Two7 76A1 Neoplasm of Testis - Germ Cell Tumors - Basics and diagnosis

  1. Age for the testicular tumour?
    Testis tumours are most common between the ages of 15 and 55. The incidence rate rises rapidly after puberty, peaking at ages 25 to 35, and then slowly declines such that men aged 50 to 54 years have the same incidence as males aged 15 to 19.

    • - teratoma between 20 and 30 years
    • - seminoma between 30 and 40 years.   On average,  seminomas occur at an older average age than NSGCT, with most cases diagnosed in the fourth or fifth decade of life

    Tumors in older age - Spermatocytic tumors, sex cord stromal tumors, lymphoma
  2. Five risk factors of testicular cancer?
    • White race 
    • Cryptoorchidism - 4-6 times, 2-3 times if orchidopexy before puberty, contralateral risk 1.74 [@ risk reduced to half if orchidopexy is done before puberty - from 4-6 to 2-3 times] 
    • Family history - 8-12 times
    • Personal history - 12 times 
    • ITGCN - 50% risk of GCT in next 5 years, 70% within 7 years
  3. Why orchodopexy does not completely eliminate the risk of carcinoma testis?
    It is genetic change that causes cancer - even if the patient has orchidopexy, or contralateral normal testis - there is risk of cancer
  4. Classify testicular tumors?
    • A. Germ cell tumors (95%)  - 95% from testes, 5% extragonadal origin (retroperitoneal, mediastinal) 
    • - Seminomatous - 52-56%
    • - Non seminomatous  - 44-48%

    B. Non germ cell tumors (5%)

    • Most common testicular tumor in children - Teratoma, benign 
    • Most common malignant prepubertal tumor - YST (CC12-1123) 

    If any tiny proportion of NSGCT is present in seminoma, it should be managed as NSGCT. 

    • Image Upload 1
    • Figure: from Nature Review 2018

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    Prepubertal testicular tumors differ markedly from those of postpubertal males in that benign lesions are more common and malignant tumors have a more favorable course.
  5. What are seminoma?
    • Gross
    • - soft tan to white diffuse or multinodular mass
    • - Necrosis may be present but is usually focal and not as prominent as other GCTs.

    • Microscopy
    • - sheet-like arrangement of cells with polygonal nuclei and clear cytoplasm, with the cells divided into nests by fibrovascular septae that contain lymphocytes
    • - Lymphocytic infiltrates and granulomatous reactions are often seen, and seminomas appear to be associated with an increased incidence of sarcoidosis
    • - Immunohistochemistry - CD30 negative, CD117 positive, Placental alkaline phosphatase (PLAP) strongly positive

    • The ability of seminoma to transform into NSGCT elements has
    • important therapeutic implications for the management of seminoma
  6. Spermatocytic tumor?
    Spermatocytic tumor used to be known as spermatocytic seminoma and classified under subtype of seminoma, now it is considered as a separate entity.

    • Unlike other GCTs, spermatocytic tumor
    • - does not arise from GCNIS
    • - not associated with a history of cryptorchidism or bilaterality
    • - does not demonstrate i(12p)
    • - does not occur as part of mixed GCTs .
    • - peak at older age (median age of 62 years)
    • It is a benign tumor and rarely metastasize. They do not merit treatment apart from orchiectomy.
  7. Embryonal Carcinoma?
    EC is the most undifferentiated cell type of NSGCT, with totipotential capacity to differentiate to other NSGCT cell types (including teratoma) within the primary tumor or at metastatic sites
  8. Choriocarcinoma?
    • Choriocarcinoma is a rare and aggressive tumor that typically is seen with extremely highly elevated serum HCG levels and disseminated disease. They are typically poor-risk (stage IIIC) at diagnosis because of the serum HCG level and/or nonpulmonary organ metastases.
    • Choriocarcinoma commonly spreads by hematogenous routes, and common sites of metastases include lungs, liver and brain.

    Areas of hemorrhage and necrosis are prominent. As in gestational trophoblastic disease, testicular choriocarcinoma is prone to hemorrhage, sometimes spontaneously and immediately after chemotherapy is initiated; such bleeding can be catastrophic, particularly when it occurs in the lungs or  brain.

    In addition, choriocarcinomas are associated with hormonal disturbances, most likely because of highly elevated serum HCG. Stimulation of receptors for thyroid stimulating hormone and luteinizing hormone (LH) by HCG (which shares an identical alpha-subunit) can result in hyperthyroidism and elevated androgen production.
  9. Yolk sac tumor?
    Also called as endodermal sinus tumor or juvenile embryonal carcinoma

    Well demarcated heterogenous masses, which may have hemorrhage or necrosis on US

    • Schiller-Duval bodies consist of a central blood vessel surrounded by two layers of tumor cells and are pathopneumonic for YST.
    • AFP levels are elevated in about 90% of patients and represent a reliable marker for follow-up studies

    Juvenile YST -  When metastases occur, YST often exhibit hematogenous spread to the lungs (~20%), without retroperitoneal disease. For these reasons retroperitoneal lymph node dissection (RPLND) plays very little role in prepubertal YST. RPLND is used exclusively for patients with a residual retroperitoneal mass or persistently elevated AFP after chemotherapy and orchiectomy. (C12-1123)
  10. Teratoma?
    Teratomas are tumors that contain well or incompletely differentiated elements of at least two of the three germ cell layers: endoderm, mesoderm, and ectoderm.

    Characteristically, all components are intermixed. Well-differentiated tumors are labeled mature teratomas, whereas those that are incompletely differentiated (i.e., similar to fetal or embryonal tissue) are called immature teratomas. In adolescent and adult males, there is no clinical significance to the distinction between mature and immature teratomas, and histopathologists do not typically distinguish between the two entities. Mature teratomas may include elements of mature bone, cartilage, teeth, hair, and squamous epithelium, a fact that most likely explains the name teratoma, which roughly means “monster tumor,”

    Teratoma is resistant to chemotherapy. Thus, given its frequent presence at metastatic sites in advanced NSGCT, patients with residual masses after chemotherapy require consolidative surgical resection. The inherent chemo-resistance of teratoma is a limitation to treatment strategies for NSGCT that use chemotherapy alone.

    Teratomas may grow uncontrollably, invade surrounding structures, and become unresectable On rare occasions, teratoma may transform into a somatic malignancy such as rhabdomyosarcoma, adenocarcinoma, or primitive neuroectodermal tumor. These tumors are called teratoma with somatic-type malignancy” or “teratoma with malignant transformation.” These tumors frequently have abnormalities of chromosome 12 or i(12p), indicating their origin from GCT. Malignant transformation is highly aggressive, resistant to conventional chemotherapy, and associated with a poor prognosis. Only 4% of teratoma with somatic-type malignancy arise within the testis. The majority arise at metastatic sites, usually within 3 to 4 years after completion of chemotherapy as a consequence of unresected teratoma. Last, unresected teratoma in patients with advanced NSGCT may result in late relapse. All of these events may have lethal consequences. 

    Teratoma is histologically benign. Teratoma at metastatic sites is believed to arise from differentiation of metastatic non-teratoma GCT elements.
  11. Teratoma in children?
    • Benign tumor
    • Contain mature elements only 
    • Treatment - partial orchidectomy
  12. Management of prepubertal testis tumor?
    Image Upload 3

    • • A large percentage of prepubertal testis tumors are benign; therefore testicular preservation approaches are often indicated. 
    • • Ultrasonography cannot reliably distinguish benign from malignant lesions. 
    • • AFP is the relevant biomarker in prepubertal testis tumors, and elevation is associated with YSTs.
    • • AFP levels must be interpreted with caution because physiologic elevation above normal values is common in children younger than age 1.

    Orchiectomy could be considered only if normal testicular parenchyma is no longer detectable in the preoperatively high-resolution ultrasound and/or the AFP is > 100 ng/mL in a > 12-month-old boy: highly suspicious of a yolk sac tumour.
  13. Clinical features of testicular cancer?
    • - painless testis mass - most common presentation. Acute testicular pain is less common and is caused by rapid expansion of the testis resulting from intra-tumor hemorrhage or infarction caused by rapid tumor growth. Pain is more commonly associated with NSGCT; these tumors tend to be more vascular and exhibit more rapid growth compared with seminomas.
    • - A firm intratesticular mass should be considered cancer until proven otherwise and should be evaluated further with a scrotal ultrasound. In patients with a presumptive diagnosis of epididymo-orchitis, patients should be re-evaluated within 2 to 4 weeks of completion of an appropriate course of oral antibiotics. A persistent mass or pain should be evaluated further with a scrotal ultrasound.
    • - Patients frequently report a history of testicular trauma, although incidental trauma is likely responsible for bringing the testis mass to the patient’s attention for the first time.
    • - vague scrotal discomfort or heaviness
    • - Bulky retroperitoneal metastasis may cause a palpable mass, abdominal pain, flank pain resulting from ureteral obstruction, back pain because of involvement of the psoas muscle or nerve roots, lower extremity swelling resulting from compression of the inferior vena cava, or gastrointestinal (GI) symptoms.
    • - Pulmonary metastasis may present with dyspnea, chest pain, cough, or hemoptysis.
    • - Metastasis to supraclavicular lymph nodes
    • - Although approximately two-thirds of men with GCT have diminished fertility, it is an uncommon initial presentation
    • - Atrophy of the affected or contralateral testis is common, particularly in patients with a history of cryptorchidism. Any firm area within the testis should be considered suspicious for malignancy and should prompt further investigations.
    • - A hydrocele may accompany a testis cancer and impair the examiner’s ability to evaluate the testis.
    • - Gynecomastia
  14. Differential diagnosis of a testis mass
    • - epididymo-orchitis
    • - torsion
    • - hematoma, or
    • - para-testicular neoplasm (benign or malignant)
    • - hernia, varicocele, or spermatocele, although these usually can be distinguished from a testis mass by physical examination.

    A firm intratesticular mass should be considered cancer until proven otherwise and should be evaluated further with a scrotal ultrasound. In patients with a presumptive diagnosis of epididymo-orchitis, patients should be re-evaluated within 2 to 4 weeks of completion of an appropriate course of oral antibiotics. A persistent mass or pain should be evaluated further with a scrotal ultrasound.
  15. Gross appearance of testicular tumours?
    Seminoma - tan to white, multinodular, necrosis very minimal 

    • NSGCT - necrosis present
    • - EC - haemorrhage, necrosis 
    • - Choriocarcinoma - haemorrhage, necrosis
  16. USG finding of testicular tumors?
    • 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 homogenous echotexture.
    • Presence of increased flow within the lesion on color Doppler sonography is suggestive of malignancy, although its absence does not exclude GCT.
    • 2% incidence of bilateral tumors - do USG bilaterally

    Teratomas - heterogenous complex lesions on US, reflective of their composition, which typically includes three germ cell layers. They may contain cystic and solid components. Bony elements appear as calcifications with shadowing. Adipose tissue appears as echogenic areas without shadowing. Epidermoid cysts represent a monolayer teratoma and have a characteristic appearance described as “onion skin,” made up of concentric rings of alternating hypo-/hyperechoic lesions.
  17. Imaging in testicular tumor?
    CECT - chest, abdomen and pelvis in patients with diagnosis of Testicular cancer  (EAU 2020). It is reasonable to obtain chest x-ray at time of diagnosis, and CT chest can be done in elevated post orchidecotmy tumor markers, LVI/EC in NSGCT evidence of mets on abdominal CT or abnormal finding in chest x-ray. (Campbell 12)  Thoracic mets in absence of retroperitoneal mets in uncommon. 

    MRI of the brain if facilities available (or brain CECT if not available) in multiple lung metastases or high β-hCG values (>10000)  or those in the poorprognosis IGCCCG risk group. MRI has a primary role in the detection of brain metastasis because it is more sensitive than CECT.

    No PET CT or bone scan for staging - visceral mets to bone  is uncommon in absence of symptoms

    Management decision should be based on imaging and tumor marker level not older than 4 weeks
  18. Isochrome 12p?
    Gain of the short arm of chromosome 12, most commonly as an isochromosome 12p[i(12p)] All GCT, except spermatocytic tumors, universally contain i12p. 

    This genetic marker may be used in the diagnosis of GCT (e.g., for carcinomas of unknown primary) and non-GCT somatic malignancy arising from malignant transformation of teratoma.
  19. Management of <1cm, impalpable intratesticular lesions?
    • 50% of tumors < 1cm are malignant 
    • 80% of tumors 1-2 cm are malignant 

    • Management options 
    • - Inguinal orchidectomy 
    • - Testis sparing surgery 
    • - Excision with Frozen section to rule out malignancy
  20. Why so aggressive early orchidecotmy in ca testis?
    Ca testis is rapidly growing tumor 

    It's curable in almost all patients even in presence of mets - need for rapid diagnosis and early treatment, so that patients do not die early 

    We take the aggressive approach - chemo irrespective of renal insuffiencey, low WBC, thrombocytopenia , surgery even if it involves multiple anatomic sites, chemo even in absence of histological evidence just with raised AFP

    Because of Blood testes barrier - chemo does not work well in testes
  21. Indication of contralateral biopsy?
    Between 5% and 9% of patients with GCT have GCNIS within the unaffected contralateral testis, although the incidence of contralateral GCNIS increases to about 36% in men with testicular atrophy or cryptorchidism. 

    • For diagnosis of GCNIS for high risk patients, perform open inguinal biopsy 
    • - testicular volume < 12 mL
    • - a history of cryptorchidism and
    • - age < 40 years

    [@ ConTraVAteral - C, TV, A]  
  22. Extragonadal Germ Cell Tumor?
    • Approximately 5% of GCTs are extragonadal
    • Thus GCT should be considered in any male with a midline mass and a normal testicular examination.
    • Of the patients with metastatic GCT without a testis mass, only one-third definitively have a primary extragonadal GCT. The majority of these cases represent a “burned-out” primary testicular tumor that has undergone spontaneous regression as 30% to 50% have evidence of GCNIS in the testis and one-third have sonographic evidence of a “burned-out” tumor on the basis of a scar or coarse calcification.

    The presence of elevated serum AFP and/or HCG with a normal testicular evaluation is sufficient for the diagnosis of GCT, and histologic confirmation by biopsy is not necessary before starting treatment. In cases of normal serum tumor markers, biopsy of the mass should be performed to confirm the diagnosis of GCT before commencing treatment.

    • Diagnosis of extragonadal GCT with malignant transformation may be considered and supported by the expression of i(12p) in biopsy specimens.
    • Patients with suspected extragonadal GCT should undergo inguinal orchiectomy at some point during their treatment course if the pattern of metastasis is consistent with a right- or left-sided testicular primary or if there is sonographic evidence of a “burned-out” primary tumor.

    For patients in whom the retroperitoneal disease lateralizes with a distribution strongly suggestive of a testicular primary, a radical orchiectomy on that side has been advocated.
  23. Describe the role of tumor markers in the testicular tumor. (TU 69-5)

    Tumor markers in the testicular tumors?
    If AFP is significantly raised, it is NSGCT even if HPE is seminoma, manage it as NSGCT. When raised in borderline, interpret with caution. Normal serum markers levels do not exclude the presence of TC.  Persistence or increase of elevated serum tumour markers following orchidectomy indicates the likely presence of metastatic disease.

    • Tumor markers 
    • - AFP - specific for YST, EC. AFP levels may also be raised in patients with HCC, cancers of the stomach, pancreas, biliary tract and lung
    • - HCG - Choreocarcinoma, EC and  15% seminoma secrete HCG. Cross-reactivity of the HCG assay with LH may cause false-positive HCG elevations in patients with primary hypogonadism. Elevated serum HCG results caused by hypogonadism will normalize within 48 to 72 hours after the administration of testosterone, and this can be done to distinguish between true- and false-posi tive HCG results. Marijuana use may also cause false-positive HCG results, ß-hCG is not useful in prepubertal boys since hCG producing tumors are rare in prepubertal boys.

    - LDH in both seminoma and NSGCT. Lymphoma may also cause elevated LDH levels. Of the five isoenzymes of LDH, LDH-1 is the most frequently elevated isoenzyme in GCT. The magnitude of LDH elevation correlates with the bulk of disease. As a nonspecific marker for GCT, its main use is in the prognostic assessment of GCT at diagnosis.

    Half life AFP>hCG>LDH = 5 days > 1-1.5 days > 1 day

    As a result of the physiologically persistent elevation in children younger than 1 year of age, interpretation of AFP levels in young children undergoing evaluation for testis mass must be performed with caution.

    • Image Upload 4
    • [@ SEC HCG - hcg in seminoma, EC and Choreocarcinoma, AFP - YET Mixed, Yolk sac tumor, EC, Teratoma]

    Our lab - HCG <5, AFP <7.5 is the normal range

    Alpha-fetoprotein has a serum biological half-life of 5 days and should be measured 5 days after tumour  resection/orchiectomy in those with an elevated AFP. (EAU 2021)

  24. Bilateral testicular tumor?
    2% risk of bilateral tumor 

    5-9% of contralateral GCNIS in contralateral testis in patients with GCT 

    USG should be done of both testis
  25. Can we proceed for chemotherapy without biopsy?
    In rare patients whose disease burden has resulted in a need to start treatment very urgently, substantially elevated serum AFP and/ or hCG may be considered sufficient for diagnosis of GCT. For such rare, medically unstable patients, treatment need not be delayed until histology results permit a tissue diagnosis.

    • Indications are 
    • - Life threatening disease 
    • - Mets near vital vessels (reference? ) 

    These patients should undergo radical orchiectomy after the completion of chemotherapy because the testis is a sanctuary site for malignant GCT owing to the blood testis barrier and testis frequently contains residual invasive GCT, teratoma or ITGCT

    If performance status is poor and does not tolerate BEP, can give only cisplatin
  26. What is testicular microlithiasis? (TU 75,2.5)
    Testicular microlithiasis are calcium deposits within the seminiferous tubules. Mechanisms including inflammation, defective phagocytosis by Sertoli cells, immune response, nanoparticles, or rapid cell turn over.

    Testicular microlithiasis are not a precursor lesion for testicular cancer, not are they a causal factor for the development of testicular cancer. They are common finding on scrotal ultrasound, present in around 5% of asymptomatic men and up to 15% of symptomatic men.

    In men with history of GCT, testicular microlithiasis in contralateral testis is associated with increased risk of ITGCN

    Do not perform testicular biopsy, follow-up scrotal ultrasound (US), measure biochemical tumour markers, or abdominal or pelvic computed tomography, in men with isolated microlithiasis without associated risk factors (e.g., infertility, cryptorchidism, testicular cancer, and atrophic testis). Strong (EAU 2020)

    Routine self examination is the current recommendation followed by many. (C12-1125)

    For microlitiasis, do serial USG, if microlithiasis increases (6-8 in number) -  do a biopsy (ref?)
Card Set
Two7 76A1 Neoplasm of Testis - Germ Cell Tumors - Basics and diagnosis
Germ cell tumors