Case 15-2004 — A 31-Year-Old Man with Bilateral Testicular Enlargement
http://www.100md.com
《新英格兰医药杂志》
Karen K. Ballen, M.D., and Robert P. Hasserjian, M.D.
Presentation of Case
A 31-year-old man was admitted to the hospital because of a testicular mass.
The patient had been well until three months before admission, when he noted bilateral testicular swelling that coincided with a two-week illness characterized by fever and cough. When the fever and cough resolved, the testicular swelling appeared to improve. One month later, while on a cruise, the patient had an upper respiratory tract infection associated with fever and cough, and again noted enlargement of his testes. He read It's Not about the Bike, by Lance Armstrong1 while on the cruise, and became concerned about testicular cancer. Again, he believed that the testicular enlargement improved but that it did not go away completely when the fever and cough resolved.
Two weeks before admission, he saw his physician because he was concerned about the persistent testicular swelling. An ultrasound examination performed at another institution confirmed the presence of diffuse bilateral testicular enlargement, with a heterogeneous pattern and hypoechoic areas. Computed tomographic (CT) images of the head, chest, abdomen, and pelvis, also obtained at the other institution, were reported to be normal. Tests for the subunit of human chorionic gonadotropin and for alpha-fetoprotein were negative. He was referred to a urologist at this hospital.
The patient had been well except for a hospitalization at the age of 10 years for gastroenteritis. The results of a test for the human immunodeficiency virus performed three years previously had been negative. He said that he did not have fatigue, fever, chills, change in appetite, headache, swollen glands, cough, chest pain, abdominal pain, or bleeding, and he did not have difficulty with urination or erectile function. He had experienced intermittent night sweats for the previous two weeks and had lost 10 lb (4.5 kg) through dieting. One of his five sisters had a history of thyroid cancer, which had been treated with radioactive iodine; the other siblings were well. Both parents were living; his mother had coronary artery disease and had undergone coronary-artery bypass grafting at the age of 49 years. He lived with his parents and had a steady girlfriend. He worked as an accountant. There was no history of foreign travel, transfusions, or alcohol, tobacco, or intravenous-drug use. He was taking no medications.
On physical examination, he appeared well, and the vital signs were normal. There was no palpable supraclavicular, cervical, axillary, or inguinal lymphadenopathy. The lungs were clear. The cardiac examination revealed no murmurs. There was no gynecomastia. The abdomen was normal, and the liver and spleen were not palpable. Both testes were markedly enlarged and firm, without discrete masses; the left testis was 14 cm in diameter and the right testis 12 cm in diameter. The neurologic examination revealed no abnormalities. Magnetic resonance imaging (MRI) of the pelvis revealed a rounded, left periaortic lymph node, 1.2 cm in diameter, and a rounded, left renal hilar lymph node, 1.3 cm in diameter, both of which were partially heterogeneously enhancing, and a nonenhancing, precaval lymph node, 0.8 cm in diameter.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Karen K. Ballen: Although I am aware of the diagnosis in this case, the patient's clinical presentation provides an opportunity to discuss the approach to the differential diagnosis of testicular enlargement. The causes of testicular enlargement in a young man include infectious and neoplastic processes. Infectious orchitis or epididymitis, or a combination of the two, is more common than cancer. Acute epididymitis is usually unilateral. In young, sexually active men, acute epididymitis is most often caused by infection with chlamydia or Neisseria gonorrhoeae. In older men, acute epididymitis is more likely to be caused by urinary pathogens. A trial of antibiotics is often used, and bed rest and scrotal elevation may also help with the swelling. The bilateral swelling and the absence of fever make epididymitis less likely in this case.
Testicular torsion is diagnosed less frequently than epididymitis; it usually occurs in young men and is associated with the sudden onset of acute testicular pain and swelling. The testicle is elevated and there is absence of blood flow on Doppler examination. Torsion is a surgical emergency. The fact that the swelling in this case is persistent and is associated with only mild pain makes testicular torsion unlikely.
A variety of neoplastic lesions can involve the testes. The most common are the germ-cell tumors, which include seminoma, embryonal carcinoma, teratoma, yolk-sac tumor, and choriocarcinoma. Germ-cell tumors are the most common solid tumor in men between the ages of 20 and 35 years. Seminomas represent 50 percent of all germ-cell tumors and usually occur in men in their 30s. Nonseminomatous germ-cell tumors most frequently occur in the third decade of life. Germ-cell tumors are more common in white men than in men of other races and are more common in men with a history of cryptorchidism. The patient may present with a painless testicular mass. However, more common symptoms on presentation are diffuse testicular pain and swelling or firmness (or both). Ultrasonographic examination shows an intratesticular hypoechoic mass or diffuse calcifications. Early diagnosis is important, since a delay in diagnosis can allow the tumor to spread and thus render it less curable. Germ-cell tumor would be high in the differential diagnosis in this situation.
Leydig-cell tumors account for 2 percent of testicular tumors. Patients may present with a palpable mass or testicular swelling, similar to the features of germ-cell tumors. Some patients have associated gynecomastia or decreased libido. Twenty-five percent of cases are seen in children and may be associated with early sexual development. In the current case, there were no associated findings, such as decreased libido or gynecomastia, to suggest a Leydig-cell tumor.
Sertoli-cell tumors represent less than 1 percent of primary testicular tumors. Patients with Sertoli-cell tumors may also present with a painless, enlarging mass. These tumors occur in boys and may be associated with feminization. There is an association between Sertoli-cell tumors and pituitary adenoma, hyperpigmented skin, and mucosal lesions.2
Rare tumors of the testes include mesothelioma, sarcoma, and adenocarcinoma of the collecting system of the testis. Metastatic cancer manifesting as a testicular mass is also rare. The possible primary sites include the prostate, lung, melanoma, and kidney. Patients usually present with diffuse systemic disease, and the involvement is more likely to be unilateral than bilateral. There is no suggestion of another primary site in this patient.
Primary testicular lymphoma is rare, accounting for 2 percent of all non-Hodgkin's lymphomas, with an incidence of 0.26 per 100,000 people per year.3 Lymphomas represent 2 to 5 percent of all testicular cancers, but are the most common testicular cancer in men older than 50 years of age. They can also occur in younger men. Ninety percent of testicular lymphomas are diffuse large-B-cell lymphomas. Painless testicular swelling is common, and 30 percent of patients have bilateral involvement. About half the patients also have weight loss, fever, or night sweats. In the case under discussion, the bilateral swelling, the recent weight loss, and the night sweats support the diagnosis of lymphoma. Testicular involvement by diffuse large-B-cell lymphoma, as compared with nodal lymphoma and extranodal lymphomas of other sites, is associated with an increased risk of bone marrow and central nervous system involvement.3
The diagnostic procedure of choice in this situation is a testicular biopsy with intraoperative examination of a frozen section and triage of tissue for appropriate diagnostic studies, such as immunophenotyping and cytogenetic analysis.
Clinical Diagnosis
Primary testicular lymphoma, probably diffuse large-B-cell lymphoma.
Pathological Discussion
Dr. Robert P. Hasserjian: Dr. Alex Althausen, of the Department of Urology, performed a transinguinal biopsy of the left testis, and the specimen was sent for frozen-section examination. A preliminary diagnosis of lymphoma was made, and additional tissue was requested for flow-cytometric and cytogenetic analyses. Microscopical examination of permanent sections revealed a dense lymphoid infiltrate, which caused expansion of the interstitium and surrounded, but did not infiltrate, the seminiferous tubules (Figure 1A). The lymphoid cells were slightly larger than small lymphocytes and had finely dispersed chromatin, markedly irregular nuclear contours, and very scant cytoplasm — histologic features typically associated with immature lymphoid cells known as lymphoblasts (Figure 1B). Numerous mitotic figures were present (Figure 1C). Immunophenotyping of disaggregated cells by flow cytometry revealed a predominant population of cells expressing the B-cell marker CD19, as well as CD10, but lacking CD20. Surface immunoglobulin was not detected. Immunohistochemical studies on tissue sections showed that the cells expressed terminal deoxynucleotidyl transferase, a nuclear enzyme expressed in lymphoid precursor cells (Figure 1D). This constellation of findings confirmed the diagnosis of precursor B-cell lymphoblastic lymphoma. Conventional cytogenetic analysis of the biopsy specimen was unsuccessful. Fluorescence in situ hybridization studies were negative for the BCR-ABL fusion gene and for MLL gene rearrangement, genetic mutations that are associated with an unfavorable prognosis in precursor B-cell lymphoblastic neoplasms.
Figure 1. Biopsy Specimen of the Testis.
There is expansion of the interstitium (Panel A) by diffuse sheets of lymphoid cells, which surround but do not infiltrate the seminiferous tubules (hematoxylin and eosin, x504). The neoplastic lymphoid cells are somewhat larger than a small, mature lymphocyte (Panel B, arrow; hematoxylin and eosin, x250) and have markedly irregular nuclei and finely dispersed chromatin with mitotic activity (Panel C; hematoxylin and eosin, x1200). The neoplastic cells show nuclear immunoreactivity for antibody to terminal deoxynucleotidyl transferase as indicated by brown nuclear staining superimposed on the blue hematoxylin counterstain (Panel D); scattered, smaller mature lymphocytes are negative (immunoperoxidase stain, x500).
The current World Health Organization classification system divides T-cell and B-cell lymphomas into precursor and mature neoplasms.4 The former are characterized by an immature stage of lymphoid differentiation resembling that of normal B-cell and T-cell precursors in the bone marrow and thymus, respectively. Precursor B-cell and T-cell lymphoblastic neoplasms may manifest as predominantly mass-forming tumors or as leukemic processes involving the blood and bone marrow. These neoplasms are conventionally called lymphomas if the patient presents with an extramedullary mass lesion with no or minimal peripheral-blood involvement and involvement of less than 25 percent of the bone marrow space. Approximately 90 percent of lymphoblastic lymphomas are of T-cell lineage; a common manifestation of precursor T-cell lymphoblastic lymphoma is a large mediastinal mass and supradiaphragmatic lymphadenopathy in an adolescent or young adult.
In contrast, precursor B-cell lymphoblastic neoplasms constitute 90 percent of acute lymphoblastic leukemias, and manifestation as lymphoma is much less common, typically in extranodal sites such as the skin, bone, and soft tissue.5 Although the testis is a common site of relapse in patients treated for precursor B-cell acute lymphoblastic leukemia, it is a very rare manifestation of precursor B-cell lymphoblastic lymphoma; no cases were identified in a recent series of 64 primary testicular lymphomas.6
Examination of bone marrow and peripheral blood from the patient under discussion revealed no neoplastic lymphoblasts, and cytologic and flow-cytometric studies of the cerebrospinal fluid were also negative for lymphomatous involvement.
Pathological Diagnosis
Precursor B-cell lymphoblastic lymphoma.
Discussion of Management
Dr. Ballen: The pathologist provided valuable guidance to the clinical team by calling us to report the diagnosis, thereby expediting the patient's consultation and treatment. We saw the patient in the clinic one week after the biopsy and admitted him to the hospital for further staging of the disease and for treatment. Staging studies in patients with testicular lymphoma include bone marrow analysis, lumbar puncture with cerebrospinal fluid analysis, and CT scans of the chest, abdomen, and pelvis.3 Repeated CT scanning of the chest and abdomen confirmed the presence of two slightly enlarged abdominal lymph nodes. CT and MRI scanning of the brain revealed no metastatic disease. Lumbar puncture and evaluation of the cerebrospinal fluid by cytopathology and flow cytometry revealed no evidence of lymphoma. According to the Ann Arbor staging system for extranodal lymphoma, this patient's disease would fall into stage IIE (in which there is involvement of an extranodal site and regional lymph nodes).
Large-B-cell lymphoma is by far the most common lymphoma of the testis. The prognosis for patients with this lymphoma is worse than that for patients with large-cell lymphomas at other sites. In a survey of 393 patients from several international centers, the long-term, disease-free survival rate was only 25 percent.7 Seventy-two percent of patients who had a recurrence had disease in extranodal sites, including the contralateral testis, the central nervous system, and bone. Treatment with an anthracycline-based regimen such as a regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone and the use of prophylactic intrathecal therapy and scrotal irradiation were associated with a longer survival in the multivariate analysis.
Lymphoblastic lymphoma is more common in children than in adults, and testicular involvement typically occurs in the setting of acute leukemia. A retrospective review of 25 patients with precursor B-cell lymphoblastic lymphoma revealed that their median age was 20 years (range, 5 to 68).5 Pain was the most common symptom on presentation. The most common sites of primary disease were skin, bone, and soft tissue. Survival data were available for 14 patients, who had been treated with a variety of chemotherapy regimens, with a follow-up that ranged from 6 to 144 months. Of the 14, 9 had complete remission of disease, 1 had relapsed disease, and 4 died.
Treatment regimens for lymphoblastic lymphoma have evolved over the years to include intensive induction therapy, maintenance therapy, and prophylaxis against central nervous system complications with regimens similar or identical to those used to treat acute lymphoblastic leukemia. Results improved when patients were treated with regimens designed for acute leukemia, rather than with the less intensive regimens designed for lymphoma.8 The M.D. Anderson Cancer Center has developed a regimen of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) for adult patients with acute lymphoblastic leukemia.9 This regimen includes a dose-intensive phase and a maintenance phase. The dose-intensive phase consisted of eight cycles of chemotherapy: four cycles of cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with four cycles of high-dose methotrexate and cytarabine. All the patients received central nervous system prophylaxis. The maintenance phase consisted of two years of chemotherapy with mercaptopurine, methotrexate, vincristine, and prednisone. All the patients received prophylactic treatment with antibiotic and antiviral agents. Ninety-one percent of 204 patients achieved complete remission; 6 percent died of infections during remission induction, and 3 percent had resistant disease. However, the relapse rate was high, and the five-year survival rate was 39 percent. Patients under 20 years of age, as expected, did better than older patients.
The Cancer and Leukemia Group B has been studying various regimens of combination chemotherapy for the treatment of adult acute lymphoblastic leukemia. The basic principle of treatment calls for high-intensity, multiple-drug induction regimens, prophylaxis against central nervous system complications, and prolonged maintenance treatment for 24 months. Another study used an induction regimen of cyclophosphamide, daunorubicin, vincristine, prednisone, and asparaginase.10 Eighty-five percent of the patients had a complete remission, and 9 percent died during induction. The patients then received intensification therapy consisting of intrathecal methotrexate, cranial irradiation, cyclophosphamide, mercaptopurine, cytarabine, vincristine, asparaginase, doxorubicin, dexamethasone, and thioguanine. Maintenance therapy with vincristine, prednisone, mercaptopurine, and methotrexate continued for two years after the start of therapy. The three-year disease-free survival rate was 43 percent and was not changed by the use of growth factors.11 The scheme for this complex treatment regimen, most of which is given in the outpatient setting, is outlined in Table 1.
Table 1. Cancer and Leukemia Group B Treatment Regimen for Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma for Patients Less Than 60 Years of Age.
We chose the Cancer and Leukemia Group B treatment regimen for this patient because of the reports of favorable results and because of our familiarity with this regimen and its side effects. We were concerned that the testis is a sanctuary site of disease that systemic therapy may not treat effectively. Some studies of acute lymphoblastic leukemia in children have demonstrated that high-dose, intravenous methotrexate may reduce testicular recurrence.12 Because of this reported advantage, high-dose, intravenous methotrexate has been added to pediatric treatment regimens for lymphoma with testicular involvement,13 and for this reason, intravenous methotrexate at a dose of 4 g per square meter of body-surface area was added to the induction and intensification phases for this patient.
After the initial chemotherapy regimen was chosen, two other management issues became important in the care of this patient. Should he receive an autologous or allogeneic stem-cell or bone marrow transplant? Should he receive radiation therapy to the testes? In general, for adult patients with acute lymphoblastic leukemia who have a high risk of relapse, transplantation is undertaken during the first remission. The age of the patient, the presence or absence of cytogenetic abnormalities, and availability of a donor all affect this decision. For example, in patients with acute lymphoblastic leukemia that is positive for the Philadelphia chromosome (and hence BCR-ABL), the risk of treatment failure is high; the survival rate with standard chemotherapy is less than 10 percent. For these patients, allogeneic transplantation would be recommended during the first remission if they are less than 60 years of age, are clinically well, and have a matched related or unrelated donor.14
There have been few reports of transplantation specifically to treat patients with lymphoblastic lymphoma. The International Bone Marrow Transplant Registry, a voluntary working group of more than 350 transplantation centers worldwide, recently published a retrospective study of autologous and allogeneic stem-cell transplantation for lymphoblastic lymphoma.15 Seventy-six patients received an allogeneic transplant from an HLA-matched sibling. The treatment-related mortality rate was 18 percent, the relapse rate 34 percent, and the five-year disease-free survival rate 36 percent. One hundred twenty-eight patients underwent autologous stem-cell transplantation. As expected, the treatment-related mortality rate (3 percent) was lower than that associated with allogeneic transplantation. The relapse rate was 56 percent, and the five-year disease-free survival rate was 39 percent.
The decision to proceed with transplantation during the first remission in this patient was controversial. The patient and his family were tested to determine their HLA type, and his sister was found to be an HLA-identical match. The large bulk of the disease, its manifestation in the testes, and the fact that he was an adult all suggested a high risk of recurrence. However, a 15 to 20 percent mortality rate related to transplantation was of obvious concern. We recommended that he seek a second opinion, which he did; the consultant also favored proceeding with transplantation after the first three months of chemotherapy.
The use of scrotal irradiation is also controversial in a situation such as this one. There is concern that systemic agents may not treat the testes effectively, so that irradiation may be needed as an adjuvant.16 However, testicular irradiation is associated with the loss of endocrine gonadal function. Some trials of acute lymphoblastic leukemia have demonstrated that if methotrexate is given in doses greater than 500 mg per square meter, the risk of testicular recurrence is low.12,17 In this case, a boost of radiation to the testis of 18 Gy was given after the transplantation, for a total dose to the testis of 31.2 Gy.
The patient completed three months of chemotherapy according to the regimen in Table 1, with the addition of two doses of high-dose, intravenous methotrexate, one dose during induction and the other during the intensification phase. The chemotherapy was tolerated well, and the testicular swelling improved dramatically within the first week of therapy. He subsequently received an allogeneic stem-cell transplant from his HLA-matched sister, after a pretransplantation conditioning regimen that included total-body irradiation to a dose of 13.2 Gy in twice-daily fractions over a period of four days and 60 mg of cyclophosphamide per kilogram on two successive days. He experienced transient skin erythema and mucositis; by day 16 after the transplantation, his absolute neutrophil count was greater than 0.5 per cubic millimeter and he was discharged on the 20th day after the transplantation. Six months after the allograft procedure (11 months after the diagnosis), he has had no graft-versus-host disease, recurrence of lymphoma, or serious infections, and he is feeling well.
In summary, this patient had an unusual manifestation of an unusual neoplasm: precursor B-cell lymphoblastic lymphoma primarily involving the testes. Because of the rarity of this clinical scenario, treatment recommendations were not straightforward. Applying the principles derived from experience with the treatment of acute lymphoblastic leukemia in adults as well as experience with the management of testicular lymphoma, we devised a regimen that resulted in complete resolution of his lymphoma and that offers a good possibility of long-term survival.
Presented at the Multidisciplinary Leukemia Conference at Massachusetts General Hospital.
Source Information
From the Division of Hematology and Oncology (K.K.B.) and the Department of Pathology (R.P.H.), Massachusetts General Hospital; and the Departments of Medicine (K.K.B.) and Pathology (R.P.H.), Harvard Medical School.
References
Armstrong L, Jenkins S. It's not about the bike: my journey back to life. New York:Putnam, 2000.
Thrasher J, Frazier H. Non-germ cell testicular tumors. Prob Urol 1994;8:167-85.
Shahab N, Doll DC. Testicular lymphoma. Semin Oncol 1999;26:259-269.
Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. Vol. 3 of World Health Organization classification of tumours. Lyon, France: IARC Press, 2001.
Lin P, Jones D, Dorfman DM, Medeiros LJ. Precursor B-cell lymphoblastic lymphoma: a predominantly extranodal tumor with low propensity for leukemic involvement. Am J Surg Pathol 2000;24:1480-1490.
Ferry JA, Harris NL, Young RH, Coen J, Zietman A, Scully RE. Malignant lymphoma of the testis, epididymis, and spermatic cord: a clinicopathologic study of 69 cases with immunophenotypic analysis. Am J Surg Pathol 1994;18:376-390.
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;21:20-27.
Hoelzer D, Gokbuget N, Digel W, et al. Outcome of adult patients with T lymphoblastic lymphoma treated according to protocols for acute lymphoblastic leukemia. Blood 2002;99:4379-4385.
Kantarjian HM, O'Brien S, Smith TL, et al. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol 2000;18:547-661.
Larson RA, Dodge RK, Burns CP, et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood 1995;85:2025-2037.
Larson RA, Dodge RK, Linker CA, et al. A randomized trial of filgastrim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111. Blood 1998;92:1556-1564.
Tiedemann J, Chessells JM, Sandland RM. Isolated testicular relapse in boys with acute lymphoblastic leukaemia: treatment and outcome. Br Med J (Clin Res Ed) 1992;285:1614-1616.
Dalle JH, Mechinaud F, Michon J, et al. Testicular disease in childhood B-cell non-Hodgkin's lymphoma: the French Society of Pediatric Oncology experience. J Clin Oncol 2001;19:2397-2403.
Stirewalt DL, Guthrie KA, Beppu L, et al. Predictors of relapse and overall survival in Philadelphia chromosome-positive acute lymphoblastic leukemia after transplantation. Biol Blood Marrow Transplant 2003;9:206-212.
Levine JE, Harris RE, Loberiza FR Jr, et al. A comparison of allogeneic and autologous bone marrow transplantation for lymphoblastic lymphoma. Blood 2003;101:2476-2482.
Lal A, Kwan E, al Mahr M, et al. Molecular detection of acute lymphoblastic leukaemia in boys with testicular relapse. Mol Pathol 1998;51:277-281.
Millot F, Suciu S, Philippe N, et al. Value of high-dose cytarabine during interval therapy of a Berlin-Frankfurt-Munster-based protocol in increased-risk children with acute lymphoblastic leukemia and lymphoblastic lymphoma: results of the European Organization for Research and Treatment of Cancer 58881 randomized phase III trial. J Clin Oncol 2001;19:1935-1942.
Related Letters:
Case 15-2004: Cancer Therapy and Sperm Banking
Amory J. K., Ballen K. K., Hasserjian R. P.
Presentation of Case
A 31-year-old man was admitted to the hospital because of a testicular mass.
The patient had been well until three months before admission, when he noted bilateral testicular swelling that coincided with a two-week illness characterized by fever and cough. When the fever and cough resolved, the testicular swelling appeared to improve. One month later, while on a cruise, the patient had an upper respiratory tract infection associated with fever and cough, and again noted enlargement of his testes. He read It's Not about the Bike, by Lance Armstrong1 while on the cruise, and became concerned about testicular cancer. Again, he believed that the testicular enlargement improved but that it did not go away completely when the fever and cough resolved.
Two weeks before admission, he saw his physician because he was concerned about the persistent testicular swelling. An ultrasound examination performed at another institution confirmed the presence of diffuse bilateral testicular enlargement, with a heterogeneous pattern and hypoechoic areas. Computed tomographic (CT) images of the head, chest, abdomen, and pelvis, also obtained at the other institution, were reported to be normal. Tests for the subunit of human chorionic gonadotropin and for alpha-fetoprotein were negative. He was referred to a urologist at this hospital.
The patient had been well except for a hospitalization at the age of 10 years for gastroenteritis. The results of a test for the human immunodeficiency virus performed three years previously had been negative. He said that he did not have fatigue, fever, chills, change in appetite, headache, swollen glands, cough, chest pain, abdominal pain, or bleeding, and he did not have difficulty with urination or erectile function. He had experienced intermittent night sweats for the previous two weeks and had lost 10 lb (4.5 kg) through dieting. One of his five sisters had a history of thyroid cancer, which had been treated with radioactive iodine; the other siblings were well. Both parents were living; his mother had coronary artery disease and had undergone coronary-artery bypass grafting at the age of 49 years. He lived with his parents and had a steady girlfriend. He worked as an accountant. There was no history of foreign travel, transfusions, or alcohol, tobacco, or intravenous-drug use. He was taking no medications.
On physical examination, he appeared well, and the vital signs were normal. There was no palpable supraclavicular, cervical, axillary, or inguinal lymphadenopathy. The lungs were clear. The cardiac examination revealed no murmurs. There was no gynecomastia. The abdomen was normal, and the liver and spleen were not palpable. Both testes were markedly enlarged and firm, without discrete masses; the left testis was 14 cm in diameter and the right testis 12 cm in diameter. The neurologic examination revealed no abnormalities. Magnetic resonance imaging (MRI) of the pelvis revealed a rounded, left periaortic lymph node, 1.2 cm in diameter, and a rounded, left renal hilar lymph node, 1.3 cm in diameter, both of which were partially heterogeneously enhancing, and a nonenhancing, precaval lymph node, 0.8 cm in diameter.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Karen K. Ballen: Although I am aware of the diagnosis in this case, the patient's clinical presentation provides an opportunity to discuss the approach to the differential diagnosis of testicular enlargement. The causes of testicular enlargement in a young man include infectious and neoplastic processes. Infectious orchitis or epididymitis, or a combination of the two, is more common than cancer. Acute epididymitis is usually unilateral. In young, sexually active men, acute epididymitis is most often caused by infection with chlamydia or Neisseria gonorrhoeae. In older men, acute epididymitis is more likely to be caused by urinary pathogens. A trial of antibiotics is often used, and bed rest and scrotal elevation may also help with the swelling. The bilateral swelling and the absence of fever make epididymitis less likely in this case.
Testicular torsion is diagnosed less frequently than epididymitis; it usually occurs in young men and is associated with the sudden onset of acute testicular pain and swelling. The testicle is elevated and there is absence of blood flow on Doppler examination. Torsion is a surgical emergency. The fact that the swelling in this case is persistent and is associated with only mild pain makes testicular torsion unlikely.
A variety of neoplastic lesions can involve the testes. The most common are the germ-cell tumors, which include seminoma, embryonal carcinoma, teratoma, yolk-sac tumor, and choriocarcinoma. Germ-cell tumors are the most common solid tumor in men between the ages of 20 and 35 years. Seminomas represent 50 percent of all germ-cell tumors and usually occur in men in their 30s. Nonseminomatous germ-cell tumors most frequently occur in the third decade of life. Germ-cell tumors are more common in white men than in men of other races and are more common in men with a history of cryptorchidism. The patient may present with a painless testicular mass. However, more common symptoms on presentation are diffuse testicular pain and swelling or firmness (or both). Ultrasonographic examination shows an intratesticular hypoechoic mass or diffuse calcifications. Early diagnosis is important, since a delay in diagnosis can allow the tumor to spread and thus render it less curable. Germ-cell tumor would be high in the differential diagnosis in this situation.
Leydig-cell tumors account for 2 percent of testicular tumors. Patients may present with a palpable mass or testicular swelling, similar to the features of germ-cell tumors. Some patients have associated gynecomastia or decreased libido. Twenty-five percent of cases are seen in children and may be associated with early sexual development. In the current case, there were no associated findings, such as decreased libido or gynecomastia, to suggest a Leydig-cell tumor.
Sertoli-cell tumors represent less than 1 percent of primary testicular tumors. Patients with Sertoli-cell tumors may also present with a painless, enlarging mass. These tumors occur in boys and may be associated with feminization. There is an association between Sertoli-cell tumors and pituitary adenoma, hyperpigmented skin, and mucosal lesions.2
Rare tumors of the testes include mesothelioma, sarcoma, and adenocarcinoma of the collecting system of the testis. Metastatic cancer manifesting as a testicular mass is also rare. The possible primary sites include the prostate, lung, melanoma, and kidney. Patients usually present with diffuse systemic disease, and the involvement is more likely to be unilateral than bilateral. There is no suggestion of another primary site in this patient.
Primary testicular lymphoma is rare, accounting for 2 percent of all non-Hodgkin's lymphomas, with an incidence of 0.26 per 100,000 people per year.3 Lymphomas represent 2 to 5 percent of all testicular cancers, but are the most common testicular cancer in men older than 50 years of age. They can also occur in younger men. Ninety percent of testicular lymphomas are diffuse large-B-cell lymphomas. Painless testicular swelling is common, and 30 percent of patients have bilateral involvement. About half the patients also have weight loss, fever, or night sweats. In the case under discussion, the bilateral swelling, the recent weight loss, and the night sweats support the diagnosis of lymphoma. Testicular involvement by diffuse large-B-cell lymphoma, as compared with nodal lymphoma and extranodal lymphomas of other sites, is associated with an increased risk of bone marrow and central nervous system involvement.3
The diagnostic procedure of choice in this situation is a testicular biopsy with intraoperative examination of a frozen section and triage of tissue for appropriate diagnostic studies, such as immunophenotyping and cytogenetic analysis.
Clinical Diagnosis
Primary testicular lymphoma, probably diffuse large-B-cell lymphoma.
Pathological Discussion
Dr. Robert P. Hasserjian: Dr. Alex Althausen, of the Department of Urology, performed a transinguinal biopsy of the left testis, and the specimen was sent for frozen-section examination. A preliminary diagnosis of lymphoma was made, and additional tissue was requested for flow-cytometric and cytogenetic analyses. Microscopical examination of permanent sections revealed a dense lymphoid infiltrate, which caused expansion of the interstitium and surrounded, but did not infiltrate, the seminiferous tubules (Figure 1A). The lymphoid cells were slightly larger than small lymphocytes and had finely dispersed chromatin, markedly irregular nuclear contours, and very scant cytoplasm — histologic features typically associated with immature lymphoid cells known as lymphoblasts (Figure 1B). Numerous mitotic figures were present (Figure 1C). Immunophenotyping of disaggregated cells by flow cytometry revealed a predominant population of cells expressing the B-cell marker CD19, as well as CD10, but lacking CD20. Surface immunoglobulin was not detected. Immunohistochemical studies on tissue sections showed that the cells expressed terminal deoxynucleotidyl transferase, a nuclear enzyme expressed in lymphoid precursor cells (Figure 1D). This constellation of findings confirmed the diagnosis of precursor B-cell lymphoblastic lymphoma. Conventional cytogenetic analysis of the biopsy specimen was unsuccessful. Fluorescence in situ hybridization studies were negative for the BCR-ABL fusion gene and for MLL gene rearrangement, genetic mutations that are associated with an unfavorable prognosis in precursor B-cell lymphoblastic neoplasms.
Figure 1. Biopsy Specimen of the Testis.
There is expansion of the interstitium (Panel A) by diffuse sheets of lymphoid cells, which surround but do not infiltrate the seminiferous tubules (hematoxylin and eosin, x504). The neoplastic lymphoid cells are somewhat larger than a small, mature lymphocyte (Panel B, arrow; hematoxylin and eosin, x250) and have markedly irregular nuclei and finely dispersed chromatin with mitotic activity (Panel C; hematoxylin and eosin, x1200). The neoplastic cells show nuclear immunoreactivity for antibody to terminal deoxynucleotidyl transferase as indicated by brown nuclear staining superimposed on the blue hematoxylin counterstain (Panel D); scattered, smaller mature lymphocytes are negative (immunoperoxidase stain, x500).
The current World Health Organization classification system divides T-cell and B-cell lymphomas into precursor and mature neoplasms.4 The former are characterized by an immature stage of lymphoid differentiation resembling that of normal B-cell and T-cell precursors in the bone marrow and thymus, respectively. Precursor B-cell and T-cell lymphoblastic neoplasms may manifest as predominantly mass-forming tumors or as leukemic processes involving the blood and bone marrow. These neoplasms are conventionally called lymphomas if the patient presents with an extramedullary mass lesion with no or minimal peripheral-blood involvement and involvement of less than 25 percent of the bone marrow space. Approximately 90 percent of lymphoblastic lymphomas are of T-cell lineage; a common manifestation of precursor T-cell lymphoblastic lymphoma is a large mediastinal mass and supradiaphragmatic lymphadenopathy in an adolescent or young adult.
In contrast, precursor B-cell lymphoblastic neoplasms constitute 90 percent of acute lymphoblastic leukemias, and manifestation as lymphoma is much less common, typically in extranodal sites such as the skin, bone, and soft tissue.5 Although the testis is a common site of relapse in patients treated for precursor B-cell acute lymphoblastic leukemia, it is a very rare manifestation of precursor B-cell lymphoblastic lymphoma; no cases were identified in a recent series of 64 primary testicular lymphomas.6
Examination of bone marrow and peripheral blood from the patient under discussion revealed no neoplastic lymphoblasts, and cytologic and flow-cytometric studies of the cerebrospinal fluid were also negative for lymphomatous involvement.
Pathological Diagnosis
Precursor B-cell lymphoblastic lymphoma.
Discussion of Management
Dr. Ballen: The pathologist provided valuable guidance to the clinical team by calling us to report the diagnosis, thereby expediting the patient's consultation and treatment. We saw the patient in the clinic one week after the biopsy and admitted him to the hospital for further staging of the disease and for treatment. Staging studies in patients with testicular lymphoma include bone marrow analysis, lumbar puncture with cerebrospinal fluid analysis, and CT scans of the chest, abdomen, and pelvis.3 Repeated CT scanning of the chest and abdomen confirmed the presence of two slightly enlarged abdominal lymph nodes. CT and MRI scanning of the brain revealed no metastatic disease. Lumbar puncture and evaluation of the cerebrospinal fluid by cytopathology and flow cytometry revealed no evidence of lymphoma. According to the Ann Arbor staging system for extranodal lymphoma, this patient's disease would fall into stage IIE (in which there is involvement of an extranodal site and regional lymph nodes).
Large-B-cell lymphoma is by far the most common lymphoma of the testis. The prognosis for patients with this lymphoma is worse than that for patients with large-cell lymphomas at other sites. In a survey of 393 patients from several international centers, the long-term, disease-free survival rate was only 25 percent.7 Seventy-two percent of patients who had a recurrence had disease in extranodal sites, including the contralateral testis, the central nervous system, and bone. Treatment with an anthracycline-based regimen such as a regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone and the use of prophylactic intrathecal therapy and scrotal irradiation were associated with a longer survival in the multivariate analysis.
Lymphoblastic lymphoma is more common in children than in adults, and testicular involvement typically occurs in the setting of acute leukemia. A retrospective review of 25 patients with precursor B-cell lymphoblastic lymphoma revealed that their median age was 20 years (range, 5 to 68).5 Pain was the most common symptom on presentation. The most common sites of primary disease were skin, bone, and soft tissue. Survival data were available for 14 patients, who had been treated with a variety of chemotherapy regimens, with a follow-up that ranged from 6 to 144 months. Of the 14, 9 had complete remission of disease, 1 had relapsed disease, and 4 died.
Treatment regimens for lymphoblastic lymphoma have evolved over the years to include intensive induction therapy, maintenance therapy, and prophylaxis against central nervous system complications with regimens similar or identical to those used to treat acute lymphoblastic leukemia. Results improved when patients were treated with regimens designed for acute leukemia, rather than with the less intensive regimens designed for lymphoma.8 The M.D. Anderson Cancer Center has developed a regimen of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) for adult patients with acute lymphoblastic leukemia.9 This regimen includes a dose-intensive phase and a maintenance phase. The dose-intensive phase consisted of eight cycles of chemotherapy: four cycles of cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with four cycles of high-dose methotrexate and cytarabine. All the patients received central nervous system prophylaxis. The maintenance phase consisted of two years of chemotherapy with mercaptopurine, methotrexate, vincristine, and prednisone. All the patients received prophylactic treatment with antibiotic and antiviral agents. Ninety-one percent of 204 patients achieved complete remission; 6 percent died of infections during remission induction, and 3 percent had resistant disease. However, the relapse rate was high, and the five-year survival rate was 39 percent. Patients under 20 years of age, as expected, did better than older patients.
The Cancer and Leukemia Group B has been studying various regimens of combination chemotherapy for the treatment of adult acute lymphoblastic leukemia. The basic principle of treatment calls for high-intensity, multiple-drug induction regimens, prophylaxis against central nervous system complications, and prolonged maintenance treatment for 24 months. Another study used an induction regimen of cyclophosphamide, daunorubicin, vincristine, prednisone, and asparaginase.10 Eighty-five percent of the patients had a complete remission, and 9 percent died during induction. The patients then received intensification therapy consisting of intrathecal methotrexate, cranial irradiation, cyclophosphamide, mercaptopurine, cytarabine, vincristine, asparaginase, doxorubicin, dexamethasone, and thioguanine. Maintenance therapy with vincristine, prednisone, mercaptopurine, and methotrexate continued for two years after the start of therapy. The three-year disease-free survival rate was 43 percent and was not changed by the use of growth factors.11 The scheme for this complex treatment regimen, most of which is given in the outpatient setting, is outlined in Table 1.
Table 1. Cancer and Leukemia Group B Treatment Regimen for Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma for Patients Less Than 60 Years of Age.
We chose the Cancer and Leukemia Group B treatment regimen for this patient because of the reports of favorable results and because of our familiarity with this regimen and its side effects. We were concerned that the testis is a sanctuary site of disease that systemic therapy may not treat effectively. Some studies of acute lymphoblastic leukemia in children have demonstrated that high-dose, intravenous methotrexate may reduce testicular recurrence.12 Because of this reported advantage, high-dose, intravenous methotrexate has been added to pediatric treatment regimens for lymphoma with testicular involvement,13 and for this reason, intravenous methotrexate at a dose of 4 g per square meter of body-surface area was added to the induction and intensification phases for this patient.
After the initial chemotherapy regimen was chosen, two other management issues became important in the care of this patient. Should he receive an autologous or allogeneic stem-cell or bone marrow transplant? Should he receive radiation therapy to the testes? In general, for adult patients with acute lymphoblastic leukemia who have a high risk of relapse, transplantation is undertaken during the first remission. The age of the patient, the presence or absence of cytogenetic abnormalities, and availability of a donor all affect this decision. For example, in patients with acute lymphoblastic leukemia that is positive for the Philadelphia chromosome (and hence BCR-ABL), the risk of treatment failure is high; the survival rate with standard chemotherapy is less than 10 percent. For these patients, allogeneic transplantation would be recommended during the first remission if they are less than 60 years of age, are clinically well, and have a matched related or unrelated donor.14
There have been few reports of transplantation specifically to treat patients with lymphoblastic lymphoma. The International Bone Marrow Transplant Registry, a voluntary working group of more than 350 transplantation centers worldwide, recently published a retrospective study of autologous and allogeneic stem-cell transplantation for lymphoblastic lymphoma.15 Seventy-six patients received an allogeneic transplant from an HLA-matched sibling. The treatment-related mortality rate was 18 percent, the relapse rate 34 percent, and the five-year disease-free survival rate 36 percent. One hundred twenty-eight patients underwent autologous stem-cell transplantation. As expected, the treatment-related mortality rate (3 percent) was lower than that associated with allogeneic transplantation. The relapse rate was 56 percent, and the five-year disease-free survival rate was 39 percent.
The decision to proceed with transplantation during the first remission in this patient was controversial. The patient and his family were tested to determine their HLA type, and his sister was found to be an HLA-identical match. The large bulk of the disease, its manifestation in the testes, and the fact that he was an adult all suggested a high risk of recurrence. However, a 15 to 20 percent mortality rate related to transplantation was of obvious concern. We recommended that he seek a second opinion, which he did; the consultant also favored proceeding with transplantation after the first three months of chemotherapy.
The use of scrotal irradiation is also controversial in a situation such as this one. There is concern that systemic agents may not treat the testes effectively, so that irradiation may be needed as an adjuvant.16 However, testicular irradiation is associated with the loss of endocrine gonadal function. Some trials of acute lymphoblastic leukemia have demonstrated that if methotrexate is given in doses greater than 500 mg per square meter, the risk of testicular recurrence is low.12,17 In this case, a boost of radiation to the testis of 18 Gy was given after the transplantation, for a total dose to the testis of 31.2 Gy.
The patient completed three months of chemotherapy according to the regimen in Table 1, with the addition of two doses of high-dose, intravenous methotrexate, one dose during induction and the other during the intensification phase. The chemotherapy was tolerated well, and the testicular swelling improved dramatically within the first week of therapy. He subsequently received an allogeneic stem-cell transplant from his HLA-matched sister, after a pretransplantation conditioning regimen that included total-body irradiation to a dose of 13.2 Gy in twice-daily fractions over a period of four days and 60 mg of cyclophosphamide per kilogram on two successive days. He experienced transient skin erythema and mucositis; by day 16 after the transplantation, his absolute neutrophil count was greater than 0.5 per cubic millimeter and he was discharged on the 20th day after the transplantation. Six months after the allograft procedure (11 months after the diagnosis), he has had no graft-versus-host disease, recurrence of lymphoma, or serious infections, and he is feeling well.
In summary, this patient had an unusual manifestation of an unusual neoplasm: precursor B-cell lymphoblastic lymphoma primarily involving the testes. Because of the rarity of this clinical scenario, treatment recommendations were not straightforward. Applying the principles derived from experience with the treatment of acute lymphoblastic leukemia in adults as well as experience with the management of testicular lymphoma, we devised a regimen that resulted in complete resolution of his lymphoma and that offers a good possibility of long-term survival.
Presented at the Multidisciplinary Leukemia Conference at Massachusetts General Hospital.
Source Information
From the Division of Hematology and Oncology (K.K.B.) and the Department of Pathology (R.P.H.), Massachusetts General Hospital; and the Departments of Medicine (K.K.B.) and Pathology (R.P.H.), Harvard Medical School.
References
Armstrong L, Jenkins S. It's not about the bike: my journey back to life. New York:Putnam, 2000.
Thrasher J, Frazier H. Non-germ cell testicular tumors. Prob Urol 1994;8:167-85.
Shahab N, Doll DC. Testicular lymphoma. Semin Oncol 1999;26:259-269.
Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. Vol. 3 of World Health Organization classification of tumours. Lyon, France: IARC Press, 2001.
Lin P, Jones D, Dorfman DM, Medeiros LJ. Precursor B-cell lymphoblastic lymphoma: a predominantly extranodal tumor with low propensity for leukemic involvement. Am J Surg Pathol 2000;24:1480-1490.
Ferry JA, Harris NL, Young RH, Coen J, Zietman A, Scully RE. Malignant lymphoma of the testis, epididymis, and spermatic cord: a clinicopathologic study of 69 cases with immunophenotypic analysis. Am J Surg Pathol 1994;18:376-390.
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;21:20-27.
Hoelzer D, Gokbuget N, Digel W, et al. Outcome of adult patients with T lymphoblastic lymphoma treated according to protocols for acute lymphoblastic leukemia. Blood 2002;99:4379-4385.
Kantarjian HM, O'Brien S, Smith TL, et al. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol 2000;18:547-661.
Larson RA, Dodge RK, Burns CP, et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood 1995;85:2025-2037.
Larson RA, Dodge RK, Linker CA, et al. A randomized trial of filgastrim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111. Blood 1998;92:1556-1564.
Tiedemann J, Chessells JM, Sandland RM. Isolated testicular relapse in boys with acute lymphoblastic leukaemia: treatment and outcome. Br Med J (Clin Res Ed) 1992;285:1614-1616.
Dalle JH, Mechinaud F, Michon J, et al. Testicular disease in childhood B-cell non-Hodgkin's lymphoma: the French Society of Pediatric Oncology experience. J Clin Oncol 2001;19:2397-2403.
Stirewalt DL, Guthrie KA, Beppu L, et al. Predictors of relapse and overall survival in Philadelphia chromosome-positive acute lymphoblastic leukemia after transplantation. Biol Blood Marrow Transplant 2003;9:206-212.
Levine JE, Harris RE, Loberiza FR Jr, et al. A comparison of allogeneic and autologous bone marrow transplantation for lymphoblastic lymphoma. Blood 2003;101:2476-2482.
Lal A, Kwan E, al Mahr M, et al. Molecular detection of acute lymphoblastic leukaemia in boys with testicular relapse. Mol Pathol 1998;51:277-281.
Millot F, Suciu S, Philippe N, et al. Value of high-dose cytarabine during interval therapy of a Berlin-Frankfurt-Munster-based protocol in increased-risk children with acute lymphoblastic leukemia and lymphoblastic lymphoma: results of the European Organization for Research and Treatment of Cancer 58881 randomized phase III trial. J Clin Oncol 2001;19:1935-1942.
Related Letters:
Case 15-2004: Cancer Therapy and Sperm Banking
Amory J. K., Ballen K. K., Hasserjian R. P.