that a correct diagnosis is made based upon the microscopic and the immunohistochemical characteristics of the tumour, because differentiation of DLBCL from other types of lymphoma is helpful in selecting the correct chemotherapeutic regimen, and the appropriate regimen differs depending upon the specific type of lymphoma. Oncologists and urologists from around the world should meet in order to organize a global multicentre trial to identify the best chemotherapy regimen for improving the long-term survival of patients and the best treatment to reduce CNS, extranodal and contralateral testis recurrences. The multicentre trial should also aim to improve the long-term outcome and quality of life of patients with advanced disease.

Acknowledgements

The Archives of Pathology & Laboratory Medicine and the Association of American Pathologists are acknowledged for granting permission for the figures and table from the journal to be reproduced in the paper. Please note, any further use of the figures and the table would require copyright permission from Archives of Pathology & Laboratory Medicine.

References

1. 

Gordetsky J. Testis and epididymis. Other tumors not specific to testis. Lymphoma. PathologyOutlines.com, October 2013. URL:www.pathologyoutlines.com/topic/testislymphoma.html (accessed 12 November 2014).

2. 

Ahmad SS, Idris SF, Follows GA, Williams MV. Primary testicular lymphoma. Clin Oncol (R Coll Radiol) 2012; 24:358–65. http://dx.doi.org/101016/j.clon.2012.02.005

3. 

Kim J, Abu-Yousef M. Testicular lymphoma. Ultrasound Q 2013; 29:247–8. http://dx.doi.org/10.1097/RUQ.0b013e3182a0ac0e

4. 

Cronin CGC, Swords R, Truong MT, et al. Clinical utility of PET/CT in lymphoma. Am J Roentgenol 2010; 194:W91–W103. http://dx.doi.org/10.2214/AJR.09.2637

5. 

Bruzzi JF, Macapinlac H, Tsimberidou AM, et al. Detection of Richter’s transformation of chronic lymphocytic leukaemia by PET/CT. J Nucl Med 2006; 47:1267–73.

6. 

Tatsumi M, Cohade C, Nakamoto Y, Fishman EK, Wahl RL. Direct comparison of FDG PET and CT findings in patients with lymphoma: initial experience. Radiology 2005; 237:1038–45. http://dx.doi.org/10.1148/radiol.2373040555

7. 

Freudenberg LS, Antoch G, Shütt P, et al. FDG-PET/CT in re-staging of patients with lymphoma. Eur J Nucl Med Mol Imaging 2004; 31:325–9. http://dx.doi.org/10.1007/s00259-003-1375-y

8. 

Spaepen K, Stroobants S, Dupont P, et al. Prognostic value of positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose after first-line chemotherapy in non-Hodgkin’s lymphoma: is [18F]FDG-PET a valid alternative to conventional diagnostic methods? J Clin Oncol 2001; 19:414–19.

9. 

Spaepen K, Stroobants S, Dupont P, et al. Can positron emission tomography with 18F Fluoro-deoxyglucose after first-line treatment distinguish Hodgkin’s disease patients who need additional therapy from others in whom additional therapy would mean avoidable toxicity? Br J Haematol 2001; 115:272–8. http://dx.doi.org/10.1046/j.1365-2141.2001.03169.x

10. 

Horne MJ, Adeniran AJ. Primary diffuse large B-cell lymphoma of the testis. Arch Pathol Lab Med 2011; 135:1363–7. http://dx.doi.org/10.5858/arpa.2010-0158-RS

11. 

Shahab N, Doll DC. Testicular lymphoma. Semin Oncol 1999; 26:259–69.

12. 

Vitolo U, Ferreri AJ, Zucca E. Primary testicular lymphoma. Crit Rev Oncol Hematol 2008; 65:183–9. http://dx.doi.org/10.1016/j.critrevonc.2007.08.005

13. 

Moller MB, d’Amore F, Christensen BE. Testicular lymphoma: a population-based study of incidence, clinicopathological correlations and prognosis. The Danish Lymphoma Study Group. LYFO. Eur J Cancer 1994; 30A:1760–4. http://dx.doi.org/10.1016/0959-8049(94)00311-R

14. 

Doll DC, Weiss RB. Malignant lymphoma of the testis. Am J Med 1986; 81:515–24. http://dx.doi.org/10.1016/0002-9343(86)90308-6

15. 

Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A (eds.). AJCC Cancer Staging Manual, 7th edn. New York: Springer; 2010.

16. 

Ulbright TM, Amin MB, Young RH. Tumors of the Testis, Adnexa, Spermatic Cord and Scrotum (Atlas of Tumor Pathology; 3rd series. Fascicle 25). Washington, DC: American Registry of Pathology; 1999.

17. 

Paladugu RR, Bearman RM, Rappaport H. Malignant lymphoma with primary manifestation in the gonad: a clinicopathologic study of 38 patients. Cancer 1980; 45:561–71. http://dx.doi.org/10.1002/1097-0142(19800201)45:3<561::AID-CNCR2820450324>3.0.CO;2-A

18. 

Turner RR, Colby TV, MacKintosh FR. Testicular lymphomas: a clinicopathologic study of 35 cases. Cancer 1981; 48:2095–102. http://dx.doi.org/10.1002/1097-0142(19811101)48:9<2095::AID-CNCR2820480930>3.0.CO;2-R

19. 

Swerdlow SH, Campo E, Harris NL, et al. World Health Organization Classification of Tumors: Pathology and Genetics of Tumours of Hematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2008.

20. 

Loddenkemper C, Anagnostopoulos I, Hummer M, et al. Differential Emu enhancer activity and expression of BOB.1/OBF.1,Oct, PU.1, and immunoglobulin in reactive B-cell populations, B-cell non-Hodgkin lymphoma, and Hodgkin lymphoma. J Pathol 2004; 202:60–9. http://dx.doi.org/10.1002/path.1485

21. 

Tagawa H, Suguro M, Tsuzuki S, et al. Comparison of distinct subgroups of diffuse large B-cell lymphoma. Blood 2005; 106:1770–1. http://dx.doi.org/10.1182/blood-2005-02-0542

22. 

Berglund M, Thunberg U, Amini RM, et al. Evaluation of immunophenotype in diffuse large-B-cell lymphoma and its impact on prognosis. Mod Pathol 2005; 18:1113–20. http://dx.doi.org/10.1038/modpathol.3800396

23. 

Colomo L, López-Guillermo A, Perales M, et al. Clinical impact of the differentiation profile assessed by immunophenotyping in patients with diffuse large B-cell lymphoma. Blood 2003; 101:78–84. http://dx.doi.org/10.1182/blood-2002-04-1286

24. 

Miller TP, Grogan TM, Dahlberg S, et al. Prognostic significance of the Ki-67-associated proliferative antigen in aggressive non-Hodgkin’s lymphomas: a prospective Southwest Oncology Group trial. Blood 1994; 83:1460–6.

25. 

Rosenwald A, Chan WC, Connors JM, et al., with the Lymphoma/Leukemia Molecular Profiling Project. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 2002; 346:1931–47. http://dx.doi.org/10.1056/NEJMoa012914

26. 

Al-Abbadi MA, Hattab EM, Tarawneh MS, Amr SS, Orazi A, Ulbright TM. Primary testicular diffuse large B-cell lymphoma belongs to the nongerminal center B-cell-like subgroup: a study of 18 cases. Modern Pathol 2006; 19:1521–7. http://dx.doi.org/10.1038/modpathol.3800691

27. 

Bosga-Bouwer AG, Kok K, Booman M, et al. Array comparative genomic hybridization reveals a very high frequency of deletions of the long arm of chromosome 6 in testicular lymphoma. Genes Chromosomes Cancer 2006; 45:976–81. http://dx.doi.org/10.1002/gcc.20361

28. 

Rickert CH, Dockhorn-Dworniczak B, Simon R, Paulus W. Chromosomal imbalances in primary lymphomas of the central nervous system. Am J Pathol 1999; 155:1445–51. http://dx.doi.org/10.1016/S0002-9440(10)65458-2

29. 

Bea S, Zetti A, Wright G, et al., with the Lymphoma/Leukemia Molecular Profiling Project. Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction. Blood 2005; 106:3183–90. http://dx.doi.org/10.1182/blood-2005-04-1399

30. 

Kramer MH, Hermans J, Wijburg E, et al. Clinical relevance of BCL2, BCL6, and MYC rearrangements in diffuse large B-cell lymphoma. Blood 1998; 92:3152–62.

31. 

Tanaka S, Louie DC, Kant JA, Reed JC. Frequent incidence of somatic mutations in translocated BCL2 oncogenes of non-Hodgkin’s lymphomas. Blood 1992; 79:229–37.

32. 

Tondini C, Ferreri AJM, Siracussano L, et al. Diffuse large cell lymphoma of the testis. J Clin Oncol 1999; 17:2854–8.

33. 

Linassier C, Desablens B, Lefrancq T, et al., with the GOELAMS Study Group. Stage I–IIE primary non-Hodgkin’s lymphoma of the testis: results of a prospective trial by GOELAMS Study Group. Clin Lymphoma 2002; 3:167–72. http://dx.doi.org/10.3816/CLM.2002.n.023

34. 

Coiffier B. Rituximab therapy in malignant lymphoma. Oncogene 2007; 26:3603–13. http://dx.doi.org/10.1038/sj.onc.1210376

35. 

Zucca E, Conconi A, Mughal TI, et al., with the International Extranodal Lymphnode Group. 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; 21:20–7. http://dx.doi.org/10.1200/JCO.2003.11.141

36. 

Sussman EB, Hajdu SI, Lieberman PH, Whitmore WF. Malignant lymphoma of the testis: a clinicopathologic study of 34 cases. J Urol 1977; 118:1004–7.

37. 

Ulbright TM. The most common, clinically significant misdiagnosis in testicular tumor pathology, and how to avoid them. Adv Anat Pathol 2008; 15:18–27. http://dx.doi.org/10.1097/PAP.0b013e318159475d

38. 

Bacon CM, Ye H, Diss TC, et al. Primary follicular lymphoma of the testis and epididymis in adults. Am J Surg Pathol 2007; 31:1050–8. http://dx.doi.org/10.1097/PAS.0b013e31802ee4ab

39. 

Lu D, Medeiros LJ, Eskenazi AE, Abruzzo LV. Primary follicular large-cell lymphoma of the testis in a child. Arch Pathol Lab Med 2001; 126:551–4.

40. 

Moertel CL, Watterson J, McCormick SR, Simonton SC. Follicular large cell lymphoma of the testis in a child. Cancer 1995; 75:1182–6. http://dx.doi.org/10.1002/1097-0142(19950301)75:5<1182::AID-CNCR2820750520>3.0.CO;2-Y

41. 

Finn LS, Viswanatha DS, Belasco JB, et al. Primary follicular lymphoma of the testes in childhood. Cancer 1999; 85:1626–35. http://dx.doi.org/10.1002/(SICI)1097-0142(19990401)85:7<1626::AID-CNCR27>3.0.CO;2-0

42. 

Vidyavathi K, Prabhakar K, Harendra KM. Primary testicular lymphoma with rupture: an unusual presentation. J Natl Sci Biol Med 2013; 4:232–5. http://dx.doi.org/10.4103/0976-9668.107314

43. 

Wang C, Wang H, Wang Q, Shi B. Primary testicular lymphoma: experience with 13 cases and literature review. Int J Hematol 2013; 97:240–5. http://dx.doi.org/10.1007/s12185-013-1261-8

44. 

Vural F, Cagirgan S, Saydam G, Hekimgil M, Soyer NA, Tombuloglu M. Primary testicular lymphoma. J Natl Med Assoc 2007; 99:1277–82.

45. 

Guner SI, Karacetin D, Yuksel M. Primary testicular diffuse large B-cell lymphoma: a case report. World J Oncol 2013; 4:61–5. http://dx.doi.org/10.4021/wjon629w

46. 

Mlika M, Chelly I, Benrhouma M, et al. A primary testicular diffuse large B-cell lymphoma belonging to the germinal center B-cell-like group. J Clin Med Res 2010; 2:47–9. http://dx.doi.org/10.4021/jocmr2009.12.1284

47. 

Petrescu A, Dobrea C, Vasilica M, Andrei FL, Niculescu L. Primary malignant lymphoma of the testis. Rom J Morphol Embryol 2005; 46:83–6. http://dx.doi.org/10.1590/51516–31802007000500007

48. 

Pileri SA, Sabattini E, Rosito P, et al. Primary follicular lymphoma of the testis in childhood: an entity with peculiar clinical and molecular characteristics. J Clin Pathol 2002; 55:684–8. http://dx.doi.org/10.1136/jcp.55.9.684

49. 

Harris NL, Jaffe ES, Stein H, et al. A revised European–American classification of lymphoid neoplasms: a proposal from the international lymphoma study group. Blood 1994; 84:1361–92.

50. 

Nathwani BN, Piris MA, Harris NL, et al. Follicular lymphoma. In: Jaffe ES, Harris NL, Stein H, et al. (eds.) Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2001, pp. 162–7.

51. 

Wiernberger DD, Gascoyne RD, Bierman PJ, et al. Clinical significance of the t(14;18) and BCL2 overexpression in follicular large cell lymphoma. Leuk Lymphom 2000; 36(5–6):513–23.

52. 

Capello D, Violo U, Pasqualucci L, et al. Distribution and pattern of BCL-6 mutations throughout the spectrum of B-cell neoplasia. Blood 2000; 95;651–9.

53. 

Lo Coco F, Gaidano G, Louie DC, Offit K, Chaganti RS, Dalla-Favera R. p53 mutations are associated with histologic transformation of follicular lymphoma. Blood 1993; 82:2289–95.

54. 

Yano T, Jaffe ES, Longo DE, Raffeld M. MYC rearrangements on histologically progressed follicular lymphoma. Blood 1992; 80:758–67.

55. 

Murphy SB, Fairclough DL, Hutchinson RE, Berard CW. Non-Hodgkin’s lymphoma of childhood: an analysis of the histology, staging, and response to treatment of 338 cases at a single institution. J Clin Oncol 1989; 7:186–9.

56. 

Kay R. Prepubertal testicular tumor registry. J Urol 1993; 150(2 Pt2):871–4.

57. 

Zucca E, Conconi A, Mughal TI, et al. Patterns of survival in primary diffuse large B-cell lymphoma (DLCL) of the testis: an international survey of 373 patients. 42nd Annual Meeting of the American Society of Hematology, 1–5 December 2000, San Francisco, CA [abstract] Blood 2000; 96:A1443.

58. 

Turley HK, Moore TD. Malignant lymphoma primary manifested as a testicular tumour. J Urol 1952; 68:744–6.

59. 

Weitzner S, Gropp A. A primary reticulum sarcoma of testis in a 12-year-old boy. Cancer 1976; 37:935–8. http://dx.doi.org/10.1002/1097-0142(197602)37:2<935::AID-CNCR2820370248>3.0.CO;2-6

60. 

Rao SP, Miller ST, Menell J, Glaasberg KI. Localized non-Hodgkin’s lymphoma of testis in a child. Am J Pediatr Hematol Oncol 1993; 15:443.

61. 

Haroon S, Ahmed A. Peripheral T-cell lymphoma presenting as testicular mass: a diagnostic challenge. World J Surg Oncol 2013; 11:68. http://dx.doi.org/10.116/1477-7819-11-68

62. 

Demir C, Atmaca M, Tasdemir E, Günes M, Bulut G. [Primary testicular lymphoma: a case report.] Dicle Tip Der/Dicle Med J 2010; 37:171–3.

63. 

McDonald JR, Husain J, Thompson A, Dauleh MI. Case reports: A 60-year-old male with B-cell testicular lymphoma presenting as epididymo-orchitis. Book-Med, Professional Medical Encyclopedia 2015. URL: book-med.info/lymphoma/40980.

64. 

Surti KM, Ralls PW. Sonographic appearance of plasmablastic lymphoma of the testes. J Ultrasound Med 2008; 27:965–7.

65. 

Tavora F, Gonzalez-Cuyar LF, Sun CC, Burke A, Zhao XF. Extra-oral plasmablastic lymphoma: report of a case and review of the literature. Hum Pathol 2006; 37:1233–6. http://dx.doi.org/10.1016/j.humpath.2006.04.009

66. 

Nasta SD, Carrum GM, Shahab I, Hannania NA, Udden MM. Regression of a plasmablastic lymphoma in a patient with HIV on highly active antiretroviral therapy. Leuk Lymphoma 2002; 43:423–6. http://dx.doi.org/10.1080/10428190290006260

67. 

Delecluse HJ, Anagnostopoulos I, Dallenbach F, et al. Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection. Blood 1997; 89:1413–20.

68. 

Teruya-Feldstein J. Diffuse large B-cell lymphoma with plasmablastic differentiation. Curr Oncol Rep 2005; 7:357–63. http://dx.doi.org/10.1007/s11912-005-0062-5

69. 

Schichman SA, McClure R, Schaefer RF, Mehta P. HIV and plasmablastic lymphoma manifesting in sinus, testicles, and bones: a further expansion of the disease spectrum. Am J Hematol 2004; 77:291–5. http://dx.doi.org/10.1002/ajh.20190

70. 

Bude RO. Testicular plasmacytoma: appearance on gray-scale and power Doppler sonography. J Clin Ultrasound 1999; 27:345–6. http://dx.doi.org/10.1002/(SICI)1097-0096(199907/08)27:6<345::AID-JCU6>3.0.CO;2-U

71. 

Anghel G, Petti N, Remotti D, Ruscio C, Blandino F, Majolino I. Testicular plasmacytoma: report of a case and review of the literature. Am J Hematol 2002; 71:98–104. http://dx.doi.org/10.1002/ajh.10174

72. 

Häusermann P, Khannab N, Buess M, et al. Cutaneous plasmablastic lymphoma in an HIV-positive male: an unrecognized cutaneous manifestation. Dermatology 2004; 208:287–90. http://dx.doi.org/10.1159/000077324

73. 

World Health Organization classification, Jaffe ES, Harris NL, Stein H, Vardiman JW (eds.). World Health Organization Classification of Tumors: Pathology and Genetics of Tumors of Hematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2001.

74. 

Tepperman BS, Gospodarowicz MK, Bush RS, Brown TC. Non-Hodgkin lymphoma of the testis. RadioGraphics 1982; 142:203–8. http://dx.doi.org/10.1148/radiology.142.1.7053533

75. 

Verma N, Chaudhary UB, Costa LJ, Gudena V, Lazarchick J. Primary testicular lymphoma and AIDS in 2005. Ann Clin Lab Sci 2010; 40:75–9.

76. 

Cortes J, Thomas D, Rios A, et al. Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone and highly active antiretroviral therapy for patients with acquired immunodeficiency syndrome-related Burkitt lymphoma/leukemia. Cancer 2002; 94:1492–9. http://dx.doi.org/10.1002/cncr.10365

77. 

Thomas DA, Faderl S, O’Brien S, et al. Chemoimmunotherapy with hyper CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer 2006; 106:1569–80. http://dx.doi.org/10.1002/cncr.21776

78. 

Lagrange JL, Ramaioh A, Theodore CH, et al., for the RTG and the GETUG (FNCLCC). Non-Hodgkin’s lymphoma of the testis: a retrospective study of 84 patients treated in the French anticancer centres. Ann Oncol 2001; 12:1313–19. http://dx.doi.org/10.1023/A:1012224123385

79. 

Crocetti E, Capocaccia R, Casella C, Ferretti S, Guzzinati S, Rosso S. Cancer trends in Italy: figures from the cancer registries (1986–1997). Epidemiol Prev 2004; 28(2 Suppl.):1–6.

80. 

Zouhair A, Belkacémi Y, Ketterer N, et al., with the Rare Cancer Network. Outcome and patterns of failure in testicular lymphoma: a multicenter rare cancer network study. Int J Radiat Oncol Biol Phys 2002; 52:652–6. http://dx.doi.org/10.1016/S0360-3016(01)02647-5

81. 

Tralongo V, Becchina G, Nagar C, et al. Primary follicular lymphoma of the epididymis positive for t(14;18)(q32;q21)/IGH-BCL2 and negative for BCL2 protein expression: a case report. J Med Case Rep 2012; 6:24. http://dx.doi.org/10.1186/1752-1947-6-24




Add comment 





Home  Editorial Board  Search  Current Issue  Archive Issues  Announcements  Aims & Scope  About the Journal  How to Submit  Contact Us
Find out how to become a part of the HMJ  |   CLICK HERE >>
© Copyright 2012 - 2013 HMJ - HAMDAN Medical Journal. All Rights Reserved         Website Developed By Cedar Solutions INDIA