Retroperitoneal Lymph Node

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2021, Case 10, and is metastatic Leydig cell tumor in a retroperitoneal lymph node. The information provided in this case was accurate and correct at the time of publication in 2021. Any changes in terminology since the time of publication may not be reflected in this case.

Sections show a lymph node replaced by a neoplasm with a uniform population of cells with eosinophilic cytoplasm and occasional visible nucleoli arranged in nests and sheets. The cells have somewhat defined cytoplasmic borders. No areas of necrosis are identified. The neoplasm is mitotically active, with some areas showing up to 5 mitoses per 10 high-power fields (HPF). The neoplasm is positive for SF1, inhibin, Melan-A, and vimentin and is negative for pancytokeratin, S100, PLAP, and SALL4. The findings are consistent with a metastatic Leydig cell tumor.

Leydig cell tumor is the most common sex cord stromal tumor in the testis and accounts for 1% to 3% of testicular tumors. It usually occurs in two age ranges: 5 to 10 years and 30 to 35 years. It usually presents with painless testicular enlargement and may produce steroid hormones, eliciting symptoms such as gynecomastia, decreased libido, and precocious puberty. Leydig cell tumors may be associated with cryptorchidism, testicular atrophy, and infertility. Cases are bilateral in 3% of ​patients​. Most Leydig cell tumors are benign, however, approximately 10% are malignant ​as demonstrated by ​metastasi​s​. The most common site of metastasis is retroperitoneal lymph nodes, followed by the liver, lung, and bones. Most malignant tumors are associated with an older age at presentation.

Grossly, Leydig cell tumors are well-circumscribed masses with homogeneous yellow, brown, or white cut surfaces. Hemorrhage and necrosis may be seen. Microscopic features are usually characterized by a solid growth pattern, although other patterns such as nodular, insular, pseudoglandular, and trabecular may be seen. Neoplastic cells are medium to large with abundant eosinophilic cytoplasm and distinct cell borders. The cytoplasm may be clear. Nuclei are round, and nucleoli are usually easily identified. Pigmented cells (containing lipofuscin) may be seen. Reinke crystals are a diagnostic feature, however, they are only present in 30% to 40% of cases. The stroma may show fibrosis, edema, or myxoid change. Mild nuclear atypia and rare mitoses may be seen in benign Leydig cell tumors. Features ​​suggestive of malignant potential include large size (greater than 5 cm), marked nuclear atypia, increased mitoses (more than 3/10 HPF), atypical mitoses, necrosis, vascular invasion, infiltrative borders, and DNA aneuploidy. A definitive diagnosis of malignancy can only be made based on the presence of metastasis.

The diagnosis of Leydig cell tumor is frequently based on morphologic findings. Sometimes, especially in the metastatic setting, immunohistochemical stains aid in establishing the diagnosis. SF1, Inhibin, calretinin, and Melan-A are positive in Leydig cell tumors. These tumors are negative for pancytokeratin, S100, HMB45, PLAP, podoplanin (D2-40), OCT3/4, and SALL4.

Treatment of testicular Leydig cell tumors usually involves orchiectomy. Malignant Leydig cell tumors are treated with orchiectomy and retroperitoneal lymph node dissection. These tumors do not respond to radiation or chemotherapy. Malignant Leydig cell tumors have a poor prognosis, with an average survival of 2 years.

The differential diagnosis of metastatic malignant Leydig cell tumor identified within a lymph node includes lymphoma and metastatic lesions, such as carcinoma, melanoma, and germ cell tumors such as seminoma. Immunohistochemistry can be useful in establishing the diagnosis in most of these scenarios (see table 1). Sertoli cell tumors are composed of cells with uniform round nuclei having occasional nucleoli. They may have moderate eosinophilic or clear cytoplasm, as seen in Leydig cell tumors, however, they usually show some areas of tubular differentiation that is not identified in Leydig cell tumors. Seminomas show large uniform tumor cells with clear cytoplasm and prominent nucleoli, but they usually have a lymphocytic infiltrate in the background, as well as occasional granulomas. Carcinomas may show glandular formations and express pan-cytokeratin. Lymphoma, including ​diffuse large B-cell l​ymphoma usually lacks the abundant eosinophilic cytoplasm seen in Leydig cell tumors. Melanoma may show pigment as seen in Leydig cell tumors and may show any number of histologic patterns. Melan-A is positive in both Leydig cell tumor and melanoma.

1. What feature indicates definitive malignancy in a Leydig cell tumor?
   
   
   1. Metastasis
   2. Mitotic rate >3/10 HPF
   3. Necrosis
   4. Older age at presentation
   5. Vascular invasion
2. What immunoprofile best fits a Leydig cell tumor?
   
   
   1. SALL4-, pancytokeratin-, Melan-A-, SF1+
   2. SALL4-, pancytokeratin-, Melan-A+, SF1+
   3. SALL4-, pancytokeratin-, Melan-A+, SF1-
   4. SALL4-, pancytokeratin+, Melan-A+, SF1+
   5. SALL4+, pancytokeratin+, Melan-A-, SF1-
3. In a neoplasm, what histologic feature is pathognomonic for Leydig cell tumor?
   
   
   1. Calcification
   2. Granulomas
   3. Hemosiderin
   4. Lipofuscin
   5. Reinke crystals

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1. Metastasis (a)
2. SALL4-, pancytokeratin-, Melan-A+, SF1+ (b)
3. Reinke crystals (e)