Introduction

Primary testicular follicular lymphoma (PTFL) is a rare neoplasm of germinal centre B cells confined to the testis. It occurs almost exclusively in children and young adults and carries excellent prognosis. It is a unique extranodal variant of follicular lymphoma presenting as stage 1E disease. They differ biologically from nodal FL in that they lack evidence of the BCL2 translocation.[1] They are of high cytological grade, usually grade 3A.[2,3] Microscopically, TFL has a follicular or follicular and diffuse pattern and is composed predominantly of centroblasts. Although not recognized as a separate entity, the 4^th edition of the World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues lists TFL as a distinctive variant of follicular lymphoma.[4]

Case Report

A 5-year-old apparently healthy and active boy, presented with a painless right scrotal swelling of 5 months duration which gradually increased in size. There was no history of fever, night sweats, malaise, weight loss or recent change in bowel habits. He had no significant past medical or surgical history. Antenatal and postnatal periods were uneventful and he had a recorded birth weight of 2.9kg. He was immunized according to National immunization schedule. There was no history of malignancy in the family. On physical examination, a 4x3cm non tender swelling was felt confined to the right testis which was soft to firm in consistency. Cord structures were normal. Inguinal nodes were not palpable. Examination of the left testis and of other systems was unremarkable.

Ultrasound of scrotum showed an enlarged hypoechoic right testis with increased vascularity. No obvious focal lesions were found. Routine hematological examination was unremarkable. Tumors markers – Serum Alpha Feto Protein (AFP), Human Chorionic Gonadotropin (HCG) and Lactate Dehydrogenase (LDH) were within normal limits. Chest X-ray was unremarkable. MRI of the scrotum revealed an enlarged right testis measuring 28x14mm, and was suggestive of right epididymo-orchitis.

The child underwent right high inguinal orchidectomy by Chevassu procedure. Intra-operatively, right testis was bulky measuring 4x3cm, with normal cord structures. Frozen section report was given as malignant small round blue cell tumor.

On cut section, the testis was replaced by a grey-white tumor measuring 2.5 x 2 x 1.5 cm and was limited to within the testis parenchyma. The epididymis and spermatic cord appeared grossly free of the tumor. The tunica vaginalis and tunica albuginea were grossly uninvolved (Fig.1).

Figure 1: Cut section, testis shows an irregular grey white lesion measuring 2.5x2x1.5cm, limited to testis.

On microscopy, sections from the tumor showed atypical lymphoid proliferation seen predominantly in a nodular/follicular pattern. The atypical lymphoid cells showed variable morphology and were composed of small to medium cleaved cells and admixed large centroblasts cells (>15/hpf). The follicles were seen back-to-back and seen permeating in between and inside the seminiferous tubules (Fig. 2-3). Scattered mitoses were seen within the tumor. No necrosis was identified.

Figure 2: Haematoxylin & eosin staining: Atypical lymphoid proliferation seen predominantly in a nodular/follicular pattern (10X & 40X).	Figure 3: The follicles are seen back-to-back and seen permeating in-between and inside the seminiferous tubules These atypical lymphoid cells show variable morphology and are composed of small to medium cleaved cell and admixed large centroblasts-like cells (>15/hpf),40x

On immunohistochemistry, the atypical lymphoid cell follicles / nodules were diffuse positive for CD20, PAX5 and BCL6. They were negative for CD10, CD117, CD30, CD34, MPO, Tdt, BCL2 and MUM1(Fig. 4-8). The Ki 67/MIB1 labeling index was approximately 50-60% in the highest proliferating regions (Fig. 9).

Figure 4: CD3 stains the T cells in the periphery of the follicles.	Figure 5: The atypical lymphoid cell follicles / nodules are diffuse positive for CD20, CD79a(Not shown)
Figure 6: Negative for BCL2(), CD117, CD30, CD34, MPO, Tdt, and MUM1(Not shown).	Figure 7: Positive for PAX5
Figure 8: Positive for BCL6	Figure 9: Ki- 67 indicates a moderate to high proliferation rate (50-60%)

The final impression was given as a B-cell non-Hodgkin lymphoma with a follicular architecture and a diagnosis of Primary Testicular Follicular Lymphoma was considered.

Discussion

This study presents a case of primary testicular follicular lymphoma in a 5-year-old child. The lymphoma exhibited characteristic morphologic features of follicular lymphoma and expressed the germinal center marker BCL6. However, the neoplastic cells did not express BCL2. Distinction from a reactive process was possible owing to the unique morphology of the lesion and the presence of an extensive, dense infiltrate of BCL-6 positive atypical B lymphocytes. A diagnosis of primary testicular lymphoma was considered as the disease was primarily present in the testis and a concomitant clinical and radiological evaluation did not reveal any other site of involvement. In addition, the lymphoma is morphologically, immunohistochemically, similar to the other cases described, and secondary involvement of the testis by follicular lymphoma is exceptionally rare.[5,6]

Primary testicular lymphoma is uncommon, constituting approximately 1% of all lymphomas and 2% to 5% of all testicular tumors.[6] Typically affecting adult men, it is rarely seen in children.[7,8,9] About 80% to 98% of cases are Primary testicular diffuse large B cell lymphoma (PT-DLBCL).[1] Secondary testicular involvement is seen commonly in blastic lymphomas. The true incidence of PTFL is unknown owing to its rarity. Nevertheless, about 25 cases have been reported in the literature so far.[1]

Clinically, it manifests as unilateral painless testicular enlargement. Ultrasound appearance is diffuse or well-delineated hypoechoic unilateral mass lesion with increased vascularity. Comprehensive staging investigations almost invariably show extra nodal and organ-confined disease.

Grossly they are tan/white fleshy ill-defined tumors primarily located in the testicular parenchyma with frequent extension to the epididymis. Microscopically, the distorted testicular parenchyma shows dense lymphoid infiltrate with a follicular growth pattern and are predominantly composed of centroblasts and fewer mixed centrocytes. The neoplastic follicles permeate among seminiferous tubules. Immunohistochemically, tumor cells are positive for B-cell lineage markers – CD19, CD20 and CD79a. They express at least one of the two germinal center-associated antigens CD10 and BCL6. BCL2 is characteristically negative in the neoplastic cells. The proliferation index assessed by Ki-67 is moderately high ranging from 40% to 80%.

Genetically, TFL characteristically lacks the t(14;18)/IGH-BCL2. Mutations commonly involve EZH2, EGFR, IRF8, PABPC1, KMT2D, TNFRSF14.[1] FLs lacking BCL2 rearrangement display CNAs and mutations similar to BCL2-R FL, but with different frequencies. However, in contrast to BCL2-R FL which expresses GC B-cell signatures, the gene expression profile of FLs lacking BCL2 rearrangement is reminiscent of late/post-GC cells.

Differentiating PTFL from reactive follicular hyperplasia in the course of chronic orchitis poses as a diagnostic challenge. Because the lack of BCL2 protein expression and BCL2 gene rearrangement can make the diagnosis of FL less obvious, a series of parameters should always be considered. This includes the absence of previous infectious diseases, lack of inflammation or granulomas in the epididymis and spared testis, back-to-back follicular growth pattern, non-polarized germinal centers, Ig light chain restriction, and the detection of a monoclonal Ig gene rearrangement. Microscopically neoplastic follicles characteristically permeate in between and within the seminiferous tubules. These follicles lack well-defined mantle cuffs and germinal centre polarisation.

A comprehensive review of the literature published found cases of testicular tumors of follicular Non-Hodgkin Lymphoma (NHL) in 10 children. As seen in all prior cases reported, our patient was negative for BCL-2. Table 1 outlines how our studies compare with the prior cases of primary testicular follicular NHL. Each child was reported to have only localized follicular NHL of a testis. Table 2 depicts differences between nodal follicular lymphoma and testicular follicular lymphoma

Treatment of PTFL involves a combined approach of unilateral orchidectomy and anthracycline-containing chemotherapy. An excellent prognosis is usually achieved without recurrence after long-term follow up.

References

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