Testicular cancer differential diagnosis

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

## Overview

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Testicular cancer must be differentiated from epididymitis, hematocele, hydrocele, spermatocele, granulomatous orchitis, and varicocele.

## Differentiating Testicular cancer from other Diseases

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Abbreviations:

AFP: Alpha-fetoprotein, B-hCG: Beta-human chorionic gonadotropin, P-ALP: Placental\- Alkaline phosphatase

Diseases  | Benign/ Malignant  | Unilateral/Bilateral  | History/demography  | Metastasis  | Genetics  | Clinical manifestations | Para-clinical findings

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Symptoms  | Physical examination  | Lab findings  | Imaging  | Histopathology
Pain  | Mass  | AFP  | Beta hCG  | p-ALP
Germ Cell tumors
Seminoma[1][2] |

* Malignant

* Unilateral

* Cryptorchidism
* Most common among age of 15-35 years old

* Late metastasis

| Stains positively for:

* ALP
* C-KIT
* CD30
* EMA
* Glycogen

| \-  | \+  |

* Palpable, nontender unilateral testicular mass
* Usually homogeneous enlargement

| N/A  | N/A  | ↑  | Ultrasound

* Homogeneous hypoechoic intratesticular mass
* Cysts and calcification are uncommon
* Inhomogenous feature in larger mass

* Large cells wit watery cytoplasm
* Fried egg appearance

Embryonal carcinoma[3] |

* Malignant

* Usually located in parenchyma of testis
* May be nonpalpable

* Hemorrhagic mass with necrosis
* Rare type
* Peak incidence at the age of 30 years old

| Early metastasis to:

* Retroperitoneum
* Lung
* Liver

| Stains positively for:

* CD30
* HCG

May stain positively for :

* AFP, when mixed with other tumors

| \+  | ±  |

* Unremarkable
* May present with abdominal/ pelvic mass
* Abdominal pain may be present
* Metastatic findings

| ↑*  | ↑  | N/A  | Ultrasound

* Usually hypoechoic mass
* Invasion to tunica albuginea
* Irregular calcification

* Primitive epithelial cells with marked pleomorphism
* Often mixed histopathological features (solid, papillary, tubular, pseudoglandular)

Yolk sac tumor[4][5] |

* Malignant

* Unilateral

* Known as a endodermal sinus tumor
* Undescended testes in youth
* Most common prepubertal testicular cancer in children < 3 years of age

* Uncommon

| Stains positively for:

* AFP
* Alpha-1-antitrypsin
* PAS diastase

| \+  | \+  |

* Palpable mass
* Nontender mass
* Unilateral mass

| ↑  | N/A  | N/A  | Ultrasound

* Diffuse enlargement of the testis with a heterogeneous appearance

MRI

* Areas of hemorrhage and necrosis

* Yellow, mucinous, encapsulated mass

* Schiller-Duval bodies (perivascular structures)
* Hyaline-type globules

Teratoma[6][7] |

* Benign
* Malignant

* Unilateral

* May present in both prepubertal and adult men

* Benign form in children under 4 years oldCongenital disease such as:
* Klinefelter's syndrome
* Down syndrome

* Spina bifida

* Uncommon in benign ones among prepubertal men

* Common in malignant ones among postpubertal ones
* Metastasis may be teratomatous

* Chromosome 12 mutations

Stains positively for:

* Cytokeratin
* HCG
* AFP

| \-  | \+  |

* Palpable mass
* Nontender mass
* Unilateral mass

| ↑  | ↑  | N/A  | Ultrasound

* Heterogeneous, cystic appearance
* Irregular calcification

* Large, heterogeneous appearance
* Presence of at least 2 germ layers

Choriocarcinoma[8][9] |

* Malignant

* Testicular mass may be small/ asymptomatic

* Cryptorchidism
* Abdominal undescended testes
* Most aggressive type

| Early metastasis:

* Liver
* Brain
* Lung

| Stains positively for:

* HCG
* Genetic changes of 12p11.2-p12.1 chromosomal region

| \+  | ±  |

* Nonpalpable or small mass
* Painless or radiating pain to groin/ abdomen
* Metastatic findings
* Gynecomastia
* Hyperthyroidism symptoms

| N/A  | ↑  | N/A  | Ultrasound

* Hemorrhage and necrosis
* May appear more cystic inhomogeneous, and calcified

* Characterized by hemorrhagic and necrotic areas
* Disordered syncytiotrophoblastic and cytotrophoblastic elements

Mixed germ cell tumors[10][11] |

* Malignant

* Unilateral

* Two or more germ cell tumors present as a single mass
* Depends on underlying components
* Average age about 30 years old
* Rare in prepubertal age
* Include one-third of all testicular germ cell tumors

* Metastasis depends on tumors types
* Metastasis to lung, liver, brain, skin

* May stain positive based on underlying components

| ±  | \+  |

* Physical exam findings based on underlying components

| ↑  | ↑  | N/A  |

* Imaging findings based on underlying components

* Variable components depends on tumor
* Accompanied with necrosis and hemorrhages

Carcinoma in situ (intratubular germ cell neoplasia )[12][13][14] |

* Malignant

* Unilateral

* Bilateral

* Cryptorchid testes
* Previous testicular cancer
* Abnormal sexual differentiation
* A precursor of most testicular germ cell tumors
* Adjacent to a other testicular germ cell tumors > 90% of all

| Common:

* Lymph nodes
* Any other organs

Stain positively for:

* Placental ALP

* Genetic changes in chromosome 12

| \-  | \-  |

* N/A

| N/A  | N/A  | ↑  |

* N/A

* Proliferation of neoplastic germ cells in seminiferous tubules

Diseases  | Benign/ Malignant  | Unilateral/Bilateral  | History/Demography  | Metastasis  | Genetics  | Pain  | Mass  | Physical exam  | AFP  | Beta hCG  | p-ALP  | Imaging  | Histopathology
Non-germ cell tumors
Leydig cell tumor[15] |

* Malignant in up to 20% of adult cases

* Benign among children

* Unilateral

* Based on large size, vascular invasion, and mitotic activity classify into benign / malignant
* Bimodal age distribution in both adults and children

* Uncommon metastasis

* Mutation in fumarate hydratase

Stains positively for:

* Inhibin A
* Calretinin
* WT-1
* SALL-4

| \-  | \+  |

* Palpable mass
* Unilateral mass
* Nontender
* Gynecomastia

| N/A  | N/A  | N/A  | Ultrasound

* Well-defined, hypoechoic solid mass
* Cystic component
* Irregular calcification

* Golden brown color
* May have cystic, hemorrhagic, or necrotic areas
* Eosinophilic crystals of Reinke

Sertoli cell tumor ( Androblastoma)[16][17][18] |

* Usually Benign

* Unilateral

* Bilateral

* Classified as large cell calcifying or sclerosing types
* History of peutz-Jeghers syndrome and Carney complex
* Occur in any ages (infancy to elderly)
* Average age of 45 years
* Mean age for large cell calcifying variant is 21 years old

* Uncommon metastasis

| Stain positively for:

* Inhibin
* Cytokeratin

| \-  | \+  |

* Palpable and painless mass
* Hyperestrinism is noted in syndromic cases
* Gynecomastia

| N/A  | N/A  | N/A  | Ultrasound

* Large cell calcifying variant
* Hypoechoic

* Solid or hollow tubules divided by basement membrane

* Pale eosinophilic cytoplasm

Testicular lymphoma[19][20][21] |

* Malignant

* Unilateral

* Bilateral ( mostly up to 35% of cases)

* Aggressive extranodal non-Hodgkin lymphoma
* The most common in men older than 50 years old

| Common metastasis to :

* Skin
* Subcutaneous tissue
* Bone marrow
* Central nervous system
* Lung

| Stains positively for:

* CD45

* Depends on lymphoma subtype

| \-  | \+  |

* Palpable mass
* Nontender mass

| ↑ or ↓  | ↑ or ↓  | N/A  | Ultrasound

* Diffuse testicular infiltration and enlargement
* Hypervascularity
* Hypoechoic and solid lesion

* Pleomorphic malignant cells
* Large irregular nuclei
* Vascular invasion
* Seminiferous tubules

Granulosa cell tumors[22][23] |

* Malignant

* Unilateral

* Juvenile type in children less than 2 years old ( the most common infancy tumor)
* Adult type with average age of 44 years old ( rare)

Juvenile type associated with:

* Sex chromosome abnormalities

* Ambiguous genitalia
* Cryptorchidism

* Metastasis occur in 10%-20% of cases

| Stains positively for:

* Calretinin
* Inhibin
* Vimentin
* Actin
* MIC2

| \-  | \+  |

* Palpable mass
* Nontender mass

| N/A  | N/A  | N/A  | Ultrasound

* Hypoechoic mass
* Solid and cystic appearance

* Common features are microfollicular and diffuse
* Call-Exner bodies in adult type ( eosinophillic material)
* In juvenile type: Solid sheets or nodules and form ectatic spaces

* May stain positively when mixed.

## References

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1. ↑ Siegel RL, Miller KD, Jemal A (2016). "Cancer statistics, 2016". CA Cancer J Clin. 66 (1): 7–30. doi:10.3322/caac.21332. PMID 26742998.CS1 maint: Multiple names: authors list (link)
2. ↑ Miller FH, Whitney WS, Fitzgerald SW, Miller EI (1999). "Seminomas complicating undescended intraabdominal testes in patients with prior negative findings from surgical exploration". AJR Am J Roentgenol. 172 (2): 425–8. doi:10.2214/ajr.172.2.9930796. PMID 9930796.CS1 maint: Multiple names: authors list (link)
3. ↑ Ishida M, Hasegawa M, Kanao K, Oyama M, Nakajima Y (2009). "Non-palpable testicular embryonal carcinoma diagnosed by ultrasound: a case report". Jpn J Clin Oncol. 39 (2): 124–6. doi:10.1093/jjco/hyn141. PMID 19066212.CS1 maint: Multiple names: authors list (link)
4. ↑ Howitt BE, Berney DM (2015). "Tumors of the Testis: Morphologic Features and Molecular Alterations". Surg Pathol Clin. 8 (4): 687–716. doi:10.1016/j.path.2015.07.007. PMID 26612222.
5. ↑ Magers MJ, Kao CS, Cole CD, Rice KR, Foster RS, Einhorn LH; et al. (2014). ""Somatic-type" malignancies arising from testicular germ cell tumors: a clinicopathologic study of 124 cases with emphasis on glandular tumors supporting frequent yolk sac tumor origin". Am J Surg Pathol. 38 (10): 1396–409. doi:10.1097/PAS.0000000000000262. PMID 24921638.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
6. ↑ Simmonds PD, Lee AH, Theaker JM, Tung K, Smart CJ, Mead GM (1996). "Primary pure teratoma of the testis". J Urol. 155 (3): 939–42. PMID 8583612.CS1 maint: Multiple names: authors list (link)
7. ↑ Brosman SA (1979). "Testicular tumors in prepubertal children". Urology. 13 (6): 581–8. PMID 377749.
8. ↑ Puri S, Sood S, Mohindroo S, Kaushal V (2015). "Cytomorphology of lung metastasis of pure choriocarcinoma of testis in a 58-year-old male". J Cancer Res Ther. 11 (4): 1035. doi:10.4103/0973-1482.154010. PMID 26881635.CS1 maint: Multiple names: authors list (link)
9. ↑ Wood HM, Elder JS (2009). "Cryptorchidism and testicular cancer: separating fact from fiction". J Urol. 181 (2): 452–61. doi:10.1016/j.juro.2008.10.074. PMID 19084853.
10. ↑ Chuang KL, Liaw CC, Ueng SH, Liao SK, Pang ST, Chang YH; et al. (2010). "Mixed germ cell tumor metastatic to the skin: case report and literature review". World J Surg Oncol. 8: 21. doi:10.1186/1477-7819-8-21. PMC 2851696. PMID 20331874.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
11. ↑ Krag Jacobsen G, Barlebo H, Olsen J, Schultz HP, Starklint H, Søgaard H; et al. (1984). "Testicular germ cell tumours in Denmark 1976-1980. Pathology of 1058 consecutive cases". Acta Radiol Oncol. 23 (4): 239–47. PMID 6093440.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
12. ↑ Rajpert-De Meyts E, Skakkebaek NE (1994). "Expression of the c-kit protein product in carcinoma-in-situ and invasive testicular germ cell tumours". Int J Androl. 17 (2): 85–92. PMID 7517917.
13. ↑ Jacobsen GK, Nørgaard-Pedersen B (1984). "Placental alkaline phosphatase in testicular germ cell tumours and in carcinoma-in-situ of the testis. An immunohistochemical study". Acta Pathol Microbiol Immunol Scand A. 92 (5): 323–9. PMID 6209917.
14. ↑ Jacobsen GK, Henriksen OB, von der Maase H (1981). "Carcinoma in situ of testicular tissue adjacent to malignant germ-cell tumors: a study of 105 cases". Cancer. 47 (11): 2660–2. PMID 7260858.CS1 maint: Multiple names: authors list (link)
15. ↑ Cheville JC, Sebo TJ, Lager DJ, Bostwick DG, Farrow GM (1998). "Leydig cell tumor of the testis: a clinicopathologic, DNA content, and MIB-1 comparison of nonmetastasizing and metastasizing tumors". Am J Surg Pathol. 22 (11): 1361–7. PMID 9808128.CS1 maint: Multiple names: authors list (link)
16. ↑ Banerji JS, Odem-Davis K, Wolff EM, Nichols CR, Porter CR (2016). "Patterns of Care and Survival Outcomes for Malignant Sex Cord Stromal Testicular Cancer: Results from the National Cancer Data Base". J Urol. 196 (4): 1117–22. doi:10.1016/j.juro.2016.03.143. PMID 27036305.CS1 maint: Multiple names: authors list (link)
17. ↑ Young RH (2005). "Sex cord-stromal tumors of the ovary and testis: their similarities and differences with consideration of selected problems". Mod Pathol. 18 Suppl 2: S81–98. doi:10.1038/modpathol.3800311. PMID 15502809.
18. ↑ Gabrilove JL, Freiberg EK, Leiter E, Nicolis GL (1980). "Feminizing and non-feminizing Sertoli cell tumors". J Urol. 124 (6): 757–67. PMID 7003168.CS1 maint: Multiple names: authors list (link)
19. ↑ Shahab N, Doll DC (1999). "Testicular lymphoma". Semin Oncol. 26 (3): 259–69. PMID 10375083.
20. ↑ Kim J, Abu-Yousef M (2013). "Testicular lymphoma". Ultrasound Q. 29 (3): 247–8. doi:10.1097/RUQ.0b013e3182a0ac0e. PMID 23945480.
21. ↑ Vega F, Medeiros LJ, Abruzzo LV (2001). "Primary paratesticular lymphoma: a report of 2 cases and review of literature". Arch Pathol Lab Med. 125 (3): 428–32. doi:10.1043/0003-9985(2001)125<0428:PPL>2.0.CO;2. PMID 11231498.CS1 maint: Multiple names: authors list (link)
22. ↑ Garrett JE, Cartwright PC, Snow BW, Coffin CM (2000). "Cystic testicular lesions in the pediatric population". J Urol. 163 (3): 928–36. PMID 10688023.CS1 maint: Multiple names: authors list (link)
23. ↑ Ditonno P, Lucarelli G, Battaglia M, Mancini V, Palazzo S, Trabucco S; et al. (2007). "Testicular granulosa cell tumor of adult type: a new case and a review of the literature". Urol Oncol. 25 (4): 322–5. doi:10.1016/j.urolonc.2006.08.019. PMID 17628299.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)

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