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Primary Follicular Large Cell Lymphoma of the Testis in a Child.

Malignant lymphoma of follicle center origin is one of the most common types of non-Hodgkin lymphoma (NHL) in the United States. It accounts for approximately 20% to 30% of cases of NHL in adults, predominantly in middle and older age groups. Follicular lymphomas have been observed infrequently in children as young as 3 years.[1-5] Although the testis is a common site for secondary involvement by NHL in adults and children, it is an unusual primary site. Primary follicular lymphoma of the testis in childhood is extremely rare. To our knowledge, only 5 cases have been reported in the literature to date, 4 with molecular genetic analysis.[6,7] In these studies, none of the 4 cases evaluated expressed BCL-2 or had evidence of bcl-2 gene rearrangement. However, BCL-6 was expressed in all 3 cases studied, and bcl-6 gene rearrangement was found in the one case evaluated by Southern blot analysis.[7] Herein, we report another case of primary follicular large cell lymphoma in a 6-year-old boy.


Immunohistochemical stains were performed on fixed, paraffin-embedded tissue sections using the avidin-biotin-peroxidase complex technique and an automated immunostainer (Ventana-Biotech, Tucson, Ariz). The antibodies were specific for CD45RB (1:40, leukocyte common antigen, Dako Corporation, Carpinteria, Calif), CD20 (1:200, L26, Dako), CD79a (1:25, Dako), CD3 (1:100, Dako), CD5 (1:25, Novocastra, Newcastle-upon-Tyne, England), CD45RO (1:100, UCHL-1, Dako), CD10 (1:70, Novocastra), CD21 (1:15, Dako), BCL-2 (1:50, BioGenex, San Ramon, Calif), BCL-6 (1:10, Dako), and p53 (1:50, BioGenex). Heat-induced epitope retrieval was used for all antibodies except UCHL-1.

Evaluation for the t(14;18) translocation involving either the major or minor breakpoint cluster regions of the bcl-2 gene was performed by polymerase chain reaction on DNA obtained from formalin-fixed, paraffin-embedded sections using commercially available reagents (Gentra Systems, Minneapolis, Minn; Perkin-Elmer Cetus, Norwalk, Conn). The procedure has been described previously.[8] The sensitivity of this assay in our laboratory using a control cell line is at least 1 in [10.sup.4] cells. The quality of DNA was confirmed by a [Beta]-globin internal control.


Clinical Findings

A 6-year-old African American boy was found to have painless enlargement of the right testis. The child had no fever, night sweats, weight loss, peripheral lymphadenopathy, or hepatosplenomegaly. His growth and development were normal, and he had no clinical evidence of immunodeficiency. The family history was negative for malignancy. Ultrasound of the scrotum showed an enlarged right testis with a focal hypoechoic mass. The left testis was normal. The results of chest radiograph, computed tomographic scan of the chest and abdomen, and bone scan were unremarkable. The complete blood cell count was normal for age, and bone marrow examination showed no evidence of malignant lymphoma. The patient underwent right radical orchiectomy and right inguinal lymph node biopsy. The testis was involved by follicular large cell lymphoma with diffuse areas. The clinical stage was IE. He received treatment with multiagent chemotherapy that consisted of vincristine, doxorubicin, cyclophosphamide, and prednisone. The child has remained disease free for 7 months since the completion of chemotherapy.

Pathologic Findings

The specimen consisted of right testis (3.2 cm in greatest dimension), epididymis, spermatic cord, and inguinal lymph node. The testicular parenchyma was replaced by a fleshy, white, poorly demarcated mass that was 3.0 cm in greatest dimension. The mass appeared to involve the epididymis but not the spermatic cord. The lymph node appeared unremarkable.

On histologic examination, the normal testicular parenchyma was largely replaced by neoplastic lymphoid cells (Figure, A and B). In less involved areas, the neoplastic cells infiltrated between seminiferous tubules. The tubules that were spared were immature and without spermatogenesis. Aggregates of stromal Leydig cells were absent. The neoplastic cells infiltrated the tunica albuginea, rete testis, and epididymis but did not involve the spermatic cord. Vascular invasion was not seen. Although much of the neoplasm displayed a vaguely nodular to diffuse growth pattern, areas with an unequivocal follicular pattern, particularly within the rete testis, were conspicuous. The neoplastic follicles were relatively uniform in size and shape and lacked mantle zones. In both the follicular and diffuse areas, the neoplasm was predominantly composed of large noncleaved cells with occasional large cleaved cells. The cells had vesicular chromatin, one to several small nucleoli, and discernible cytoplasm. Mitotic figures were easily found. A low-grade follicular component was not identified. The neoplasm was classified as malignant lymphoma, follicular, large cell type (grade III) with diffuse areas. A right inguinal lymph node showed reactive follicular hyperplasia and sinus histiocytosis but no evidence of malignant lymphoma.


Immunohistochemical stains performed on fixed, paraffin-embedded tissue sections demonstrated that the neoplastic cells strongly expressed CD45RB and markers of B-cell differentiation (CD20 and CD79a) (data not shown). Antibody to CD21 demonstrated organized clusters of dendritic reticulum cells that corresponded to areas that were unequivocally follicular and accentuated the follicular growth pattern in areas that appeared vaguely nodular on hematoxylin-eosin stain (Figure, C). The neoplastic cells also expressed BCL-6 (Figure, D) and CD10 (data not shown), antigens that are expressed by follicle center cells. Staining for CD3, CD5, CD45RO, BCL-2, and p53 was negative (data not shown).


No evidence of the t(14;18) translocation involving either the major or minor breakpoint cluster regions of the bcl-2 gene was identified by polymerase chain reaction methods (data not shown).


Non-Hodgkin lymphoma can involve the testis as true primary extranodal disease, as the primary site of presentation of clinically occult nodal disease, or as the result of disseminated disease. The testis is often involved by disseminated nodal NHL, especially high-grade NHL, in both adult and pediatric populations.[9-11] Primary testicular lymphoma is rare and has been defined by long-term survival in patients treated by ablative surgery alone.[12] Involvement of the testis as the primary presentation of NHL is uncommon and accounts for only 1% of all cases of NHL.[11] In most of these cases, testicular involvement is the initial manifestation of clinically occult nodal disease rather than true primary extranodal disease.

Although testicular lymphoma is uncommon, it is the most common testicular neoplasm in men older than 60 years.[13] In several large series, most testicular lymphomas in adults, both primary and disseminated, have shown a diffuse growth pattern. Diffuse, large noncleaved cell lymphoma is the most common subtype, followed by large cell immunoblastic and large cleaved cell types.[12,14-16] Only rare cases of follicular lymphoma or diffuse lymphoma with follicular areas have been described.[15,17] This observation is somewhat surprising, since follicular lymphoma is one of the most common NHL in adults.

Follicular lymphoma in children is rare. Its incidence is about 1.2% to 2.5% of all childhood NHL.[1,4,5] Most patients are boys, and most, particularly those younger than 10 years, present with low-stage disease.[1-5] Commonly involved sites are tonsils and cervical and inguinal lymph nodes. Advanced stage disease with extranodal involvement at presentation is uncommon and appears to be associated with a poor prognosis.[2] Pinto and coworkers[3] reported the largest series of children (20 children) with follicular lymphoma. In this study, the histologic subtype was predominantly small cleaved cell in 30%, mixed small cleaved and large cell in 25%, and predominantly large cell in 45% of cases. In another study of 12 children, by Winberg and coworkers,[2] the histologic subtype in 8 cases was predominantly small cleaved cell and in 4 cases was predominantly large cell. In contrast to adults, children with follicular lymphoma usually achieve complete remissions, and progression to high-grade lymphoma is unusual.[1-5] The long-term prognosis in children is generally excellent, and conservative management is justified for children with localized disease.[5]

Primary testicular lymphoma is extremely rare in the pediatric population, with most cases reported as case reports.[18-23] Including our report, to our knowledge, 6 cases of primary follicular lymphoma of the testis in boys have been reported since 1995. The clinical and histologic findings are summarized in the Table. Histologically, all neoplasms were of follicular large cell type. The present case and 1 of 4 cases reported by Finn and coworkers[7] also had a significant diffuse component. The 6 boys ranged in age from 3 to 10 years, with a median age of 5.5 years. All had clinical stage IE disease. All underwent orchiectomy, and 5 received chemotherapy. All were free of disease following therapy at follow-ups from 7 to 24 months.
Primary Follicular Large Cell Lymphoma of the Testis in Childhood(*)

Source, y Age, y Side Diagnosis

Moertel et al,[6] 1995 8 Left F, L
Finn et al,[7] 1999 3 Left F&D, L
 3 Right F, L
 10 Left F, L
 5 Right F, L
Current case 6 Right F&D, L

Source, y Age, y Size, cm Therapy Follow-up

Moertel et al,[6] 1995 8 2 OR NED, 14 mo
Finn et al,[7] 1999 3 2.8 OR, CX NED, 18 mo
 3 2.3 OR, CX NED, 18 mo
 10 4 OR, CX NED, 19 mo
 5 4 OR, CX NED, 24 mo
Current case 6 3 OR, CX NED, 7 mo

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

The pathogenesis of follicular lymphoma of the testis in childhood is unknown. The evidence suggests that it results from the neoplastic transformation of a follicle center cell but that its pathogenesis differs from that of follicular lymphomas that arise in adults. Most cases of follicular lymphomas that arise in adults are predominantly composed of small cleaved cells. More than 85% of cases contain a characteristic translocation, t(14;18)(q32;q21).[24] This translocation results in the overexpression of a structurally normal BCL-2 protein that inhibits apoptosis. In contrast, all 6 cases of childhood follicular lymphoma of the testis reported to date have been composed of large cells; none have contained a component of small cleaved cells. None of the cases of follicular lymphoma of the testis in childhood have contained evidence of bcl-2 gene rearrangement or the t(14;18) or expressed BCL-2 protein. This finding is similar to follicular lymphoma in other sites in children. Atra and coworkers[5] reported a series of 7 children with follicular lymphoma. They found that 3 of 4 cases studied for expression of BCL-2 protein by immunohistochemistry were negative; one case was weakly positive. One additional case studied for bcl-2 rearrangement by polymerase chain reaction was negative. Follicular large cell lymphomas in adults also often express p53 protein.[25] None of the cases of follicular lymphoma of the testis in childhood have been positive for p53 protein.

Despite these differences, several findings indicate that follicular lymphoma of the testis in childhood is of follicle center cell origin. First, it has a follicular growth pattern with a network of follicular dendritic reticulum cells. Second, it expresses BCL-6 protein. The bcl-6 gene, located at chromosome 3q27, encodes a Kruppel-type zinc finger transcription factor that is expressed selectively by follicle center cells and appears to be important in germinal center formation.[26] All follicular lymphomas and many diffuse, large B-cell lymphomas express BCL-6 protein. However, expression of BCL-6 protein does not appear to correlate with cytogenetic abnormalities at 3q27. About one third of cases of malignant lymphoma that contain 3q27 abnormalities are negative for BCL-6 protein, and more than three quarters of cases that are positive for BCL-6 protein lack 3q27 abnormalities.[27] Finn and coworkers[7] demonstrated that all 3 cases of childhood follicular lymphoma of the testis that were tested expressed BCL-6 protein. They also detected bcl-6 gene rearrangement in the 1 case that they were able to evaluate by Southern blot analysis. The neoplastic cells in the case presented in our report expressed BCL-6 protein by immunohistochemical stain; fresh or frozen tissue was not available for cytogenetic or Southern blot analysis. Finally, unlike the 2 cases tested by Finn and coworkers,[7] the neoplastic cells in the case reported herein expressed CD10, another marker of follicle center cell origin.

In summary, the clinical, histologic, and immunophenotypic findings in this case support the hypothesis that follicular lymphoma of the testis represents a unique entity that arises from follicle center cells but has a different pathogenesis than follicular lymphoma in adults.

We thank Ms Cheryl Rucker and Mr Thomas Brooks for their expert technical assistance and Mr John Ebel for expert secretarial assistance.


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[3.] Pinto A, Hutchison RE, Grant LH, et al. Follicular lymphomas in pediatric patients. Mod Pathol. 1990;3:308-313.

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[5.] Atra A, Meller ST, Stevens RS, et al. Conservative management of follicular non-Hodgkin's lymphoma in childhood. Br J Haematol. 1998;103:220-223.

[6.] Moertel CL, Watterson J, McCormick SR, et al. Follicular large cell lymphoma of the testis in a child. Cancer. 1995;75:1182-1186.

[7.] Finn LS, Viswanatha DS, Belasco JB, et al. Primary follicular lymphoma of the testis in childhood. Cancer. 1999;85:1626-1635.

[8.] Alsabeh R, Medeiros LJ, Glackin C, et al. Transformation of follicular lymphoma into CD30-large cell lymphoma with anaplastic cytologic features. Am J Surg Pathol. 1997;21:528-536.

[9.] Reid H, Marsden HB. Gonadal infiltration in children with leukemia and lymphoma. J Clin Pathol. 1980;33:722-729.

[10.] Leonard MP, Schlegel PN, Crovatto A, et al. Burkitt's lymphoma of the testis: an unusual scrotal mass in childhood. J Urol. 1990;143:104-106.

[11.] Shahab N, Doll DC. Testicular lymphoma. Semin Oncol. 1999;26:259-269.

[12.] Paladugu RR, Bearman RM, Rappaport H. Malignant lymphoma with primary manifestation in the gonad: a clinicopathologic study of 38 patients. Cancer. 1980;45:561-571.

[13.] Abell MR, Holtz F. Testicular and paratesticular neoplasms in patients 60 years of age and older. Cancer. 1968;21:852-870.

[14.] Turner RR, Colby TV, MacKintosh FR. Testicular lymphomas: a clinico-pathologic study of 35 cases. Cancer. 1981;48:2095-2102.

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[16.] Fonseca R, Habermann TM, Colgan JP, et al. Testicular lymphoma is associated with a high incidence of extranodal recurrence. Cancer. 2000;88:154-161.

[17.] Talerman A. Primary malignant lymphoma of the testis. J Urol. 1977;118: 783-786.

[18.] Dargeon HW. Tumors of Childhood: A Clinical Treatise. New York, NY: Paul B Hoeber Inc; 1960:250-343.

[19.] Miller AL Jr, Sharp L. Unusual intrascrotal tumors. J Urol. 1964;91:273-279.

[20.] Willnow U, Hofmann V, Glaser A. Hodentumoren im Sauglings und Kindesalter: Klinische und Morphologische Untersuchungen. Helv Chir Acta. 1970; 37:337-355.

[21.] Weitzner S, Gropp A. Primary reticulum cell sarcoma of testis in a 12-year-old. Cancer. 1976;37:935-938.

[22.] Jackson SM, Montessori GA. Malignant lymphoma of the testis: review of 17 cases in British Columbia with survival related to pathological subclassification. J Urol. 1980;123:881-883.

[23.] Rao SP, Miller ST, Menell J, et al. Localized non-Hodgkin's lymphoma of the testis in a child. Am J Pediatr Hematol Oncol. 1993;15:443.

[24.] Yunis JJ, Oken MM, Kaplan ME, et al. Distinctive chromosomal abnormalities in histologic subtypes of non-Hodgkin's lymphoma. N Engl J Med. 1982; 307:1231-1236.

[25.] Nguyen PL, Zukerberg LR, Benedict WF, et al. Immunohistochemical detection of p53, bcl-2, and retinoblastoma proteins in follicular lymphoma. Am J Clin Pathol. 1996;105:538-543.

[26.] Ye BH, Cattoretti G, Shen Q, et al. The bcl-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nat Genet. 1997;16:161-170.

[27.] Skinnider BF, Horsman DE, Dupuis B, Gascoyne RD. Bcl-6 and Bcl-2 protein expression in diffuse large B-cell lymphoma and follicular lymphoma: correlation with 3q27 and 18q21 chromosomal abnormalities. Hum Pathol. 1999; 30:803-808.

Accepted for publication September 7, 2000.

From the Department of Hematopathology, University of Texas M. D. Anderson Cancer Center, Houston, Tex (Drs Lu, Medeiros, and Abruzzo); and Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Md (Dr Eskenazi).

Reprints: Lynne V. Abruzzo, MD, PhD, University of Texas M. D. Anderson Cancer Center, Department of Hematopathology, Box 85, 1515 Holcombe Blvd, Houston, TX 77030 (e-mail:
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Article Details
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Author:Lu, Di; Medeiros, L. Jeffrey; Eskenazi, Allen E.; Abruzzo, Lynne V.
Publication:Archives of Pathology & Laboratory Medicine
Geographic Code:1USA
Date:Apr 1, 2001
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