European Journal of Haematology 93 (537–542)
CASE REPORT
Mantle cell lymphoma and diffuse large B-cell lymphoma of the testis: a unique case of composite non-Hodgkin lymphoma Swati Andhavarapu1, Jennifer A. Crozier1, Liuyan Jiang2, Taimur Sher1 1
Department of Medicine, Mayo Clinic, Jacksonville, FL; 2Department of Pathology, Mayo Clinic, Jacksonville, FL, USA
Abstract Primary testicular non-Hodgkin lymphoma (NHL) is a rare entity with the most common histologic subtype consisting of diffuse large B-cell lymphoma (DLBCL). Patients with primary testicular lymphoma (PTL) have a poor prognosis and a higher propensity for relapse. Also rare are composite lymphomas (CL) defined as two or more morphologically and phenotypically distinct lymphomas coexisting in a single organ or tissue. Here we present the first reported case of primary testicular composite lymphoma consisting of DLBCL and mantle cell lymphoma (MCL). Key words non-Hodgkin lymphoma; mantle cell lymphoma; diffuse large b-cell lymphoma; testicular lymphoma; composite lymphoma Correspondence Taimur Sher, MD, Division of Hematology and Medical Oncology, Department of Medicine, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Tel: +904 953 2607; Fax: +904 953 2315; e-mail: [email protected] Accepted for publication 12 April 2014
Primary testicular non-Hodgkin lymphoma (NHL) is a rare entity and accounts for 1–2% of all NHLs and 3–9% of testicular cancers. The most common histologic subtype is diffuse large B-cell lymphoma (DLBCL). Patients with primary testicular lymphoma (PTL) have a poor prognosis and a higher propensity for relapse in extra-nodal sites such as the central nervous system (CNS) and testes. Recent data have shown better outcomes with combined-modality approach. We describe the first case of primary testicular composite lymphoma and discuss evidence supporting combination therapy in PTLs. Case report
A 69-year-old white male presented with a 10-week history of progressive, painless right scrotal swelling. Patient denied any B-type constitutional symptoms. Physical examination revealed a firm, rubbery right testicular mass measuring 8 9 5 cm. The spermatic cord was thickened and palpable all the way up to the external inguinal ring. Laboratory evaluation demonstrated normal complete blood count and chemistries. HIV and viral hepatitis panel were negative. Testicular tumor markers (alpha-fetoprotein, lactate dehydrogenase,
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
doi:10.1111/ejh.12344
and beta-HCG) were within normal limits. The patient underwent a testicular ultrasound that demonstrated an abnormally enlarged right testicle with increased vascular flow concerning for neoplasm. Computed tomography (CT) of the chest, abdomen, and pelvis revealed a heterogeneous right scrotal mass consistent with the ultrasound. Also noted was enlargement and thickening of the right gonadal vein extending superiorly to its origin and retroperitoneal lymphadenopathy in the aortocaval and left periaortic regions. Positron emission tomography (PET) scan demonstrated intensely hypermetabolic activity (max SUV 15.6) in the right testicle with associated extensive and confluent hypermetabolic activity in the lymph nodes and the entire length of the right gonadal vein to its drainage into the inferior vena cava. The patient underwent right radical orchiectomy. Pathology revealed a composite high-grade large B-cell lymphoma and focal interstitial mantle cell lymphoma (MCL). CD20 was positive for both DLBCL and MCL; MUM-1 was diffusely positive for the DLBCL component but negative for the MCL. Cyclin D1 was positive in the interstitial MCL and negative in the high-grade DLBCL (Fig. 1). Flow cytometry showed two distinct monoclonal B-cell
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Composite non-Hodgkin lymphoma of testis
A
B
C
D
E
F
G
H
I
Figure 1 The lymphoid proliferation in the testicle (A, H&E 9 10) is composed of focal mantle cell lymphoma (B, 940) and predominantly diffuse large B cell lymphoma (C, 940). The immunohistochemical studies show that the focus of MCL (upper right in D, E, and F) is CD19 positive negative for MUM1 (D, 910), diffusely positive for cyclin D1 (E, 910), with low proliferative rate by MIB-1 (F, 910); while DLBCL (lower left in D, E, and F) is negative for cyclin D1 but positive for MUM-1 with high proliferative rate. Flow cytometry analysis identified two distinct B cell populations (G); MCL is CD5 positive with lambda restriction (H, cells in pink); while DLBCL is CD5 negative with lambda restriction (I, cells in yellow).
populations: first clone of B cells was CD5+, CD19+, CD20+, CD10 , and CD23 accounting for 3% of total analyzed events; the second clone expressed CD19+, CD20+, CD5 , CD10 , and CD23 (Fig. 1). Fluorescent in situ hybridization (FISH) confirmed that the high-grade DLBCL and MCL were unrelated, by demonstration of BCL-6 translocation in 86% of nuclei in the high-grade DLBCL and CCND1/IgH translocation [t(11;14)] in 100% of the nuclei in the focal interstitial areas of MCL. The high-grade DLBCL component was negative for t (11;14), IgH/BCL-2, IgH/myc, or IgL/myc translocations (Fig. 2). The bone marrow biopsy revealed interstitial
538
involvement by CD20+, CD3 , CD10 , BCL-6 , and Cyclin D1-positive MCL (Fig. 3). Flow cytometry analysis identified CD5+ B cell with lambda light-chain restriction (Fig. 3). The FISH study on the bone marrow identified CCND1/IGH fusion gene (Fig. 3). Cerebrospinal fluid analysis and brain MRI were negative for CNS involvement. The patient was diagnosed with composite testicular lymphoma with coexisting stage IAE DLBCL and stage IVA MCL. He underwent six cycles of R-CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy with granulocyte colony-stimulating factor
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Andhavarapu et al.
Figure 2 Fluorescence in situ hybridization (FISH) on paraffin block of the PTL revealed the large cell population with rearrangement of the BCL-6 gene locus (A, break-apart probe, 2– 4 green signals in each cells). Image B of IgH/ BCL2 fusion probe shows multiple copies of IgH (green) and BCL-2 (red); image C of IgH/ MYC fusion probe shows 3–4 copies of IgH (green), MYC (red), and D8Z2 (aqua). The small cell population is positive for CCND1/IGH[t (11;14)] (D, CCND1-red; IgH-green; arrows indicate fusion).
Composite non-Hodgkin lymphoma of testis
A
B
C
D
support. Intrathecal chemotherapy with methotrexate was administered with every cycle. Interim PET/CT scan after three cycles demonstrated decrease in the lymphadenopathy and complete resolution of all hypermetabolic abnormality (Fig. 4). The patient also underwent radiation therapy with 3600 cGy to the contralateral testicle, scrotum, and right groin. Post-treatment PET scan and bone marrow biopsy confirmed he was in complete remission. Patient was subsequently started on maintenance therapy with rituximab based on a recent European study that demonstrated survival advantage with maintenance therapy in patients with MCL who achieve complete remission to initial therapy (1). Discussion
Primary testicular NHL is the most common testicular malignancy in older men, with mean age at presentation of 67–71 yr (2–4). Most patients present with a testicular mass or swelling, and up to 35% of the patients may have involvement of the contralateral testis during the course of their disease (4). B-type constitutional symptoms are usually seen with advanced-stage presentation. By far, the majority of PTL are B-lineage large cell lymphomas (4, 5). They can be misinterpreted for seminoma and less often as embryonal carcinoma or orchitis (5). Involvement of the epididymis and spermatic cord is more common in lymphomas in comparison with seminomas (5). Immunohistochemistry can help clarify the diagnosis if not apparent with morphological characteristics.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
MCL is an uncommon type of aggressive B-cell lymphoma that usually presents with nodal and splenic disease. In rare circumstances, MCL can present as extra nodal disease, most frequently seen in the Waldeyer’s ring and the gastrointestinal tract. Only a handful of cases of testicular involvement by MCL have been reported (6–8). To the best of our knowledge, no case of testicular involvement by two phenotypic and molecularly distinct subtypes has been reported. Our case represents the first description of this entity. Testicular large B-cell lymphomas are uniquely characterized by high risk of extranodal relapse, even in cases of localized disease at presentation (3). Extranodal sites of relapse include CNS, skin, Waldeyer’s ring, lung, and soft tissues (3, 9). In a retrospective analysis of 62 patients, Fonseca et al. observed that up to 80% of the patients who initially achieved complete response after primary treatment can experience disease recurrence. Interestingly, patients with Ann Arbor Stage I disease had a similar rate of recurrence as patients with advanced-stage disease. Approximately 50% of the relapsed patients had recurrence at extranodal sites only (28% in CNS and 12% in contralateral testis). This high rate of CNS and contralateral testis recurrence has been reported in other retrospective reviews as well (5, 10). Both of these sites are considered as sanctuary sites where lymphoma cells are thought to escape the host T-lymphocyte-mediated immunosurveillance. Furthermore, there is decreased penetration of cytotoxic drugs in these sites which contributes to high rates of relapse (11).
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Andhavarapu et al.
Composite non-Hodgkin lymphoma of testis
A
B
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D
E
F
Figure 3 The bone marrow biopsy shows diffuse interstitial infiltrate of mantle cell lymphoma (A, H&E 920); the lymphoma cells are diffusely positive for CD20 (B, 920) and cyclin D1 (C, 920). Flow cytometry analysis identified CD5-positive B-cell population (D, cells within the blue circle) with lambda light-chain restriction (E, cells in blue). The FISH study on bone marrow identified CCND1/IGH fusion gene (F, CCND1-red; IgHgreen, arrow indicates fusion gene); no other abnormalities were present.
PTLs carry poorer prognosis compared to their nodal counterpart. Even patients with Stage I disease and a goodrisk International Prognostic Index have worse outcome than that reported for DLBCL at other sites (3). Most relapses occur within the first 1–3 yr of initial therapy, mostly at extra-nodal sites. The International Extranodal Lymphoma Study Group (IELSG) observed a 5 and 10-year risk of CNS relapse of 19% and 34%, respectively, in patients with primary testicular large cell lymphoma (3). In light of this evidence, a thorough staging needs to be performed prior to institution of therapy and should include cerebrospinal fluid evaluation. Management of testicular lymphoma remains a challenge as it is an uncommon entity and no randomized controlled trials have been conducted to aid in therapeutic decision making. A recent phase II prospective trial showed very encouraging results in patients with stage I/II PTLs treated with chemoimmunotherapy in combination with CNS prophylaxis and contralateral testis irradiation (12). Orchiectomy is typically preferred over diagnostic needle aspiration or testicular biopsy as it could confer local control of the disease and remove a potential site for relapse, in addition to providing histologic diagnosis (2). The use of anthracycline-based chemotherapy following orchiectomy is a
540
widely accepted treatment option and has been associated with a 5-year survival of 30–75% (13). In IELSG-10 study, which examined the efficacy of multimodality therapy, all patients (n = 53) received R-CHOP21 (administered every 3 wk). At a median follow-up of 65 months, the 5-year progression-free survival and overall survival were 74% and 85%, respectively (12). Due to high rates of testicular and CNS relapses, prophylactic scrotal radiotherapy and CNS prophylaxis with intrathecal methotrexate are advocated. However, the best strategy for preventing CNS relapse is still a matter of debate as CNS relapses occur despite intrathecal chemotherapy and are found more frequently in brain parenchyma than in the meninges (3,12). Unlike large B-cell lymphoma, no significant literature exists about the management of testicular involvement with MCL. Hence, it is intuitively managed like other aggressive B-cell lymphomas of the testis. To our knowledge, this is the first reported case of testicular composite lymphoma with MCL and DLBCL. Composite lymphoma (CL) is defined as two or more morphologically and phenotypically distinct types of lymphomas coexisting in a single anatomic organ or tissue (14). CLs are rarely encountered and the lymphoma components may or may not be clonally related. The combination might include B-cell or
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Andhavarapu et al.
Composite non-Hodgkin lymphoma of testis
Figure 4 Interim PET showed complete resolution of the hypermetabolic activity along the course of right gonadal vein and in the retroperitoneal lymph nodes.
T-cell NHL with Hodgkin lymphoma, B-cell NHL with T-cell NHL or two distinct B- or T-cell NHL at the same anatomic site (14–16). CLs involving mantle cell lymphoma are exceedingly rare. One case series reported 11 cases of CL involving MCL and chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) (17). Those patients presented with advanced-stage disease and had a poor prognosis. Whether the finding of a CL was incidental or whether the components have a common biological progenitor is unknown. In our patient’s case, a possibility remains that the DLBCL might have transformed from MCL as has previously been reported in two cases by Tamaru, et al. (18). Both the initial and relapsed biopsy specimens revealed tumor cells positive for cyclin D1, sIgM, sIgD, and CD5, but were negative for CD10 and CD23. The immunoglobulin heavy-chain gene rearrangement, using the polymerase chain reaction method, from each paired biopsy was the same size, and in one case had an identical sequence to the non-mutated variable heavy-chain gene. This unusual transformation of mantle cell lymphoma to DLBCL is exceedingly rare, and the more common occurrence is that of MCL transforming to a blastoid variant resulting in unfavorable prognosis (19). In our case, the morphologic, immunophenotypic, and FISH findings were very distinct for the two lymphoma components. This strongly suggests that they are clonally unrelated. We questioned the possibility that testicular involvement by MCL may be secondary, as it involved the bone marrow. However, the fact that no additional extranodal sites were noted and only para-aortic lymph nodes at the junction of testicular vein and inferior vena cava were involved leads us to believe that it probably originated in the testis with secondary extra-testicular
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
spread. Our patient was treated with the combined-modality treatment (radical orchiectomy of the involved testis, RCHOP chemotherapy, intrathecal chemotherapy, and prophylactic scrotal radiotherapy) and is now in complete remission after completing 2 yrs of maintenance therapy with rituximab (1). In summary, CLs can have a similar clinical presentation as other lymphomas. The overall prognosis usually depends on the more aggressive component of CL and should be treated accordingly. Acknowledgements
None. Funding sources
None. Conflict of interest
None.
References 1. Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older patients with mantle-cell lymphoma. N Engl J Med 2012;367:520–31. 2. Ahmad SS, Idris SF, Follows GA, et al. Primary testicular lymphoma. Clin Oncol (R Coll Radiol) 2012;24:358–65. 3. Zucca E, Conconi A, Mughal TI, et al. Patterns of outcome and prognostic factors in primary large-cell lymphoma of the testis in a survey by the International Extranodal Lymphoma Study Group. J Clin Oncol 2003;21:20–7.
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4. 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. 5. Ferry JA, Harris NL, Young RH, et al. Malignant lymphoma of the testis, epididymis, and spermatic cord. A clinicopathologic study of 69 cases with immunophenotypic analysis. Am J Surg Pathol 1994;18:376–90. 6. Epstein AS, Hedvat C, Habib F, et al. Testis-isolated mantle cell lymphoma: a unique case. Clin Lymphoma Myeloma Leuk 2011;11:439–41. 7. Licci S, Morelli L, Covello R. Primary mantle cell lymphoma of the testis. Ann Hematol 2011;90:483–4. 8. Kemmerling R, Stintzing S, Muhlmann J, et al. Primary testicular lymphoma: a strictly homogeneous hematological disease? Oncol Rep 2010;23:1261–7. 9. Fonseca R, Habermann TM, Colgan JP, et al. Testicular lymphoma is associated with a high incidence of extranodal recurrence. Cancer 2000;88:154–61. 10. Seymour JF, Solomon B, Wolf MM, et al. Primary large-cell non-Hodgkin’s lymphoma of the testis: a retrospective analysis of patterns of failure and prognostic factors. Clin Lymphoma 2001;2:109–15. 11. Bart J, Groen HJ, van der Graaf WT, et al. An oncological view on the blood-testis barrier. Lancet Oncol 2002;3:357–63. 12. Vitolo U, Chiappella A, Ferreri AJ, et al. First-line treatment for primary testicular diffuse large B-cell lymphoma with
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13. 14. 15.
16.
17.
18.
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rituximab-CHOP, CNS prophylaxis, and contralateral testis irradiation: final results of an international phase II trial. J Clin Oncol 2011;29:2766–72. Vitolo U, Ferreri AJ, Zucca E. Primary testicular lymphoma. Crit Rev Oncol Hematol 2008;65:183–9. Kim H, Hendrickson R, Dorfman RF. Composite lymphoma. Cancer 1977;40:959–76. Gonzalez CL, Medeiros LJ, Jaffe ES. Composite lymphoma. A clinicopathologic analysis of nine patients with Hodgkin’s disease and B-cell non-Hodgkin’s lymphoma. Am J Clin Pathol 1991;96:81–9. Papathomas TG, Venizelos I, Dunphy CH, et al. Mantle cell lymphoma as a component of composite lymphoma: clinicopathologic parameters and biologic implications. Hum Pathol 2012;43:467–80. Hoeller S, Zhou Y, Kanagal-Shamanna R, et al. Composite mantle cell lymphoma and chronic lymphocytic leukemia/ small lymphocytic lymphoma: a clinicopathologic and molecular study. Hum Pathol 2013;41:110–21. Tamaru JI, Kawana H, Takahashi Y, et al. Expression of cell cycle regulating proteins in an unusual transformation of mantle cell lymphoma. Leuk Lymphoma 1999;36: 128–37. Raty R, Franssila K, Jansson SE, et al. Predictive factors for blastoid transformation in the common variant of mantle cell lymphoma. Eur J Cancer 2003;39:321–9.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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CASE REPORT
Mantle cell lymphoma and diffuse large B-cell lymphoma of the testis: a unique case of composite non-Hodgkin lymphoma Swati Andhavarapu1, Jennifer A. Crozier1, Liuyan Jiang2, Taimur Sher1 1
Department of Medicine, Mayo Clinic, Jacksonville, FL; 2Department of Pathology, Mayo Clinic, Jacksonville, FL, USA
Abstract Primary testicular non-Hodgkin lymphoma (NHL) is a rare entity with the most common histologic subtype consisting of diffuse large B-cell lymphoma (DLBCL). Patients with primary testicular lymphoma (PTL) have a poor prognosis and a higher propensity for relapse. Also rare are composite lymphomas (CL) defined as two or more morphologically and phenotypically distinct lymphomas coexisting in a single organ or tissue. Here we present the first reported case of primary testicular composite lymphoma consisting of DLBCL and mantle cell lymphoma (MCL). Key words non-Hodgkin lymphoma; mantle cell lymphoma; diffuse large b-cell lymphoma; testicular lymphoma; composite lymphoma Correspondence Taimur Sher, MD, Division of Hematology and Medical Oncology, Department of Medicine, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Tel: +904 953 2607; Fax: +904 953 2315; e-mail: [email protected] Accepted for publication 12 April 2014
Primary testicular non-Hodgkin lymphoma (NHL) is a rare entity and accounts for 1–2% of all NHLs and 3–9% of testicular cancers. The most common histologic subtype is diffuse large B-cell lymphoma (DLBCL). Patients with primary testicular lymphoma (PTL) have a poor prognosis and a higher propensity for relapse in extra-nodal sites such as the central nervous system (CNS) and testes. Recent data have shown better outcomes with combined-modality approach. We describe the first case of primary testicular composite lymphoma and discuss evidence supporting combination therapy in PTLs. Case report
A 69-year-old white male presented with a 10-week history of progressive, painless right scrotal swelling. Patient denied any B-type constitutional symptoms. Physical examination revealed a firm, rubbery right testicular mass measuring 8 9 5 cm. The spermatic cord was thickened and palpable all the way up to the external inguinal ring. Laboratory evaluation demonstrated normal complete blood count and chemistries. HIV and viral hepatitis panel were negative. Testicular tumor markers (alpha-fetoprotein, lactate dehydrogenase,
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
doi:10.1111/ejh.12344
and beta-HCG) were within normal limits. The patient underwent a testicular ultrasound that demonstrated an abnormally enlarged right testicle with increased vascular flow concerning for neoplasm. Computed tomography (CT) of the chest, abdomen, and pelvis revealed a heterogeneous right scrotal mass consistent with the ultrasound. Also noted was enlargement and thickening of the right gonadal vein extending superiorly to its origin and retroperitoneal lymphadenopathy in the aortocaval and left periaortic regions. Positron emission tomography (PET) scan demonstrated intensely hypermetabolic activity (max SUV 15.6) in the right testicle with associated extensive and confluent hypermetabolic activity in the lymph nodes and the entire length of the right gonadal vein to its drainage into the inferior vena cava. The patient underwent right radical orchiectomy. Pathology revealed a composite high-grade large B-cell lymphoma and focal interstitial mantle cell lymphoma (MCL). CD20 was positive for both DLBCL and MCL; MUM-1 was diffusely positive for the DLBCL component but negative for the MCL. Cyclin D1 was positive in the interstitial MCL and negative in the high-grade DLBCL (Fig. 1). Flow cytometry showed two distinct monoclonal B-cell
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Andhavarapu et al.
Composite non-Hodgkin lymphoma of testis
A
B
C
D
E
F
G
H
I
Figure 1 The lymphoid proliferation in the testicle (A, H&E 9 10) is composed of focal mantle cell lymphoma (B, 940) and predominantly diffuse large B cell lymphoma (C, 940). The immunohistochemical studies show that the focus of MCL (upper right in D, E, and F) is CD19 positive negative for MUM1 (D, 910), diffusely positive for cyclin D1 (E, 910), with low proliferative rate by MIB-1 (F, 910); while DLBCL (lower left in D, E, and F) is negative for cyclin D1 but positive for MUM-1 with high proliferative rate. Flow cytometry analysis identified two distinct B cell populations (G); MCL is CD5 positive with lambda restriction (H, cells in pink); while DLBCL is CD5 negative with lambda restriction (I, cells in yellow).
populations: first clone of B cells was CD5+, CD19+, CD20+, CD10 , and CD23 accounting for 3% of total analyzed events; the second clone expressed CD19+, CD20+, CD5 , CD10 , and CD23 (Fig. 1). Fluorescent in situ hybridization (FISH) confirmed that the high-grade DLBCL and MCL were unrelated, by demonstration of BCL-6 translocation in 86% of nuclei in the high-grade DLBCL and CCND1/IgH translocation [t(11;14)] in 100% of the nuclei in the focal interstitial areas of MCL. The high-grade DLBCL component was negative for t (11;14), IgH/BCL-2, IgH/myc, or IgL/myc translocations (Fig. 2). The bone marrow biopsy revealed interstitial
538
involvement by CD20+, CD3 , CD10 , BCL-6 , and Cyclin D1-positive MCL (Fig. 3). Flow cytometry analysis identified CD5+ B cell with lambda light-chain restriction (Fig. 3). The FISH study on the bone marrow identified CCND1/IGH fusion gene (Fig. 3). Cerebrospinal fluid analysis and brain MRI were negative for CNS involvement. The patient was diagnosed with composite testicular lymphoma with coexisting stage IAE DLBCL and stage IVA MCL. He underwent six cycles of R-CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy with granulocyte colony-stimulating factor
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Andhavarapu et al.
Figure 2 Fluorescence in situ hybridization (FISH) on paraffin block of the PTL revealed the large cell population with rearrangement of the BCL-6 gene locus (A, break-apart probe, 2– 4 green signals in each cells). Image B of IgH/ BCL2 fusion probe shows multiple copies of IgH (green) and BCL-2 (red); image C of IgH/ MYC fusion probe shows 3–4 copies of IgH (green), MYC (red), and D8Z2 (aqua). The small cell population is positive for CCND1/IGH[t (11;14)] (D, CCND1-red; IgH-green; arrows indicate fusion).
Composite non-Hodgkin lymphoma of testis
A
B
C
D
support. Intrathecal chemotherapy with methotrexate was administered with every cycle. Interim PET/CT scan after three cycles demonstrated decrease in the lymphadenopathy and complete resolution of all hypermetabolic abnormality (Fig. 4). The patient also underwent radiation therapy with 3600 cGy to the contralateral testicle, scrotum, and right groin. Post-treatment PET scan and bone marrow biopsy confirmed he was in complete remission. Patient was subsequently started on maintenance therapy with rituximab based on a recent European study that demonstrated survival advantage with maintenance therapy in patients with MCL who achieve complete remission to initial therapy (1). Discussion
Primary testicular NHL is the most common testicular malignancy in older men, with mean age at presentation of 67–71 yr (2–4). Most patients present with a testicular mass or swelling, and up to 35% of the patients may have involvement of the contralateral testis during the course of their disease (4). B-type constitutional symptoms are usually seen with advanced-stage presentation. By far, the majority of PTL are B-lineage large cell lymphomas (4, 5). They can be misinterpreted for seminoma and less often as embryonal carcinoma or orchitis (5). Involvement of the epididymis and spermatic cord is more common in lymphomas in comparison with seminomas (5). Immunohistochemistry can help clarify the diagnosis if not apparent with morphological characteristics.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
MCL is an uncommon type of aggressive B-cell lymphoma that usually presents with nodal and splenic disease. In rare circumstances, MCL can present as extra nodal disease, most frequently seen in the Waldeyer’s ring and the gastrointestinal tract. Only a handful of cases of testicular involvement by MCL have been reported (6–8). To the best of our knowledge, no case of testicular involvement by two phenotypic and molecularly distinct subtypes has been reported. Our case represents the first description of this entity. Testicular large B-cell lymphomas are uniquely characterized by high risk of extranodal relapse, even in cases of localized disease at presentation (3). Extranodal sites of relapse include CNS, skin, Waldeyer’s ring, lung, and soft tissues (3, 9). In a retrospective analysis of 62 patients, Fonseca et al. observed that up to 80% of the patients who initially achieved complete response after primary treatment can experience disease recurrence. Interestingly, patients with Ann Arbor Stage I disease had a similar rate of recurrence as patients with advanced-stage disease. Approximately 50% of the relapsed patients had recurrence at extranodal sites only (28% in CNS and 12% in contralateral testis). This high rate of CNS and contralateral testis recurrence has been reported in other retrospective reviews as well (5, 10). Both of these sites are considered as sanctuary sites where lymphoma cells are thought to escape the host T-lymphocyte-mediated immunosurveillance. Furthermore, there is decreased penetration of cytotoxic drugs in these sites which contributes to high rates of relapse (11).
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Andhavarapu et al.
Composite non-Hodgkin lymphoma of testis
A
B
C
D
E
F
Figure 3 The bone marrow biopsy shows diffuse interstitial infiltrate of mantle cell lymphoma (A, H&E 920); the lymphoma cells are diffusely positive for CD20 (B, 920) and cyclin D1 (C, 920). Flow cytometry analysis identified CD5-positive B-cell population (D, cells within the blue circle) with lambda light-chain restriction (E, cells in blue). The FISH study on bone marrow identified CCND1/IGH fusion gene (F, CCND1-red; IgHgreen, arrow indicates fusion gene); no other abnormalities were present.
PTLs carry poorer prognosis compared to their nodal counterpart. Even patients with Stage I disease and a goodrisk International Prognostic Index have worse outcome than that reported for DLBCL at other sites (3). Most relapses occur within the first 1–3 yr of initial therapy, mostly at extra-nodal sites. The International Extranodal Lymphoma Study Group (IELSG) observed a 5 and 10-year risk of CNS relapse of 19% and 34%, respectively, in patients with primary testicular large cell lymphoma (3). In light of this evidence, a thorough staging needs to be performed prior to institution of therapy and should include cerebrospinal fluid evaluation. Management of testicular lymphoma remains a challenge as it is an uncommon entity and no randomized controlled trials have been conducted to aid in therapeutic decision making. A recent phase II prospective trial showed very encouraging results in patients with stage I/II PTLs treated with chemoimmunotherapy in combination with CNS prophylaxis and contralateral testis irradiation (12). Orchiectomy is typically preferred over diagnostic needle aspiration or testicular biopsy as it could confer local control of the disease and remove a potential site for relapse, in addition to providing histologic diagnosis (2). The use of anthracycline-based chemotherapy following orchiectomy is a
540
widely accepted treatment option and has been associated with a 5-year survival of 30–75% (13). In IELSG-10 study, which examined the efficacy of multimodality therapy, all patients (n = 53) received R-CHOP21 (administered every 3 wk). At a median follow-up of 65 months, the 5-year progression-free survival and overall survival were 74% and 85%, respectively (12). Due to high rates of testicular and CNS relapses, prophylactic scrotal radiotherapy and CNS prophylaxis with intrathecal methotrexate are advocated. However, the best strategy for preventing CNS relapse is still a matter of debate as CNS relapses occur despite intrathecal chemotherapy and are found more frequently in brain parenchyma than in the meninges (3,12). Unlike large B-cell lymphoma, no significant literature exists about the management of testicular involvement with MCL. Hence, it is intuitively managed like other aggressive B-cell lymphomas of the testis. To our knowledge, this is the first reported case of testicular composite lymphoma with MCL and DLBCL. Composite lymphoma (CL) is defined as two or more morphologically and phenotypically distinct types of lymphomas coexisting in a single anatomic organ or tissue (14). CLs are rarely encountered and the lymphoma components may or may not be clonally related. The combination might include B-cell or
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Andhavarapu et al.
Composite non-Hodgkin lymphoma of testis
Figure 4 Interim PET showed complete resolution of the hypermetabolic activity along the course of right gonadal vein and in the retroperitoneal lymph nodes.
T-cell NHL with Hodgkin lymphoma, B-cell NHL with T-cell NHL or two distinct B- or T-cell NHL at the same anatomic site (14–16). CLs involving mantle cell lymphoma are exceedingly rare. One case series reported 11 cases of CL involving MCL and chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) (17). Those patients presented with advanced-stage disease and had a poor prognosis. Whether the finding of a CL was incidental or whether the components have a common biological progenitor is unknown. In our patient’s case, a possibility remains that the DLBCL might have transformed from MCL as has previously been reported in two cases by Tamaru, et al. (18). Both the initial and relapsed biopsy specimens revealed tumor cells positive for cyclin D1, sIgM, sIgD, and CD5, but were negative for CD10 and CD23. The immunoglobulin heavy-chain gene rearrangement, using the polymerase chain reaction method, from each paired biopsy was the same size, and in one case had an identical sequence to the non-mutated variable heavy-chain gene. This unusual transformation of mantle cell lymphoma to DLBCL is exceedingly rare, and the more common occurrence is that of MCL transforming to a blastoid variant resulting in unfavorable prognosis (19). In our case, the morphologic, immunophenotypic, and FISH findings were very distinct for the two lymphoma components. This strongly suggests that they are clonally unrelated. We questioned the possibility that testicular involvement by MCL may be secondary, as it involved the bone marrow. However, the fact that no additional extranodal sites were noted and only para-aortic lymph nodes at the junction of testicular vein and inferior vena cava were involved leads us to believe that it probably originated in the testis with secondary extra-testicular
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
spread. Our patient was treated with the combined-modality treatment (radical orchiectomy of the involved testis, RCHOP chemotherapy, intrathecal chemotherapy, and prophylactic scrotal radiotherapy) and is now in complete remission after completing 2 yrs of maintenance therapy with rituximab (1). In summary, CLs can have a similar clinical presentation as other lymphomas. The overall prognosis usually depends on the more aggressive component of CL and should be treated accordingly. Acknowledgements
None. Funding sources
None. Conflict of interest
None.
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