Scrotal mass differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

Differential Diagnosis

The table below summarizes the findings that differentiates scrotal mass according to the clinical features, laboratory findings, imaging features, histological features, and genetic studies.

Disease Name	History and Symptoms	Physical Examination	Lab Findings	Imaging Findings	Gross and Histologic Findings	Genetic Studies / Immunohistochemistry
Germ Cell Tumors
Seminoma	Most common 30-50 year-old with painless unilateral testicular mass or mild discomfort	Palpable, nontender unilateral testicular mass Usually homogeneous enlargement	Elevated serum placental ALP (PALP)	Hypoechogenic intratesticular well-defined mass on ultrasound with internal blood flow on Doppler ultrasound Cysts and calcificications are uncommon Hypointense lesion with inhomogeneous enhancement on MRI Homogeneous when small and heterogeneous when large	Grey-white homogeneous mass with a lobular appearance Fried egg appearance on histopathology (large cells and clear cytoplasm) Prominent lymphocytic infiltration and less commonly, granulomatous formation	Stains positively for ALP, c-KIT, CD30, EMA, and glycogen
Embryonal cell carcinoma	Young adults Painful testicular mass Manifests with early mestastasis (bone, lung, CNS)	Often unremarkable (small primary tumor)	Elevated serum hCG Elevated serum AFP, when mixed	Variable echogenicity (usually hypoechoic on ultrasound) No differentiating features on imaging Commonly invade the surrounding structures (tunica albuginea) Irregular calcifications	Pale-grey mass with areas of hemorrhagic and necrosis Often mixed histopathological features (solid, papillary, tubular, pseudoglandular)	Stains positively for CD30 and hCG stain May stain positively for AFP, when mixed
Yolk sac tumor	Most common testicular cancer in children less than 3 years of age Rapidly growing unilateral mass in an infant or a young child	Palpable, nontender unilateral testicular mass Usually heterogeneous enlargement	Elevated serum AFP	Diffuse enlargement of the testis with a heterogeneous appearance on ultrasound Areas of hemorrhage and necrosis on MRI	Yellow, mucinous, non-encapsulated, heterogeneous mass with areas of necrosis and hemorrhage Patterns that resemble embryonal structures (yolk sac, allantois) with reticular, papillary, or elongated forms Schiller-Duval bodies (perivascular structures)	Stains positively for AFP, alpha-1-antitrypsin, PAS diastase
Teratoma	Bimodal distribution of age (infants and middle aged adults) Painless tumor History of congenital disease (Down syndrome, klinefelter, spina bifida)	Palpable, nontender unilateral testicular mass Usually heterogeneous enlargement	Elevated serum hCG Elevated serum AFP	Heterogeneous, cystic appearance with mucinous or sebaceous depositions Variable echogenicity on ultrasound Calcifications usually irregular	Large, heterogeneous appearance with solid, cystic, mucoid, and/or cartilageanous components Presence of at least 2 germ layers	Chromosome 12p mutations Stains positively for cytokeratin. hCG, and AFP
Teratocarcinoma	Middle aged adult with painless testicular mass of mild discomfort May manifest with features of metastasis	Palpable, nontender unilateral testicular mass Usually heterogeneous enlargement	Elevated serum hCG Elevated serum AFP	Variable echogenicity on ultrasound	Features of both teratoma and embryonal carcinoma (more common) or both teratoma and choriocarcinoma (less common) Solid and cystic components with mucoid, cartilagenous, sebaceous gland, myxoid stroma components Additional features of underlying embryonal carcinoma or choriocarcinoma	Stains positively for cytokeratin. hCG, AFP, and CD30
Choriocarcinoma	Adolescent or young adult with extratesticular symptoms Mass is small and locally asymptomatic Manifests with early metastasis and signs of hemorrhage (hemorrhagic stroke, hyperthyroidism, cannon-ball metastasis in lung, liver involvement, neurological deficits)	Often unremarkable (small primary tumor)	Elevated serum hCG	Variable echogenicity No differentiating features on imaging Commonly invade the surrounding structures (tunica albuginea)	Prominent areas of hemorrhage and necrosis Nest and sheet pattern that simultaneously includes both cytotrophoblast and syncytiotrophoblast (rarely pure) Paucity of intermediate trophoblasts (unlike placental site trophoblastic tumor)	Stains positively for hCG
Diffuse embryoma	20-25 yo man with painful testicular mass	Tender testicular mass	Elevated serum hCG Elevated serum AFP	Poorly-defined, heterogeneous hyperechoic mass on ultrasound	Non-encapsulated mass Intermingled (lace-like) embryonal carcinoma and yolk sac components in equal proportions, but no discrete embyoid bodies Scattered trophoblastic components Necklace-like arrangement of cells	Stains positively for cytokeratin, AFP (yolk sac component), and CD30 (embyonal component)
Polyembryoma	20-25 yo man with painful testicular mass	Tender testicular mass	Elevated serum AFP Elevated serum hCG	Poorly-defined, heterogeneous hyperechoic mass on ultrasound	Multiple discrete embyoid bodies (combination of both embryonal carcinoma and yolk sac components)	Stains positively for cytokeratin, AFP (yolk sac component), and CD30 (embyonal component)
Placental site trophoblastic tumor	Infant or young adult Painful small testicular mass	Small nontender or minimally painful testicular mass	Elevated serum hCG	Variable echogenicity No differentiating features on imaging May have vascular flow	Solid yellowish mass that resembles uterine tissue Less prominent foci of hemorrhage and ncerosis Predominance of intermediate trophoblast cells (implantation-site type) that invade surrounding blood vessels Paucity of cytotrophoblast and syncytiotrophoblast cells (unlike choriocarcinoma)	Stains positively for hPL (diffuse), cytokeratin, AFP, and hCG (patchy) Negative p63 staining
Epithelioid trophoblastic tumor	Infant or young adult Painful small testicular mass	Small nontender or minimally painful testicular mass	Elevated serum hCG	Variable echogenicity No differentiating features on imaging May have vascular flow	Solid yellowish mass that resembles uterine tissue Less prominent foci of hemorrhage and ncerosis Predominance of intermediate trophoblast cells (implantation-site type) that invade surrounding blood vessels Paucity of cytotrophoblast and syncytiotrophoblast cells (unlike choriocarcinoma)	Stains positively for p63 (diffuse), p63, cytokeratin, AFP, and hCG (patchy) Negative hPL staining
Mixed germ cell tumor	Typical age at diagnosis and other clinical features based on underlying components	Physical exam findings based on underlying components	Elevated serum hCG, AFP, and/or PALP dependeing on the underlying compoenents	Imaging findings based on underlying components	Histopathological findings based on underlying components Variable proportion of choriocarcinoma, embryonal cell carcinoma, yolk sac tumor, seminoma, and/or teratoma tissue	May stain positively for any of CD30, hCG, AFP, ALP, c-KIT, CD30, EMA, alpha-1-antitrypsin, PAS diastase, and glycogen depending on underlying compoenents
Carcinoid (pure neuroendocrine neoplasm)	Middle-aged and elderly adult Manifests as a minimally painful, rapidly growing mass May manifest as carcinoid syndrome	Tender testicular mass Hydrocele or cryptorchidism	Elevated serum and urine 5-HIAA if carcinoid syndrome present	Unilateral, well-circumscribed mass without vascular invasion Solid and cystic appearance Mixed echogenicity on ultrasound Irregular calcifications	Well-circumscribed, yellowish solid mass Occasional cystic masses Small acini, cord-forming rosettes, prominent cytoplasmic granularity Salt and pepper chromatic pattern Absent features of atypia Neurosecretory granules on electron microscopy	Stains positively for cytokeratin, serotonin, chromogranin, synaptophysin, and CD56
PNET (Ewing's tumor of the testes)	30-50 yo man with rapidly enlarging mass Often metastatic at presentation	Palpable, nontender unilateral testicular mass	Unremarkable	No differentiating features on imaging Vascular flow on Doppler	Greyish necrotic mass of immature neural tissue Sheet-like / rosette distribution of small round blue tumor cells Neurosecretory granules on electron microscopy	Stains positively for synaptophysin, NSE, chromogranin, CD99, GFAP, FLI1 Split of EWS gene on chromosome 22
Sex-cord stromal tumors
Fibroma	Middle-aged adult (range 20-70 years) with slowly-growing, painless testicular mass History of nevoid basal cell carcinoma (Gorlin syndrome)	Palpable, nontender unilateral testicular mass	Unremarkable	Isoechoic mass on ultrasound with prominent acoustic shadowing (fibrous component) May be homogeneous or heterogeneous Margins often blended with the tunica albuginea No vascular flow on Dopper	Well-circumscribed, often non-encapsulated solid pale yellow mass No hemorrhage, no necrosis Pure fibromatous features of collagenized plaques and spindle cells that synthesize collagen. Low cellularity	Mutation in PTCH gene Positive staining for calretinin, inhibin, CD56, CD34, actin, vimectin Usually (but not always) negative staining for S-100, keratin, CD99/MIC-2, and desmin
Granulosa cell tumor	Young or middle-aged adult (adult-type) or infant/child (juvenile-type) patient with slowly-enlarging painless testicular mass May manifest with symptoms of metastasis or hormonal secretion (e.g. gynecomastia in estrogen-secreting tumors)	Palpable, nontender unilateral testicular mass	Unremarkable	Hypoechoic mass with solid and cystic appearance on ultrasound (swiss-cheese appearance)	Well-circumscribed tumor between the seminiferous tubules May be solid, cystic, of lobular Pseudo-capsule No hemorrhage, no necrosis Elongated grooved nuclei (coffee-bean appearance) Call-Exner bodies Variable atypia	Stains positively for calretinin, inhibin, vimentin, actin, and MIC2
Leydig (interstitial) cell tumor	Bimodal age distribution Slowly enlarging painless unilateral mass	Palpable, nontender unilateral testicular mass Signs of excess estradiol (e.g. gynecomastia)	Unremarkable	Well-defined, hypoechoic solid mass on ultrasound May have cystic component Irregular calcifications	Well-circumscribed, unencapsulated solid mass Yellowish-brown tumor May have cystic, hemorrhagic, or necrotic areas Often dffuse growth of large polygonal Leydig cells, but may have unique patterns of growth Vacuolated cells with marked atypia Reinke crystals Psammoma bodies	Mutation in fumarate hydratase Stains positively for inhibin, cytokeratin, calretinin, synaptophysin, vimentin, Melan-A
Sertoli hyperplasia (Sertoli adenoma, Pick's adenoma)	Child or young adult with history of Peutz-Jegher syndrome, androgen insensitivity syndrome, or McCune Albright syndrome Slowly enlarging painless bilateral masses	Palpable, nontender bilateral testicular masses Signs of excess estradiol (e.g. gynecomastia)	Elevated serum estradiol Elevated anti-Mullerian hormone and inhibin B Reduced androgen concentration	Hyperechogenic nodules on ultrasound	Well-demarcated yellowish nodules in the testis Unencapsulated nodules composed of Sertoli cells	Stains positively for anti-Mullerian hormone, inhibin A, CK8, and CK18 Negative staining for AFP, hCG, and p53
Large cell calcifying Sertoli cell tumor	Young patient with history of Carney syndrome, Peutz-Jeghers syndrome, or tuberous sclerosis Slowly enlarging painless unilateral/bilateral mass(es)	Palpable, nontender unilateral or bilateral testicular mass Signs of excess estradiol (e.g. gynecomastia)	Elevated serum estradiol	Diffuse and regular (smooth, rounded, large) calcifications Variable appearance on ultrasound Often multiple hyperechogenic regions with strong shadowing Possible increased blood flow	Multifocal, well-circumscribed yellowish-grey nodules Absent hemorrhage or necrosis Patterrns (sheet or trabeculae) of large cells and formation of solid tubules Psammoma bodies Charcot Bottcher crystals on electron microscopy	Stains positively for inhibin, vimentin, calretinin, S100, and cytokeratin Negative staining for laminin, PALP, AFP, and hCG
Sclerosing Sertoli cell tumor	Variable age at presentation (adolescence to elderly) Slowly enlarging painless unilateral mass	Palpable, nontender unilateral testicular mass	Unremarkable	Well-circumscribed hypoechogenic lesion on ultrasound	Well-circumscribed, yellowish-grey nodule Absent hemorrhage or necrosis Tubuules and cords of Sertoli cells surrounded by hypocellular collagenous strome (sclerosis)	Stains positively for calretinin, inhibin, and vimentin Negative staining for cytokeratin, AFP, and hCG
Sertoli tumor, non-specific	Bimodal age districution: either 40-50 year old man or infants with history of Carney syndrome or Peutz-Jegher syndrome Slowly enlarging testicular mass	Palpable, nontender unilateral testicular mass Signs of excess estradiol (e.g. gynecomastia)	Often unremarkable Elevated serum estradiol may be present, less common	Well-circumscribed mass with variable echogenicity	Well-circumscribed, yellowish-grey nodule Hemorrhage and necrosis may be present, but uncommon Features of fetal, prepubertal, and adult Sertoli cells present simultaneously Charcot Bottcher crystals on electron microscopy	Stains positively for vimentin, cytokeratin, inhibin, S100, chromogranin, synaptophysin, and CD99 Negative staining for hCG, AFP, and PLAP
Sertoli-Leylig cell tumor (SLCT)	Young adult or phenotypic female with history of androgen insensitivity Slowly enlarging painless unilateral mass	Palpable, nontender unilateral testicular mass Signs of excess estradiol (e.g. gynecomastia)	Often unremarkable Elevated serum estradiol may be present, less common Abrnomally elevated testosterone among pts with androgen insensitivity	Well-circumscribed mass with variable echogenicity Solid mass with intratumoral cysts may be present	Heterogeneous, lobulated, encapsulated yellowish solid mass Mass contains combination of Sertoli cells and Leydig cells Poorly differentiated cells (immature tubules of Sertoli cells, large Leydig cells)	Stains positively for inhibin, melanA, and CD99 Negative staining for EMA, PLAP, and S100
Testicular tumor of andrenogenital syndrome (testicular adrenal rest tumor)	Post-pubertal patient with history of congenital adrenal hyperplasia (CAH) Often asymptomatic, detected during screening in patients with CAH	Unremarkable testicular exam Other signs of congenital adrenal hyperplasia	Elevated 11-beta-hydroxylase activity Reduced concentrations of AFP, LDH, and hCG	Uniform hypoechogenicity on ultrasound Usually multifocal and bilateral lesions	Hyperplasia, bilateral lesions in testicular hilum Yellowish nodules Cells resemble adrenocortical cells, no mitoses Normal surrounding tissue Absent Reinke crystals	Stains positively for CD56, synaptophysin, and inhibin Negative staining for androgen receptor protein
Other tumors
Lymphoma	Elderly patient (>60 years) with history of lymphoma (commonly diffuse large B cell lymphoma) Unilateral or bilateral painless testicular mass	Palpable, nontender unilateral or bilateral testicular mass	Depends on lymphoma subtype	Diffuse infiltration Hypoechoic solid masses on ultrasound Hypervascularity on Doppler ultrasound	Whitish-tan colored mass Large, pleomorphic malignant cells Seminiferous tubules may be spared or undergo sclerosis Vascular invasion	Stains positively for CD45 Depends mainly on lymphoma subtype Usually negative staining for PLAP and SALL4
Angiosarcoma	Bimodal age distribution Young man with history of teratoma or elderly man with history of radiation or chronic hydrocele Painless/painful testicular mass	Tender or non-tender testicular mass Low-grade fever Scrotal swelling Flank pain Hydrocele	Often unremarkable	Hypervascularity on Doppler ultrasound	Solid vascular lesion Classical pattern of proliferating anastomosing blood-filled channels 2 patterns: solid (sheet proliferation without lumen) and primitive (small lumina filled withblood)	Stains positively for CD31, CD34, lectin, and factor VIII-related antigen Negative staining for pancytokeratin, PLAP, CD45, CD68, CAM5.2, and AE1/AE3
Chondrosarcoma	Young or middle-aged adult with history of teratoma Painless testicular mass	Palpable, non-tender, heterogeneous mass	Often unremarkable	Lobulated mass	Firm, grey mass with irregular lobulations Cartilaginous (chondroid) matrix surrounded by fibrovascular bands Most have non-cartilagenous components (rarely pure)	Stains positively for S100
Hemangioma	Painless testicular mass among pts of any age	Palpable, non-tender, homogeneous mass	Often unremarkable	Homogeneous hypoechoic mass Hypervascularity on Doppler ultrasound	Well-defined hemorrhagic mass Red blood cells in tubules	Stains positively for CD31, CD34, FLI1, and factor VIII-related antigen Negative staining for pancytokeratin, AE, keratin, PLAP, and EMA
Mesothelioma	Middle aged man with painless testicular mass and history of hydrocele or exposure to asbestos	Palpable, non-tender testicular mass Scrotal swelling	Often unremarkable	Thickening of tunica vaginais Solid paratesticular mass Hydrocele	May be benign or malignant Papillary patterns of uniform epithelioid cells with fibrovacular core Polygonal cells with microvilli on electron microscopy Psammoma bodies	Benign: stains positively for p53 (focal) and CEA Malignant: Stains positively for calretinin, WT1, EMA, thrombomodulin, CK5, CK6, CK7 and negative staining for CEA and CK20
Plasmacytoma	Adult (of any age) with concurrent or history of plasma cell neoplasia (commonly multiple myeloma) Symptoms of multiple myeloma (e.g. fatigue, back pain)	Testicular exam unremarkable	Lab findings of plasmacytosis (e.g. anemia, elevated creatinine, hypercalcemia) No specific lab finding for testicular involvement	Poorly circumscribed hypoechoic lesions on ultrasound Hypervascularity on Doppler ultrasound	Large, tan-yellow mass Areas of hemorrahge Atypical plasma cells Tubule effacement in the center and tubule sparing in the periphery	Positive staining for EMA, CD45, CD79am CD138, kappa or lambda light chains, and other plasma cell markers
AIDS-related testicular cancer	Commonly testicular lymphoma or germ cell tumor Patient with history of AIDS presents with testicular swelling or pain Systemic manifestations of underlying malignancy	Palpable testicular mass that may be tender or non-tender	Depends on underlying malignancy	Depends on underlying malignancy	Depends on underlying malignancy	Depends on underlying malignancy
Non-neoplastic mass
Adrenal cortical rest	Usually asymptomatic (incidental finding) Young man with scrotal swelling and dull pain History of congenital adrenal hyperplasia (hydroxylase deficiency)	Scrotal swelling	May be unremarkable If secretory, elevated concentration of adrenal hormone	Heterogeneous, well-circumscribed hypoechoic mass on ultrasound No or minimal vascularity on Doppler No distinguishing features	Well-circumscribed, small, round, orange-yellow nodule Adrenal cortical tissue with absence of adrenal medullary tissue	Positive staining for markers of cortical adrenal tissue
Chylocele	Scrotal swelling in a man with history of filariasis / elephantiasis	Scrotal swelling Negative trans-illumination test	Unremarkable	Fluid collection surrounding the testes	Milky chylous fluid (not waterry) on aspiration Usually no evidence of microfliariae in chylous fluid Abundant leukocytes	N/A
Cystic dysplasia	Young child with history of renal agenesis / dysplasia May be unilateral or bilateral, painless testicular mass	Palpable, non-tender testicular mass	Unremarkable	Irregular cystic spaces witht varying sizes Absence of solid or vascular components	Varying cystic spaces Formation of incomplete connective tissue septa Cells resembling the normal adult rete testes	N/A
Dermoid cyst
Stromal
Brucellosis	Patient with history of exposure to cattle/sheep/goat/swine or animal products (milk, meat, cheese) presents with acute scrotal pain and swelling Undulant fever and night sweats (characteristic wet hay odor) Relapses common with similar symptoms	Tender testicular mass Fever Hydrocele	Elevated WBC count Positive serum STA test for brucellosis Elevated Brucella IgM and IgG antibodies Urine PCR positive for Brucella	Focal/diffuse hypoechogenicity on ultrasound Focal/diffusre increased blood flow on Doppler Scrotal wall thickening	Granulomatous inflammation with lymphocytic infiltration	Urethral Gram stain demonstrates Gram-negative diplococci