A 65-year-old man presents with a palpable testicular mass. The patient has a remote history of prostate cancer, status post-prostatectomy, and is currently on androgen deprivation therapy. Laboratory findings include serum levels in the normal reference range for lactate dehydrogenase, alpha fetoprotein, and human chorionic gonadotropin. Prostate specific antigen (PSA) is 0.3 ng/mL. An orchiectomy is performed, revealing a single, tan-white, solid, and focally cystic, 4.5 cm mass without evidence of necrosis or hemorrhage. The neoplasm is confined to the testis. Immunohistochemistry is performed: the neoplastic cells express PSA and NKX3.1, and are negative for CK7, CK20, CDX-2, PLAP, WT-1, calretinin, and inhibin.

Master List of Diagnoses

  • Adenocarcinoma of rete testis/epididymis
  • Embryonal carcinoma
  • Malignant mesothelioma
  • Metastatic colorectal adenocarcinoma
  • Metastatic prostatic adenocarcinoma
  • Müllerian-type epithelial tumor
  • Sertoli cell tumor
View slide image with DigitalScope

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2017, Case 16, and is metastatic prostatic adenocarcinoma of the right testis.

Criteria for Diagnosis and Comments

Histologic sections show a circumscribed mass that is adjacent to the tunica, with interstitial and focally intratubular growth patterns. The neoplasm has a cribriform and papillary architecture and is composed of columnar cells with elongated nuclei and prominent nucleoli. Necrosis is not identified. Based on morphology alone, the origin of this neoplasm may be difficult to determine, however an appropriate immunohistochemical panel based on the patient’s clinical history and the morphology of the neoplasm aids in diagnosing this lesion. Given the patient’s history of prostatic adenocarcinoma, the morphology of the tumor and immunohistochemical expression of prostate-specific markers, PSA and NKX3.1, the diagnosis is metastatic prostatic adenocarcinoma (PCa).

Metastasis to the testis is rare, with a reported incidence of approximately 2.5% of all testicular tumors. Most metastatic tumors originate from the prostate, lung, colon, kidney and skin (melanoma). Less common are bladder, pancreas and upper gastrointestinal tract primaries. Hematolymphoid neoplasms commonly involve the testis. Sarcoma involving the testis is very rare. Features that favor a metastasis over a primary neoplasm include older age of the patient, history of other malignancy, multicentricity, bilaterality, interstitial growth pattern, lack of germ cell neoplasia in situ (GCNIS) and extensive vascular-lymphatic invasion. Often, however, metastatic tumors to the testis present as single, unilateral masses, which complicates the diagnosis.

PCa typically metastasizes to the pelvic lymph nodes, lungs, bone and liver. Although metastatic PCa is the most common metastatic carcinoma that is seen in the testis, the incidence remains low, with approximately 4% of patients developing testicular metastases. Most cases of PCa metastatic to the testis are asymptomatic and found incidentally. Proposed mechanisms for spread of PCa to the testis involve spread from the prostatic urethra by retrograde venous extension or embolism, arterial embolism, or direct invasion into the lymphatics and lumen of the vas deferens. Involvement of the prostatic urethra by PCa increases the risk for testicular metastasis. Metastatic PCa may form glands, fused glands, cribriform structures, solid sheets/cords and single cells. Ductal type of PCa has particular propensity for spread to the testis. Metastatic PCa may show intratubular growth, as seen in representative slides of this case, which leads to its confusion with a primary testicular neoplasm. PCa is typically composed of cells with uniform round nuclei with prominent nucleoli. Necrosis may be seen in high-grade PCa. Gland lumina may contain eosinophilic crystalloids or blue-tinged mucin.

In this case, a guided immunohistochemical panel helps in establishing the diagnosis. A basic immunohistochemical panel of keratin, EMA, PLAP, SALL4, inhibin, calretinin, and OCT4 will differentiate between metastatic carcinoma, germ cell tumor, malignant mesothelioma, and sex cord stromal tumor. Additional immunohistochemical stains are necessary to differentiate between different origins of metastatic carcinoma, adenocarcinoma of the epididymis/rete testis, and Müllerian-type epithelial tumor. Lymphoma is often a consideration in neoplasms of the testis, and a leukocyte common antigen (LCA) immunostain is often prudent but, in this case, lymphoma is not likely given the morphology.

There are numerous prostate-specific immunohistochemical stains to confirm prostatic origin of a metastatic tumor. PSA is probably the most widely utilized marker; however, it loses sensitivity in high-grade PCa and lacks specificity as it may be positive in breast and ovarian cancers. Prostein (P501S) shows distinctive granular cytoplasmic staining in the prostate and is both sensitive and specific. Some studies report decreased sensitivity in the metastatic setting. Homeobox protein NKX3.1 is another very sensitive and specific nuclear stain that targets secretory prostatic epithelium. Prostate specific acid phosphatase (PSAP) is specific, but not as sensitive as the previously listed markers. Prostate-specific membrane antigen (PSMA) is expressed in many prostate cancers and their metastases and does not lose sensitivity in high-grade PCa; however, it is not specific to the prostate and may be seen in a number of other malignancies, such as gastrointestinal and bladder tumors. Likewise, androgen receptor (AR) may be expressed by a variety of other tumors and is not specific to prostate. Alpha-methylacyl-CoA racemase (AMACR) is typically overexpressed in PCa but may also be seen in numerous other carcinomas from colorectal, breast, lung, ovary, and renal origins. Ets-related gene product (ERG) is relatively specific for PCa (although also positive in vascular neoplasms), but is only positive in approximately 50% of PCa, so lacks utility in the metastatic setting. A combination of markers such as PSA, NKX3.1, and P501S is the best approach when considering a diagnosis of metastatic PCa.

Metastatic PCa to the testis typically portends a poor prognosis, with an average survival of 1 year after orchiectomy. Metastasis typically occurs in cases of high Gleason grade PCa. For post-prostatectomy patients with metastasis, androgen deprivation therapy using a luteinizing hormone-releasing hormone (LHRH) agonist (medical castration) or bilateral orchiectomy (surgical castration) is the most common form of systemic therapy. Medically, this is accomplished with LHRH agonists (triptorelin, leuprolide, goserelin, and degarelix) frequently used in conjunction with an antiandrogen (flutamide, bicalutamide, nilutamide) initially to prevent any residual testosterone in the bloodstream from stimulating cancer growth, especially in the setting of a known metastasis. Additional hormonal strategies include ketoconazole with or without glucocortacoids or estrogens. For patients with castration-recurrent (hormone refractory) metastatic PCa, therapy includes bisphosphonates and systemic chemotherapy (docetaxel-based regimen) or radiation therapy.

Adenocarcinomas from other primary sites enter into the differential diagnosis of this lesion and a targeted immunohistochemical panel based on clinical history is essential to the making the correct diagnosis. Primary and metastatic carcinomas are positive for keratin and EMA. Additional site-specific markers are of utility. Colorectal adenocarcinoma is a possibility in this case, as it is typically composed of glands, albeit the glands are usually larger and more irregular than those of PCa, and they tend to have more mitotic activity, apoptosis, and tumor necrosis than PCa. The most useful antibodies to distinguish colorectal adenocarcinoma from PCa are CDX2, CK20, and SATB2, all of which are positive in colorectal adenocarcinoma and negative in PCa.

The morphology of this tumor also mimics several types of primary testicular neoplasms such as adenocarcinoma of the epididymis/rete testis, germ cell tumors (embryonal carcinoma), tumors of Müllerian origin, sex cord-stromal tumors (Sertoli cell tumor), and malignant mesothelioma.

Adenocarcinoma of the epididymis/rete testis is typically centered in the hilum or epididymis, has an invasive growth pattern with desmoplasia and solid, glandular, papillary, or tubulopapillary architecture. The neoplastic cells are cuboidal to columnar with moderate to marked nuclear pleomorphism, mitoses, and frequently necrosis. Intracytoplasmic or extracellular mucin may be seen. Areas in transition from nonneoplastic rete or epididymis to adenocarcinoma are helpful in making the diagnosis. The immunoprofile is positive for CK7, keratin, EMA, CEA, and negative for PLAP, OCT4, calretinin, and inhibin. There are no specific markers for this entity, however, and clinicopathologic correlation is essential to exclude metastasis from another location.

Tumors of Müllerian origin resemble surface tumors of the ovary and enter into the differential diagnosis. Many of these are borderline tumors; however endometrial adenocarcinoma and papillary serous carcinoma may occur in the testis. These tumors are thought to arise from Müllerian metaplasia of the tunica vaginalis, intratesticular mesothelial inclusions, or Müllerian rests in the paratesticular soft tissue. They most commonly occur in the paratestis, involving the surface of the testis or epididymis, but may occur within the testis parenchyma as well. They may show a glandular or papillary architecture with cytologically atypical cells that express WT-1, CA125, and CK7.

Malignant mesothelioma may arise from the tunica vaginalis and show a variety of patterns, including glandular formations. Immunohistochemistry is essential for making the diagnosis, as these tumors express calretinin, WT-1, and Podoplanin (D2-40).

Of the germ cell tumors, embryonal carcinoma morphologically may resemble metastatic PCa. Germ cell tumors typically occur in a younger age group than metastatic PCa, are more often unilateral and unifocal, and show a diffuse intertubular, rather than interstitial, growth pattern. The presence of GCNIS also points to a primary testicular neoplasm. Immunohistochemical expression of germ cell markers (OCT4, PLAP, and SALL4) aids in making the diagnosis.

Sertoli cell tumors enter the differential diagnosis, as they show a variety of growth patterns, including a tubular/glandular pattern, and are composed of cuboidal to columnar cells with central nucleoli. The cells are typically uniform with minimal cytologic atypia, but may show marked pleomorphism, increased mitoses, and necrosis in malignant variants. These tumors are positive for inhibin, calretinin, and WT-1, and negative for PLAP, OCT4, SALL4, and D2-40.

  1. Which of the following is the least common type of tumor that metastasizes to the testis?
    1. Carcinoma
    2. Hematopoietic neoplasm
    3. Melanoma
    4. Neuroendocrine tumor
    5. Sarcoma
  2. Which of the following features seen in metastatic prostatic adenocarcinoma to the testis may lead one to misdiagnose it as a primary testicular neoplasm?
    1. Cribriform architecture
    2. Extracellular mucin
    3. Interstitial growth pattern
    4. Intratubular growth pattern
    5. Vascular-lymphatic invasion
  3. Which of the following is the most sensitive and specific marker of prostate origin?
    1. AMACR
    2. ERG
    3. NKX3.1
    4. PSA
    5. PSAP

References

  1. Amin MB. Selected other problematic testicular and paratesticular lesions: rete testis neoplasms and pseudotumors, mesothelial lesions and secondary tumors. Mod Pathol. 2005;18:S131-S145.
  2. Dutt N, Bates AW, Baithun SI. Secondary neoplasms of the male genital tract with different patterns of involvement in adults and children. Histopathology. 2000;37(4):323-331.
  3. Epstein JI, Egevad L, Humphrey PA, Montironi R. Best practices recommendations in the application of immunohistochemistry in the prostate: Report from the International Society of Urologic Pathology Consensus Conference. Am J Surg Pathol. 2014;38(8):e6-e59,1017-1160.
  4. Gurel B, Ali TZ, Montgomery EA, Begum S, Hicks J, Goggins M, Eberhart CG, Clark DP, Bieberich CJ, Epstein JI, De Marzo AM. NKX3.1 as a marker of prostatic origin in metastatic tumors. Am J Surg Pathol. 2010;34(8);1097-1105.
  5. Kwon SY, Jung HS, Lee JG, Choi SH, Kwon TG, Kim TH. Solitary testicular metastasis of prostate cancer mimicking primary testicular cancer. Korean J Urol. 2011;52(10):718-720.
  6. Queisser A, Hagedorn SA, Braun M, Vogel W, Duensing S, Perner S. Comparison of different prostatic markers in lymph node and distant metastases of prostate cancer. Mod Pathol. 2015;28:138-145.
  7. Sogni F, Monga G, Terrone C, Gontero P. Primary adenocarcinoma of the rete testis: diagnostic problems and therapeutic dilemmas. Scand J Urol Nephrol. 2008;42(1):83-85.
  8. Tu SM, Reyes A, Maa A, et al. Prostate carcinoma with testicular or penile metastases. Clinical, pathologic, and immunohistochemical features. Cancer. 2002;94:2610-2617.
  9. Ulbright TM. Metastatic carcinoma to the testis: a clinicopathologic analysis of 26 nonincidental cases with emphasis on deceptive features. Am J Surg Pathol. 2008;32(11):1983-1993.
  10. Zhang J, Dong M, Hu X, et al. Prostatic adenocarcinoma presenting with metastases to the testis and epididymis: A case report. Oncol Lett. 2016:11(1):792-794.

Author

Danielle E. Westfall, M.D.
Surgical Pathology Committee
TOPA Diagnostics
Thousand Oaks, CA


Answer Key

  1. Sarcoma (e)
  2. Intratubular growth pattern (d)
  3. NKX3.1 (c)