A recent study demonstrated that NKX3.1-positive staining can uncommonly be seen in testicular Sertoli cell tumors (1 of 4 cases). Also, it was reported that 2 of 3 Leydig cell tumors of the testis showed diffuse cytoplasmic staining for P501S, although it was unclear whether it was specific granular staining that defines true positivity. However, Sertoli cell tumors do not typically pose a diagnostic dilemma with metastatic prostate carcinoma to the testis. In contrast, malignant Leydig cell tumors, which are exceedingly rare, can closely resemble Gleason score 5 + 5 = 10 prostatic adenocarcinoma metastatic to the testis.
To evaluate the expression of prostate markers in malignant Leydig cell tumors and steroidogenic factor 1 (SF-1) in high-grade prostate adenocarcinoma, as no data are currently published on these topics.
Fifteen cases of malignant Leydig cell tumor were collected from 2 large genitourinary pathology consult services in the United States from 1991 to 2019.
All 15 cases were negative immunohistochemically for NKX3.1, and all 9 with available additional material were negative for prostate-specific antigen and P501S and positive for SF-1. SF-1 was negative immunohistochemically in a tissue microarray with cases of high-grade prostatic adenocarcinoma.
The diagnosis of malignant Leydig cell tumor and its distinction from metastatic adenocarcinoma to the testis can be made immunohistochemically on the basis of SF-1 positivity and negativity for NKX3.1.
Sex cord–stromal cell tumors are the second most common subtype of primary testicular neoplasms reported worldwide. They have a wide array of histologic subtypes and patterns, with Sertoli cell tumors, Leydig cell tumors, fibrothecomas, and granulosa cell tumors the most common tumors in this category.1
Leydig cell tumors account for 1% to 3% of testicular neoplasms. Clinically, they usually present in young adolescent patients or in patients older than 50 years as painless unilateral testicular enlargement.2 Approximately 10% of Leydig cell tumors are malignant and show at least 3 of the following 6 features: (1) more than 3 mitotic figures per 10 high-power fields; (2) infiltrative growth pattern; (3) necrosis; (4) size greater than 5 cm; (5) vascular invasion; and (6) cytologic atypia.2,3 Histologically, Leydig cell tumors consist of polygonal cells with abundant eosinophilic granular cytoplasm, with a prominent central nucleolus. Although pathognomonic Reinke crystals can be seen in some cases, they may be extremely difficult to identify.2 Immunohistochemically, they are steroidogenic factor-1 (SF-1), inhibin, and calretinin positive.1
A recent study demonstrated that NKX3.1-positive staining can uncommonly be seen in testicular Sertoli cell tumors (1 of 4 cases).4 Also, it was reported that 2 of 3 Leydig cell tumors of the testis showed diffuse cytoplasmic staining for P501S, although it was unclear whether it was specific granular staining that defines true positivity. However, Sertoli cell tumors do not typically pose a diagnostic dilemma with metastatic prostate carcinoma to the testis. In contrast, malignant Leydig cell tumors, which are exceedingly rare, can closely resemble Gleason score 5 + 5 = 10 prostatic adenocarcinoma metastatic to the testis. No data are currently published regarding the expression of prostate markers in malignant Leydig cell tumors or concerning SF-1 in high-grade prostate adenocarcinoma.
MATERIALS AND METHODS
Fifteen cases of malignant Leydig cell tumors of the testis were collected from our institutions’ consult services from 1991 to 2019. We received unstained slides and/or blocks from radical orchiectomy specimens, depending on their availability. Immunohistochemistry for NKX3.1 was performed on all 15 cases. Additionally, on 9 of these cases with available additional material, we performed immunohistochemistry for prostate-specific antigen (PSA), P501S, and SF-1 (Table 1).
A tissue microarray with 77 spots of Gleason pattern 5 prostatic adenocarcinoma was assessed immunohistochemically with SF-1.
RESULTS
Six cases represented metastatic malignant Leydig cell tumor to retroperitoneal lymph nodes, and a seventh case was a metastasis to the abdominal wall. The remaining 8 cases were from orchiectomy specimens, and the histologic features in the cases that were used to establish malignancy in Leydig cell tumors are listed in Table 2. At least 3 features listed in Table 2 were required for the diagnosis of malignant Leydig cell tumor (Figure, A through D).
![A, Sheets of malignant Leydig cell tumor mimicking high-grade prostate cancer. B, Malignant Leydig cell tumor with atypia and necrosis (lower left), bearing resemblance to high-grade prostate cancer. C, Nest of malignant Leydig cell tumor, appearing similar to high-grade prostate cancer. D, Diffuse steroidogenic factor 1 immunoreactivity in malignant Leydig cell tumor (hematoxylin-eosin, original magnification ×40 [A through C]; original magnification ×20 [D]).](https://allen.silverchair-cdn.com/allen/content_public/journal/aplm/147/12/10.5858_arpa.2022-0424-oa/2/m_i1543-2165-147-12-1458-f01.png?Expires=1744124091&Signature=r7umV9MUHRijhTtu8NYoXNxUekwvFzLf9UwivTKlJzr13eNKJBR9TnDRx08KYo1Lj87kiOvAyggWPRd70N6PaFF3Ce1h2Xvx5Cd0sJhE2DAbLolkGUWOH3GiFPADdfL1ekOOP6SQLemuS1BzThKFV4qvHkT6XiunID7PimHzCWXqY7v57rpEJ0MdKBln2J88i1nnspqoGGbIkwfH4thOnZdcS4juruDkc60JgV3JZsVY4qy3FCtJE4RetgpQTxYXR5SRqqMOoy8sgBJ2wwTBZxaS-BUAWJ0bGPAEkaoQWqdr1C~2LlA4MVsgYT8pLVHuAvNPotqRA~3JYDKPabepOA__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
A, Sheets of malignant Leydig cell tumor mimicking high-grade prostate cancer. B, Malignant Leydig cell tumor with atypia and necrosis (lower left), bearing resemblance to high-grade prostate cancer. C, Nest of malignant Leydig cell tumor, appearing similar to high-grade prostate cancer. D, Diffuse steroidogenic factor 1 immunoreactivity in malignant Leydig cell tumor (hematoxylin-eosin, original magnification ×40 [A through C]; original magnification ×20 [D]).
A, Sheets of malignant Leydig cell tumor mimicking high-grade prostate cancer. B, Malignant Leydig cell tumor with atypia and necrosis (lower left), bearing resemblance to high-grade prostate cancer. C, Nest of malignant Leydig cell tumor, appearing similar to high-grade prostate cancer. D, Diffuse steroidogenic factor 1 immunoreactivity in malignant Leydig cell tumor (hematoxylin-eosin, original magnification ×40 [A through C]; original magnification ×20 [D]).
All 15 cases were negative immunohistochemically for NKX3.1, and all 9 cases with available additional material were negative for PSA and P501S and positive for SF-1. None of the cases showed nongranular staining for P501S, which would also have been interpreted as negative. SF-1 was negative immunohistochemically in a tissue microarray of 77 cases of high-grade prostatic adenocarcinoma.
DISCUSSION
Prostate carcinoma is the most diagnosed malignancy in 112 countries and the second most common neoplastic cause of death in men after lung cancer in the United States.5 The most common sites of metastatic adenocarcinoma of the prostate are bone, lymph nodes, liver, and thorax. Prostate cancer also has a propensity to metastasize to the testis.6 Before the advent of medical antiandrogen therapy for advanced prostate cancer, when surgical castration was the primary therapy for metastatic prostate cancer, approximately 6% of such cases harbored metastatic prostate cancer.6
Prior literature has described prostate adenocarcinoma as a mimic of rete testis adenocarcinoma and Sertoli cell tumor.4 When other tumors involve the testis, they can pose diagnostic challenges for pathologists.7 Malignant Leydig cell tumors, which are exceedingly rare, can closely resemble Gleason score 5 + 5 = 10 prostatic adenocarcinoma metastatic to the testis. Malignant Leydig cell tumors are rare, with limited immunohistochemical expression studied in these tumors.
Prior studies have reported the utilization of SF-1, inhibin, and calretinin in the identification of sex cord tumors. SF-1 nuclear staining positivity has become the most sensitive and preferred marker for identifying sex cord–stromal tumors.1 In a large series of testicular sex cord–stromal tumors, 11 of 12 malignant Leydig cell tumors (92%) were positive for SF-1.1 Other less commonly used markers to confirm sex cord–stromal origin include FOXL2 and SOX9.1 There is very limited information on the expression of prostatic markers in sex cord–stromal tumors. NKX3.1 immunoreactivity was recently reported in 1 of 4 testicular Sertoli cell tumors.4 In addition, 2 of 3 Leydig cell tumors of the testis showed diffuse cytoplasmic staining for P501S, yet whether in these cases the staining was granular, which is required for indicating prostatic origin, was not specified. However, malignant Leydig cell tumors, which can closely resemble adenocarcinoma of the prostate, have not been studied with prostate-specific markers.
NKX3.1, PSA, and P501S are currently the preferred prostatic origin markers being used. They have proven to be extremely sensitive at identifying metastatic cases of high-grade prostatic carcinomas.8,9 Among these prostate-specific markers, NKX3.1 has the greatest sensitivity and specificity. SF-1 immunoreactivity in adenocarcinoma of the prostate has not been reported to date.
In the current study, all 15 cases of malignant Leydig cell tumors were negative immunohistochemically for NKX3.1, and 9 of these cases with available additional material were negative for PSA, P501S, and positive for SF-1. SF-1 was negative immunohistochemically in a tissue microarray with cases of high-grade prostatic adenocarcinoma. Consequently, the diagnosis of malignant Leydig cell tumor and its distinction from metastatic adenocarcinoma to the testis can be made immunohistochemically on the basis of SF-1 positivity and negativity for NKX3.1.