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A 69-year-old man with an enlarging painless right testis underwent orchiectomy. The testis contained a 5.0 cm lobulated white-gray mass replacing most of the parenchyma and involving paratesticular structures. A workup revealed no evidence of involvement elsewhere.
Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2009, case 17, and is primary testicular lymphoma, diffuse large B-cell type
Criteria for Diagnosis and Comments:
This case is a high grade malignant neoplasm consisting of sheets and cords, as well as individual tumor cells, which infiltrate and replace interstitium, surround and separate remaining sclerotic seminiferous tubules, and invade vascular structures. Marked cytologic atypia, mitotic activity and necrosis are present. Lymphoid follicle formation is absent. The tumor cells are CD20 +, CD45 +, Bcl-2 +, Bcl-6 –, CD10 –, CD3 –, CD117 –, PLAP – and OCT3/4 –. The overall features are that of primary testicular lymphoma (PTL), diffuse large B-cell type (DLBCL).
PTL represents 1% of all lymphomas, 2 – 5% of all extra-nodal lymphomas and 5% of all testicular malignancies. It is the most common testicular neoplasm in the elderly, with >85% occurring in the 60 – 80 year age group. It is more often bilateral than germ cell tumors, and more than half of all bilateral testicular tumors are malignant lymphoma. Nonetheless, patients most often present clinically with unilateral (painless) testicular swelling whereas contralateral involvement (occurring in up to a third of patients) more often occurs later in the clinical course, as metachronous disease. There is no known association of PTL with trauma, orchitis or cryptorchidism.
The most common subtype in adults is, by far, diffuse large B-cell lymphoma (DLBCL) accounting for 80 – 90% of PTL. High proliferative activity is typical. Other types of PTL, such as marginal zone lymphoma, follicular lymphoma, anaplastic large cell lymphoma and T-cell lymphoma are very rare. In children, testicular lymphoma is almost always the result of secondary involvement by Burkitt’s or lymphoblastic lymphoma in which bilateral involvement is typical. Primary follicular lymphoma of the testis in prepubertal children represents a distinct entity with grade 3 features, unusual IHC phenotype including bcl-2 –, bcl-6 + and variable CD10, and excellent prognosis. While secondary testicular involvement due to lymphoma elsewhere is not uncommon in adults, it is more often seen in advanced cases or at autopsy.
Some have recently found that PTL of DLBCL type can be further subdivided into two prognostically significant subtypes. Around 90% have been found to mark as non-germinal center B-cell-like with an IHC profile of CD10 –, Bcl-6 – and MUM1 +. Moreover, these also tend to be overwhelmingly Bcl-2 + which, along with high Ki-67 scores, correlates histologically with the high proliferative activity typically present in these tumors (as in our case) and which may correlate with the more aggressive behavior and shortened survival in this variant. The germinal center B-cell-like variant exhibits an IHC profile of CD10 and/or Bcl-6 + and MUM1 – and usually carries a more favorable prognosis. Some of these rare germinal center variants have been found in HIV + patients and in fact may be their initial HIV manifestation, although the relationship between HIV and the germinal center B-cell-like phenotype is not clear.
The cure of some patients in the past after orchiectomy alone has favored the existence of primary testicular lymphoma (i.e., stage IE disease, defined as the presence of a testicular mass in the absence of lymph node or bone marrow involvement) versus just the initial manifestation of occult, and subsequent generalized, lymphomatous disease. This topic is still somewhat controversial. Even in these cases of seemingly localized (1E) disease, PTL has the worst prognosis amongst all extranodal lymphomas with 5 yr survival rates of 70 – 80%. Relapses occur in >50% of cases of which 70 – 90% involve non-contiguous extranodal sites, most often contralateral testis, CNS and Waldeyer’s ring with the latter two associated with ominous implications; but also skin, lung, pleura and soft tissue. The cause of this high incidence of extranodal relapse compared with primary lymphomas of other sites is unknown. The highest incidence of relapses occurs in the CNS (even in 20% of 1E cases), and the contralateral testis. The overall prognosis of adult testicular lymphoma is poor, taking all histologic types and stages into account, with 5 and 10 year survivals being 37 – 48% and 19 – 27%, respectively. Young age, low stage and tumor sclerosis are favorable prognostic factors although historically, even stage I and IIE patients who have achieved complete remission, have poor prognoses with late relapses. Many, but not all, advocate systemic chemotherapy following orchiectomy for early stage disease, with CNS prophylaxis and contralateral testicular irradiation. With advent of doxorubicin-based therapy, some newer studies have shown improved survival. Addition of rituxin may further improve outcome.
The differential diagnosis includes primarily seminoma and embryonal carcinoma. Grossly, both seminoma and PTL can appear identical with a solid cream-colored homogeneous appearance. Imaging studies that show bilaterality and paratesticular involvement strongly favors lymphoma. Microscopically, seminoma cells are nested, evenly spaced, fairly uniform, have distinct cell membranes, clear glycogen-rich cytoplasm, “squared off” nuclear contours, and are often associated with a granulomatous component and sometimes syncytial trophoblastic cells. Tubular lumina are typically replaced by seminoma whereas lymphoma tends to surround, but spare them, at least initially. Involvement of paratesticular tissues strongly favors lymphoma. Immunohistochemically, seminoma cells are typically positive for PLAP, OCT3/4, D2-40 (podoplanin) and CD117, and negative for lymphoid markers.
Embryonal carcinoma normally has an overall epithelial appearance, often with glandular and/or papillary formations. Although hemorrhage and necrosis may be found in both embryonal carcinoma and PTL, cells of the former are typically larger with more cytoplasm and vesicular nuclei that are less twisted and irregular than those in PTL. The presence of intratubular germ cell neoplasia (ITGCN) in residual seminiferous tubules is often found in embryonal carcinoma, but not in PTL. Immunohistochemically, embryonal carcinoma cells are positive for PLAP, OCT3/4, cytokeratin and CD30 and negative for lymphoid markers (as well as seminoma markers D2-40 and CD117). Moreover, patients with embryonal carcinoma are typically much younger than those with PTL.
The blastic type of myeloid (granulocytic) sarcoma may occasionally enter into the differential diagnosis and would be excluded based upon the characteristic finding of myeloid, and especially eosinophilic, precursors amongst the more primitive background blast population. And since this can rarely predate the leukemic condition (AML, CML, myelofibrosis, polycythemia vera, etc.), strong suspicion is crucial. Immunohistochemistry, including anti-myeloperoxidase, CD117, CD68 and CD31 (for megakaryocytic differentiation), along with myeloperoxidase staining of touch preparations, would be very useful in confirming myeloid lineage. Bone marrow exam would also be indicated for confirmation (if involved), and staging.
Finally, chronic orchitis may rarely enter the differential. However, it rarely presents as a mass lesion leading to orchiectomy. If confronted with this scenario, however, the presence of a mixed population of chronic inflammatory cells without atypia should easily separate it from lymphoma.