General Concepts, Germ Cell Tumors



General Concepts, Germ Cell Tumors


Steven S. Shen, MD, PhD

Jae Y. Ro, MD, PhD








Schematic diagram of testis and paratestis is shown. The testicular parenchyma is separated by fibrous septae image. The tubules converge and exit to the rete testis image, efferent ducts image, epididymis image, and vas deferens image.






Schematic diagram shows seminiferous tubule with spermatogenesis (spermatogonia image, spermatocytes image, spermatids image, spermatozoa image). Sertoli cells image and Leydig cells image are also shown.


TERMINOLOGY


Synonyms



  • Germ cell tumor (GCT), seminoma, nonseminomatous germ cell tumor (NSGCT), mixed germ cell tumor (MGCT)


Definitions



  • Diverse group of tumors arising from totipotential germ cells with embryonic or extraembryonic differentiation


EPIDEMIOLOGY


Age Range



  • Most GCTs occur between 20-50 years of age with peak incidence at 30 years


  • Seminoma occurs at age ranging 35-45 years


  • NSGCTs occur at age ranging 25-35 years (10 years younger than seminoma)


Ethnicity Relationship



  • Incidence is higher in Western and Northern Europe, Australia/New Zealand, and North America (5.4-7.9 per 100,000)


  • Incidence is lower in Africa, Caribbean, and Asia (2 per 100,000)


Incidence



  • Estimated 8,400 new cases and 380 deaths from testicular cancer in USA in 2009 (American Cancer Society)


  • Approximately 49,000 new cases and 9,000 deaths each year worldwide (2002 data)


  • Worldwide incidence has more than doubled in last 40 years


Natural History



  • Intratubular germ cell neoplasia (ITGCN) is a precursor to most GCTs except for spermatocytic seminoma and infantile germ cell tumors


  • NSGCTs are more likely than seminoma to present with metastasis


  • Choriocarcinoma often presents with early vascular dissemination to lung, liver, and bone



    • May present with choriocarcinoma syndrome (hemorrhagic metastasis)


  • Metastasis of GCTs occurs in stepwise pattern of lymphatic spread through testicular mediastinum to retroperitoneal lymph nodes


ETIOLOGY/PATHOGENESIS


Cytogenetic Changes



  • GCTs arising in prepubertal gonads (teratoma and yolk sac tumor) are usually diploid


  • GCTs in postpubertal men typically have 1 or more copies of chromosome 12p (most commonly i[12p]), and other forms of 12p abnormalities and aneuploidy


  • Approximately 80% of GCTs have at least 1 isochromosome 12 (i[12p])


  • Other genetic changes in postpubertal men include loss of chromosome 11, 13, 18, and Y, and gains of 7, 8, and X


  • Spermatocytic seminoma may be either diploid or aneuploid and may show loss of chromosome 9


Risk Factors



  • Prior history of GCT


  • Positive family history of GCT


  • Cryptorchidism


  • Testicular dysgenesis


  • Klinefelter syndrome


  • Infertility



CLINICAL IMPLICATIONS


Clinical Presentation



  • Often unilateral painless testicular swelling or mass (bilaterality is rare: < 2%)


  • Gynecomastia or exophthalmos may be presenting symptom (related to human chorionic gonadotropin [hCG] production)


  • Approximately 10% may present with symptoms related to metastasis at initial presentation


  • Elevation of serum tumor markers, including lactate dehydrogenase(LDH), α-fetoprotein(AFP), hCG


Laboratory Tests



  • Elevated serum AFP usually seen in yolk sac tumor


  • Highly elevated serum hCG suggests choriocarcinoma; borderline hCG elevation is not uncommon in seminoma and in germ cell tumors with syncytiotrophoblasts


  • Serum levels of LDH, AFP, and hCG are incorporated into TNM staging


Treatment



  • Treatment options depend on TNM stage and whether tumor is seminoma or NSGCT



    • Stage I seminoma



      • Radical inguinal orchiectomy followed by surveillance protocol (serum markers, chest radiographs, and CT scan), single-dose carboplatin adjuvant therapy, or radiation therapy


    • Stage I NSGCT



      • Radical inguinal orchiectomy followed by retroperitoneal lymph node dissection (RPLND), surveillance protocol, or cisplatin-based adjuvant chemotherapy


    • Stage II seminoma



      • Radical inguinal orchiectomy followed by radiation or cisplatin-based adjuvant therapy


    • Stage II NSGCT



      • Radical inguinal orchiectomy followed by RPLND, RPLND and chemotherapy, or chemotherapy and delayed RPLND


    • Stage III seminoma or NSGCT



      • Radical inguinal orchiectomy followed by multidrug chemotherapy


Prognosis



  • Depends on histologic type, stage, and treatment


  • Most types have favorable prognosis and respond well to chemotherapy &/or radiation therapy, as appropriate for tumor type


  • Overall 95% survival rate in USA


  • Morphologic prognostic factors



    • Lymphovascular invasion (pathologic stage at least pT2)


    • Proportion of embryonal carcinoma (> 80% poor prognosis)


    • Proportion of teratoma component (> 50% favorable prognosis)


    • Others: Tumor size (> 4 cm) and rete testis invasion (for seminoma)


Imaging Findings



  • General Features



    • Testicular ultrasound may detect a testicular mass


    • Abdominopelvic computed tomographic (CT) scan may detect retroperitoneal lymph node metastasis


    • Chest radiograph and CT scan may detect lung metastasis


    • Magnetic resonance imaging (MR) may detect metastasis to bone and brain


MACROSCOPIC FINDINGS


Anatomic Features



  • Testes are paired ovoid organ with average weight of 15-19 g and dimension of 2 x 3 x 4 cm


  • Surrounded by thick capsule composed of 3 layers: Tunica vaginalis (outer layer), albuginea (middle), and vasculosa (inner)


  • Posterior mediastinum contains blood vessels, lymphatics, and rete testis


  • Fibrous septae divide testis into approximately 250 lobules: Seminiferous tubules and interstitium


  • GCTs replace normal structures and present with tumoral pattern


General Features



  • Testicular mass with variable appearance depending on histologic type and component


Specimen Handling



  • Radical Resection



    • Orient specimen and ink appropriately, if necessary


    • Procure spermatic cord margin before specimen is opened/bivalved


    • Submit tumor entirely if small (< 2 cm)


    • For large tumors, at least 1 section per cm tumor



      • Section to include areas with different appearance


      • Section to include hemorrhagic and necrotic area (usually high-grade component, such as embryonal or choriocarcinoma)


      • More sections may be required in pure seminoma to rule out other germ cell components, especially if there are areas of hemorrhage and necrosis or serum AFP levels are elevated


      • Section to include rete testis and epididymis


      • Section to include uninvolved testicular parenchyma adjacent to tumor


      • At least 1 section of uninvolved testicular parenchyma away from tumor


  • Subtotal Resection



    • Orient specimen and ink resection margins appropriately


    • Perpendicular section of tumor with margin for possible frozen section for margin and diagnosis


    • Sections usually include entire tumor


    • Section to include uninvolved testicular parenchyma



MICROSCOPIC FINDINGS


Normal Anatomy and Histology



  • Histologic compartment of testis



    • Testis is composed of seminiferous tubules and interstitium


  • Seminiferous tubules and spermatogenesis



    • Composed of Sertoli cells and germ cells in varying stages of differentiation or maturation


    • Germ cells mature from base to center of lumen and are divided into different stages based on their levels of maturation



      • Spermatogonia: Situated adjacent to basement membrane; small, round, dense nuclei with finely granular and vesicular chromatin and small nucleolus, clear or basophilic cytoplasm


      • Primary spermatocytes: More centrally located; largest cell type; variable nuclear appearance, clumped chromatin (spireme type), beaded cytoplasm


      • Secondary spermatocytes: More centrally located; smaller and fewer than primary spermatocytes; coarsely granular chromatin; no nucleoli


      • Spermatids: Located near lumen; small cells with darkly stained chromatin


      • Spermatozoa: Located in lumen; elongated eccentric nucleus with long cytoplasmic tail


    • Sertoli cells: Elongated pyramidal cells attached to basal lamina (10-12 Sertoli cells/tubules; germ cells:Sertoli cells ratio ~ 13:1)


  • Interstitium is divided into intertubular and peritubular regions



    • Peritubular region contains basement membrane and thin lamina propria


    • Intertubular interstitium contains blood vessels, lymphatics, nerve, and Leydig cells


General Features

Jul 7, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on General Concepts, Germ Cell Tumors
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