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]

Overview

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


References

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