1. Neoplasms of the Testis
Ch. 31
Omar Alhunaidi

2. Introduction 95% of testicular neoplasms are germ cell tumors (GCTs)
GCTs are broadly categorized as seminoma and nonseminoma (NSGCT)
GCTs are relatively rare malignancies, accounting for 1% to 2% of cancers among men in the US

3. Approximately 90% of GCTs arise in the testis and 2% to 5% are extragonadal
long-term survival for men with metastatic GCT is 80% to 90%

4. Non-GCTs of the testis are rare and include:
sex cord/stromal tumors
lymphoid and hematopoietic tumor
tumors of the collecting duct
tumors of the testicular adnexa

5. Epidemiology
In the US testicular cancer is the most common malignancy among men aged 20 to 40 years
It is the second most common cancer after leukemia among males aged 15 to 19 years
The incidence of bilateral GCT is approximately 2%
Testicular lymphoma is less common than GCT but it is the most common testicular tumor in men > 50 years

6. Risk Factors Four well-established risk factors:
Cryptorchidism ( risk increase 4 to 6 times)
Family history of testicular cancer
Personal history of testicular cancer
Intratubular germ cell neoplasia (ITGCN)
* Infertile men also have a higher incidence of testicular cancer

7. Most GCTs arise from a precursor lesion called intratubular germ cell neoplasia (ITGCN) (which is also referred to as carcinoma in situ).
ITGCN is present in adjacent testicular parenchyma in 80% to 90% cases of invasive GCT
Gene expression profile analysis indicates that ITGCN develops before birth from an arrested gonocyte

8. In men with a history of GCT, the finding of testicular microlithiasis on ultrasound evaluation of the contralateral testis is associated with an increased risk of ITGCN (Karellas et al, 2007).
However, the significance of microlithiasis in the general population is unclear

9. Pathogenesis and Biology
The carcinogenesis of GCTs is poorly understood
Testicular GCTs develop from a precursor lesion, ITGCN, which, in turn, appears to develop from arrested primordial germ cells or gonocytes that failed to differentiate into prespermatogonia
Hussain et al, 2008
Approximately 70% of GCTs have an extra copy of chromosome 12 in the form of an isochromosome 12p (i[12p]

10. Increased incidence of other male reproductive disorders, such as:
Hypospadias
Cryptorchidism
Subfertility
These findings led to the hypothesis that testicular cancer and these other disorders all resulted from a TESTICULAR DYSGENESIS SYNDROME, which is due to  environmental and/or lifestyle factors

11. Environmental and/or lifestyle factors:
Increased prenatal estrogen exposure
reduction in androgen activity
mothers of children with testicular cancer have more pollutant in their blood
*ALL ARE HYPOTHESIS

12. GCTs is sensitive to cisplatin-based chemotherapy, which enables cure in the vast majority of patients with widely metastatic disease.

13. Up to 10% of GCTs are extragonadal 2 main hypothesis:
they originate from germ cells that mismigrated along the genital ridge and were able to survive in an extragonadal environment
Reverse migration from the testis to extragonadal locations

14. Histologic Classification
GCTs classified as:
Seminoma (52% to 56%)
NSGCT (44% to 48%)
Embryonal carcinoma (EC)
yolk sac tumor
Teratoma
choriocarcinoma

16. Intratubular Germ Cell Neoplasia
all adult invasive GCTs arise from ITGCN except for spermatocytic seminoma
consists of undifferentiated germ cells that have the appearance of seminoma that are located basally within the seminiferous tubules
tubule usually shows decreased or absent spermatogenesis
presence of ITGCN in an orchiectomy specimen in men with testicular cancer does not carry any prognostic implications

17. Seminoma Seminoma is the most common type of GCT
Most cases diagnosed in the fourth or fifth decade
Grossly, seminoma is a soft tan
to white diffuse or multinodular
mass

18. Spermatocytic Seminoma
Rare and accounts for less than 1% of GCTs
Unlike other GCTs:
does not arise from ITGCN
not associated with a history of cryptorchidism
does not express PLAP or i(12p)
does not occur as part of mixed GCTs
It is a benign tumor (only one documented case having metastasized) and is almost always cured with orchiectomy (Chung et al, 2004a).

19. Embryonal Carcinoma.
most undifferentiated cell type of NSGCT, with totipotential capacity to differentiate to other NSGCT cell types
Grossly, it is a tan to yellow neoplasm that often exhibits large areas of hemorrhage and necrosis
aggressive tumor associated with a high rate of metastasis, often in the context of normal serum tumor markers

20. Choriocarcinoma rare and aggressive tumor
typically presents as elevated serum hCG levels and disseminated disease
commonly spreads by hematogenous routes
common sites of metastases:
Lungs
Brain ( DON’T FRGET TO IMAGE THE BRAIN)
Eye and skin metastases are also been reported

21. Yolk Sac Tumors
Pure yolk sac tumors represent a very small fraction of adult-type GCTs but are more common in mediastinal and pediatric GCTs
Schiller-Duval body is a characteristicfeature
almost always produce AFP but not hCG

22. Teratomas
are tumors that contain well-differentiated or incompletely differentiated elements of at least two of the three germ cell layers of:
endoderm
mesoderm
Ectoderm
Teratomas are generally associated with normal serum tumor markers, but they may cause mildly elevated serum AFP levels
In adults, teratomas are histologically benign but are frequently found at metastatic sites in patients with advanced NSGCT
Teratoma is resistant to chemotherapy

23. Growing Teratoma Syndrome:
Is when teratoma grows uncontrollably, invade surrounding structures, and become unresectable
Rarely, it may transform into a somatic malignancy such as rhabdomyosarcoma, adenocarcinoma, or primitive neuroectodermal tumor
Malignant transformation is highly aggressive, resistant to conventional chemotherapy, and associated with a poor prognosis

24. Initial Presentation
The most common presentation of testicular cancer is a painless testicular mass
Acute testicular pain is less common and is caused by rapid expansion of the testis due to intratumor hemorrhage or infarction
Pain is more commonly associated with NSGCT, because these tumors tend to be more vascular and exhibit more rapid growth
Symptoms related to metastatic disease are the presenting complaint in 10% to 20% of patients

25. Retroperitoneal metastasis may cause:
palpable mass
abdominal pain
flank pain due to ureteral obstruction
back pain due to involvement of the psoas muscle or nerve roots
lower extremity swelling due to compression of the inferior vena cava
gastrointestinal symptoms.

26. Pulmonary metastasis may present as
dyspnea
chest pain
cough
hemoptysis
Metastasis to supraclavicular lymph nodes may present as
neck mass

27. Approximately 2% of men have GYNECOMASTIA, resulting from either:
elevated serum hCG levels
decreased androgen production
increased estrogen levels (most commonly seen in men withLeydig cell tumors)
Although approximately two thirds of men with GCT have diminished fertility, it is an uncommon initial presentation

28. Physical Examination physician should carefully examine both testis
Atrophy of the affected or contralateral testis is common, more with h/o cryptorchidism
Any firm area within the testis is suggestive of malignancy
hydrocele may accompany a testicular cancer and impair the examination

29. Patient should also be examined for any evidence of:
palpable abdominal mass or tenderness
inguinal lymphadenopathy (mainly if he had prior inguinal or scrotal surgery)
gynecomastia
supraclavicular lymphadenopathy
Auscultation of the chest

30. A firm intratesticular mass should be considered cancer until proven otherwise and should be evaluated further with scrotal U/S

31. Diagnostic Testing
Scrotal U/S should be considered after examination because it is inexpensive and noninvasive
On ultrasonography the typical GCT is hypoechoic and two or more discrete lesions may be identified
Heterogeneous echotexture within a lesion is more commonly associated with NSGCT, because seminomas usually have a homogeneous echotexture

33. Serum Tumor Markers LDH AFP hCG
They are essential in its diagnosis, prognosis, treatment, and monitoring
AFP is elevated in:
50% to 70% of low-stage (CS I, IIA, IIB) NSGCT
60% to 80% of advanced (CS IIC, III) NSGCT

34. EC and yolk sac tumors secrete AFP
Choriocarcinomas and seminomas do not produce AFP
The half-life of AFP is 5 to 7 days
AFP levels may also be raised in patients with
hepatocellular carcinoma
Stomach ca
Pancreas ca
biliary tract ca
Lung ca

35. hCG levels are elevated in
20% to 40% of low-stage NSGCT
40% to 60% of advanced NSGCT
15% of seminomas secrete hCG
hCG is also secreted by choriocarcinoma and EC
The half life of hCG is 24 to 36 hours

36. hCG levels may be elevated in cancers of the:
liver
biliary tract
pancreas
stomach
lung
Breast
kidney
bladder

38. LDH levels are elevated in:
20% of lowstage GCTs
20% to 60% of advanced GCTs
LDH is expressed in smooth, cardiac, and skeletal muscle
Lymphoma may also cause elevated LDH levels

39. Patients suspected of having a GCT should do serum AFP, hCG, and LDH evaluation
before orchiectomy to aid in the diagnosis
and to help interpret postorchiectomy tumor marker levels

40. Initial Management
Radical inguinal orchiectomy when testicular neoplasm is suspected, with removal of the tumor-bearing testis and spermatic cord to the level of the internal inguinal ring
A transscrotal orchiectomy or biopsy is contraindicated because:
it leaves the inguinal portion of the spermatic cord intact and may alter the lymphatic drainage of the testis
increasing the risk of local recurrence
Pelvic or inguinal lymph node metastasis

41. Because of the rapid growth of GCT, orchiectomy should performed in a timely manner and delays greater than 1 to 2 weeks should be avoided

42. Testis-sparing surgery (or partial orchiectomy)
is highly controversial and has no role in the patient suspected of having a testicular neoplasm with a normal contralateral testis
It MAY be considered for organ confined tumors of less than 2 cm in patients with bilateral tumors or tumor in a solitary testis
Also it may be considered for suspected benign tumor or indeterminate lesion when serum AFP, hCG, and LDH values are normal.

43. When testis-sparing surgery is performed, biopsies of the adjacent testicular parenchyma should be done to R/O ITGCN
Adjuvant radiotherapy to the residual testis is usually sufficient to prevent the development of a GCT

44. Biopsy of the Contralateral Testis
Open inguinal biopsy of the contralateral testis may be considered in patients with risk factors for ITGCN or those with suspicious lesions on preoperative ultrasonography

45. Clinical Staging
The prognosis of GCT and initial management decisions are dictated by the clinical stage of the disease by histological and radilogical findings
Lymphatic spread is the most common route of disease dissemination, except for Choriocarcinoma.
Retroperitoneum is the initial site of metastatic spread in 70% to 80% of patients with GCT

46. Clinical Staging
CS I : disease clinically confined to the testis
CS II : indicates the presence of regional (retroperitoneal) lymph node metastasis
CS III : represents nonregional lymph node and/or visceral metastasis.

47. For RIGHT testicular tumors the primary drainage site is the interaortocaval lymph nodes inferior to the renal vessels, followed by the paracaval and para-aortic nodes.
For LEFT testicular tumors is the para-aortic lymph nodes, followed by the interaortocaval nodes
Distal iliac and inguinal lymph nodes secondary to large volume disease or aberrant testicular lymphatic drainage

48. All patients with GCT should do CT Abd+Pelvis with oral & IV contrast for staging
(MRI) is an alternative to CT

49. All patients with GCT should undergo chest imaging
Thoracic metastasis in the absence of retroperitoneal disease and/or elevated serum tumor markers is uncommon
Routine chest CT may be associated with a high rate of false-positive findings

50. Serum Tumor Markers
Postorchiectomy AFP, hCG, and LDH levels are important for staging, prognosis, and treatment selection
presence of newly elevated and / or rising serum tumor marker levels after orchiectomy indicates metastatic disease

55. Therapeutic Principles
After orchiectomy, staging imaging studies, serum tumor marker status, and treatment plans should be performed as soon as possible
Cisplatin which is a nephrotoxic chemotherapy is often administered even in the presence of moderate-to-severe renal insufficiency
Seminoma is associated with increased sensitivity to radiation therapy and platin-based chemotherapy compared with NSGCT.
Aggressive surgical approach is taken to resect all sites of residual disease after chemotherapy for NSGCT

56. Sperm cryopreservation should be offered to all patients before RPLND, chemotherapy, or radiation therapy owing to the potential effects of these treatments on fertility.

57. MANAGEMENT NSGCT
The optimal management of CS I NSGCT is controversial.
Surveillance, primary RPLND, and primary chemotherapy with BEPAx2 (+ adjuvant bleomycin-etoposide-cisplatin) are accepted treatment options, with long-term survival rates approaching 100% for each.
Surveillance is not recommended to patients who are anticipated to be poorly compliant with follow-up imaging and clinical evaluation.
BEPx2 is the standard regimen used for patients with CS I NSGCT who choose to receive chemotherapy

58. Adjuvant chemotherapy after primary RPLND for pathologic stage II disease is associated with a reduced risk of relapse
Adjuvant chemotherapy is usually recommended to patients with extensive retroperitoneal metastasis (pN2-3) and those anticipated to be noncompliant with postoperative cancer surveillance imaging and testing

59. Induction chemotherapy and primary RPLND are accepted treatment options for patients with CS IIA-B NSGCT, with long-term cure in 95%

60. management of patients with CS IS, IIC, and III NSGCT is induction cisplatin-based chemotherapy
Patients with good-risk disease should receive BEPx3 or BEPx4
Those with intermediate- and poor-risk disease should receive BEPx4
Postchemotherapy resection of all residual masses is based on the incidence of residual cancer

61. MANAGEMENT OF SEMINOMA
The optimal management of CS I seminoma is controversial
Surveillance, primary radiotherapy, and primary chemotherapy with carboplatin (one to two cycles) are accepted treatment with long-term survival rates approaching 100% for each
Surveillance is not recommended to patients who are anticipated to be poorly compliant

62. For CS IIA-B seminoma, radiotherapy and first-line chemotherapy (BEPx3 or BEPx4) are accepted treatment with nonbulky (<3 cm) retroperitoneal lymph node metastasis.
For bulky (>3 cm) and/or multifocal retroperitoneal metastases, first-line chemotherapy (BEPÅ~3 or EPÅ~4) is recommended
The treatment of patients with CS IIC and III seminoma is first-line cisplatin-based chemotherapy

63. NON–GERM CELL TUMORS

64. term refers to neoplasms containing
Sex cord/stromal tumors are rare, comprising approximately 4% of testicular neoplasms
term refers to neoplasms containing
Leydig cells
Sertoli cells
Granulosa cells
Thecal cells

65. Leydig cell tumors are the most common of the sex cord/stromal tumors
no association with cryptorchidism
occur in adult males between age 20 and 60 years
Common presentation is a painless testicular mass
Frequently p/w feminizing characteristics including:
gynecomastia
impotence,
decreased libido

66. Radical inguinal orchiectomy is the initial treatment of choice
90% of these tumors are benign, and 10% are malignant
The most frequent metastatic sites are the retroperitoneum and lung.
Metastatic Leydig cell tumors are resistant to chemotherapy and radiation therapy

67. Sertoli Cell Tumor
less than 1% of testicular neoplasms.
occur in any age group, including infants
no association with cryptorchidism
Treatment is radical inguinal orchiectomy
Ninety percent of tumors are benign, and 10% are malignant

68. Thank u