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Melanoma metastasis to the testicle: a review of the literature and the case of mistaken identity

* Trocha SD
Department Of Surgery, Prisma Health Upstate, Prisma Health Upstate, Prisma Health Upstate, Greenville, United States

*Corresponding Author:
Trocha SD
Department Of Surgery, Prisma Health Upstate, Prisma Health Upstate, Prisma Health Upstate, Greenville, United States

Published on: 2020-12-20


Melanoma is the sixth most common cancer, with an estimated 100, 350 new cases expected to be diagnosed in 2020 with an overall 5-year survival of 89.6% but 24.9% for distant metastasis. Melanoma that has metastasized to the testicle is an uncommon presentation and associated with a poor prognosis as there is typically widespread disease at that time. A literature review revealed 19 total reported cases. Here we present a case of melanoma with a presumed solitary metastasis to the testicle, suggested by limited histologic analysis following orchiectomy. Further histologic analysis and a thorough understanding of the literature revealed a rare benign Leydig cell tumor, drastically changing the prognosis for the patient. Given the rarity of this presentation, we propose a diagnostic algorithm to definitively diagnose this rare event


Melanoma; Metastasis to the Testicle; Leydig Cell Tumor; Definitive Differential


Melanoma is the sixth most common cancer, with an estimated 100,350 new cases expected to be diagnosed in 2020. [1] The 5 year survival for melanoma is 89.6% in all races and both genders [1]. Malignant melanoma with distant metastasis has a 5-year survival of 24.9% [2].

The testes have been referred to as a tumor sanctuary site and an immune privileged site. The Blood Testis Barrier (BTB), composed of specialized cell junctions between adjacent Sertoli cells, provides an impediment to microbial, chemotherapeutic agents, and other molecules from interfering with the process of spermatogenesis. Although the BTB is very effective, breaches do occur. An uncommon source of the BTB permeation is metastatic carcinoma. Diagnosis of metastasis to the testicle is rare and typically identified incidentally during autopsy [2,3]. A large autopsy series noted that testicular metastases were rare, between 0.06 to 0.46%; [2-5] prostate (34.6%), lung (17.3%), melanoma (8.2%), colon (7.7%), and kidney (5.8%) solid tumors were the most common cancers to metastasize to the testicle [6]. Melanoma that has metastasized to the testicle is an uncommon presentation and associated with a poor prognosis as there is typically widespread disease at that time. [7, 8, 9, 10]. In diagnosing this, or any rare, manifestation of disease, it is imperative to examine the differential and follow the appropriate diagnostic algorithm to achieve the correct diagnosis, treatment and prognosis. Here we present a case of mistaken identity, from imaging to pathology, in which a melanoma was assumed to metastasize in a rare manner and propose a diagnostic algorithm to guide definitive diagnosis.

Case Presentation

A 60-year-old Caucasian male presented to the surgical oncology clinic as a referral from dermatology for a new left forearm melanoma. A review of the outside pathology slides by an institutional dermatopathologist revealed invasive malignant melanoma with a Breslow depth of at least 2mm without ulceration. Three weeks later the patient underwent a 4 x12 cm Wide Local Excision (WLE) with left axillary sentinel lymph node biopsy. Pathology revealed a superficial dermal deposit of malignant melanoma consistent with a microsatellite nodule; specimen margins were free of neoplastic involvement by at least 1.5cm (Figure 1a). Metastatic malignant melanoma was identified in 3 of the 4 sentinel nodes (Figure 1b). The tumor nodules were up to 0.7cm in individual diameter with partial confluence up to 2cm in aggregate. Central tumor necrosis was seen in the largest intranodal nodule. The pathologic stage was designated as pT2a pN3c. MRI of the brain and FDG PET/CT tumor whole body imaging were recommended to complete initial staging.
MRI of the brain with and without contrast and whole body PET/CT imaging revealed no evidence of metastatic disease; however, asymmetric testicular activity was noted (Figure 2). The right testicle was FDG-avid with SUV max of 10.87. A bilateral scrotal ultrasound of the testicles demonstrated a suspicious right testicular neoplasm. The lesion measured 27mm transversely by 40mm cephalocaudally by 18mm AP diameter occupying much of the testicular parenchyma. The left testicle revealed a cystic lesion without suspicious features and was otherwise normal. The patient was referred to urology for surgical evaluation with the lesion highly suspicious for intratesticular neoplastic disease possibly related to metastasis from the patient’s known melanoma versus a primary testicular malignancy.
Prior to urological evaluation of the scrotal mass the patient underwent a left axillary lymph node dissection of levels 1, 2, and 3. Pathology of these nodes revealed all additional 19 lymph nodes negative for evidence of metastatic melanoma. The patient returned to surgical oncology for a follow up visit noticing a new lesion on his contralateral right forearm. Pathology of a punch biopsy of the lesion confirmed malignant melanoma with a Breslow depth of 0.26mm with no ulcerations. This was determined to be a new second primary lesion, pT1a. It was decided that the patient would undergo wide local excision after addressing the testicular mass with urology.
Urology recommended right radical orchiectomy and obtained routine tumor markers for primary testicular cancer which revealed AFP, LDH and beta HCG within normal limits. The patient underwent right radical orchiectomy revealing a mass (3.6 x 2.6 x 3.3cm) compromising the majority of the testis. Pathology revealed epithelioid appearing cells, positive for MART-1 with pleomorphic nuclei (melanoma stage pT2aN3cM1c; clinical stage IV; Figure 3).
The patient underwent a 2 x 8cm WLE of the right forearm melanoma two weeks after orchiectomy. Pathology showed residual malignant melanoma in situ with clear margins. On follow up with surgical oncology, the patient had no evidence of disease and was referred to the multi-disciplinary clinic with medical oncology to discuss adjuvant therapy. The medical oncologist ordered genetic testing of the positive lymph nodes from the original sentinel biopsy to guide treatment planning. Testing detected BRAF V600E/V600K mutation, PD-L1 IHC reactivity at 10% in tumor cells, and KIT mutation negative. Due to the patient’s stage IV diagnosis, and given the metastases to the right testicle and risk of recurrence, the patient was initiated on a 1-year course of adjuvant therapy with nivolumab (480mg every 4 weeks IV). Prior to beginning treatment, the patient was staged by PET/CT, seven months after initially presenting with the primary lesion on his left forearm and five months after right radical orchiectomy; imaging did not reveal any new metastatic disease.
Upon preparation of this report, it was noted that the scrotal mass had not been reviewed by an institutional pathologist and was evaluated only with MART-1, a stain which identifies a protein expressed not only melanoma, but also sex-cord stromal cells. Given that the diagnosis of a solitary melanoma metastasis to the testicle is exceedingly rare, the testicular tissue was stained with additional melanoma markers (S100, pan-melanoma, Sox 10) and Inhibin (Figure 4). The additional melanoma markers were negative and inhibin was positive, confirming the scrotal mass as a Leydig cell tumor. Patient prognosis was amended. As of this report, the patient is tolerating therapy and had no evidence of disease.


Melanoma metastatic to the testicle is a rare event, described only in 19 published case reports and always associated with other sites of metastases (Table 1). The lifetime risk for males of all races to develop melanoma is 2.77%, of which 82% are localized, 10% recur regionally, and 5% develop distant metastases [25]. None of the classification schemes include distant metastasis to sanctuary sites such as the eyes and the testis. [26,27]. Sanctuary sites are unique in that foreign tissue grafts can survive without acute rejection. While originally it was believed physical boundaries specific to these organs prevented immune cell entry and thus, recognition, [28] it is now understood that a combination of locally active immunosuppression, physical structure, and systemic immune tolerance all aid in the immune privileged status of these sites [29]. Invasion of sanctuary sites by metastases is rare; however, important in the differential is an acknowledgement that while with melanoma as the third most common cancer to metastasize to the CNS, [30] and the fourth most common cancer to metastasize to the eye [31,32] these sites are rarely solitary and are associated with widely disseminated disease, portending a poor prognosis [33].
Melanoma metastatic to the testicle comprises less than 1% of all testicular tumors; [5,6,13,34] however, autopsy studies have suggested a greater prevalence, as high as 15%, particularly in the setting of widely disseminated disease. [5,35] Given the rarity of this presentation, especially as a solitary metastasis, it is imperative to confirm the diagnosis by appropriately staging the patient and, while keeping the broad differential in mind, utilizing diagnostic tools that provide the standard of care and a definitive diagnosis. In the case presented here, the patient was appropriately and thoroughly staged for his melanoma. However, when the scrotal mass was identified, the patient chose a urologic provider outside of the center in which he was receiving care for his melanoma. While the scrotal mass was pathologically evaluated following orchiectomy and keeping the clinical history in mind, the immunohistochemical evaluation was incomplete and the specimen was stained with MART-1 only, which is unable to differentiate between a rare melanoma metastasis to the testicle and an also uncommon benign testicular Leydig cell tumor, [36,37,38,39] which comprises 1-3% of all testicular tumors [40,41,42,43]. A more thorough evaluation using additional stains for melanoma antigens and an alternative or complimentary immunohistochemical stain such as Inhibin, sensitive and specific for testicular sex-cord stromal tumors, would have assisted in definitive diagnosis.
In the management of any cancer, and specifically this case, it is imperative that treatment is based on the most accurate diagnosis to assure certainty of stage. All the more so, when the primary site or metastatic location are not concurrent with the expected distribution of disease. Ultimately, the burden of proof lies in a systemic elimination of a differential diagnosis by the site of suspected tumor spread. In this case, the stage 3b diagnosis from the axillary dissection already warranted systemic therapy and thus, did not alter that discussion. However, from a patient and treatment perspective, the prognosis was significantly different and has a real patient consequence on life goals and thoughts of how successful treatment may be. To this end, melanoma ‘the great masquerader’ implores us to consider a simple, yet important, diagnostic algorithm (Figure 5), as it relates specifically to melanoma metastasis to the testicle. In addition, an institutional review of all outside diagnoses made at other facilities would have most likely prevented this oversight.


The differential diagnosis for a solitary testicular mass in a patient with a clinical history of melanoma should include not only primary testicular lesions such as germ-cell and sex-cord tumors, but also lymphoma and metastases from other sites of disease. A thorough histologic evaluation is able to differentiate germ-cell tumors and lymphoma from sex-cord stromal tumors and other metastatic spread. Additional IHC assists in further discrimination of a definitive diagnosis. Although it may seem simple, a definitive diagnosis is the beginning and the end of defining appropriate treatment. In the setting of a testicular mass, an inaccurate diagnosis may not only result in inappropriate therapy but also inaccurate prognosis, both of which have a deleterious effect on patients. Our goal is to elucidate a mistaken identity by developing an algorithm to avoid being fooled by the ‘great masquerader’.


Figure 1: Histology. a) 100x magnification of arm melanoma. Skin with the primary underlying melanoma; b) 100x magnification of lymph node. Extensive replacement of lymph node by melanoma. Lymph node capsule and adipose tissue is noted (arrow).



Figure 2: PET scan of testicular metastasis. The right testicle was FDG-avid and with SUV max of 10.87. The lesion was a heterogenous and mildly hypoechoic hypervascular mass within the right testicular parenchyma with scattered hyperechoic foci within it, measuring 27 mm transversely by 40 mm cephalocaudally by 18 mm AP diameter occupying much of the testicular parenchyma. PET analysis found no other enhancing areas.



Figure 3: Testicular histology. Positive MART-1 staining of the testicular tissue (10x).



Figure 4: Inhibin staining of testicular tissue. a) H and E of the testicular tissue (10x). b) Inhibin stain indicating the identity of a Leydig cell tumor.



Figure 5: Diagnostic algorithm. Proposed diagnostic algorithm to assure a definitive diagnosis. *testicular mass may be incidentally identified (during melanoma or other work-up) or may be symptomatic post-melanoma diagnosis and/or treatment; †all metastases to the testicle are rare and need to be considered in the differential until proven otherwise by histology or IHC.




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