GÖZDE AKAN BERFİN GİZEM USLU Testıcular cancer GÖZDE AKAN BERFİN GİZEM USLU

ANATOMY Paired, ovoid male reproductive organ 4 x 3 x 2.5cm approximately 25 ml 250-350 lobules Lies obliquely within the scrotum suspended by the spermatic cord

FUNCTIONS Produce sperms and male hormones, primarily testosterone

LYMPHATIC DRAINAGE On the right : along the IVC  - interaortacaval region - preartic and paraaortic lymph nodes ,with possible cross- over within the retroperitoneum  On the left : preaortic and paraaortic nodes around the left renal hilum - interaortacaval nodes mostly without cross-over

EPIDEMIOLOGY Uncommon malignancy, accounting for 1–2% of all tumours in men However, it is important because its incidence is increasing worldwide Most common malignancy in young men (aged 15–34 years) in many populations worldwide The peak age of men with seminomas is 30–40 years, compared with 20–30 years for nonseminomatous GCT Contrary to the trends in incidence, the testicular cancer mortality rate has been decreasing in most European countries, largely attributable to the advent of platinum- based chemotherapy regimens and multidisciplinary approach to testicular cancer management 

Cryptorchidism -four to eight times greater risk RISK FACTORS Cryptorchidism -four to eight times greater risk  Prior Testicular Cancer- 500-fold higher rate than in the general population Genetics- Klinefelter syndrome (47XXY) Down syndrome Androgen insensitivity syndrome Family history Infertility

6.Environmental exposure 7.Scrotal trauma 8.Inguinal hernia 9.Smoking 10.Race-more common among Caucasian males Highest rates in Scandinavia, Germany and New Zealand HIV

CLINICAL FEATURES Due to metastasis; Due to primary tumor; Painless testicular lump Sensation of heaviness Rarely pain (1/3rd cases) May mimic epidedymoorchitis Gynaecomastia appears in 7% of cases Due to metastasis; Abdominal or lumbar pain (lymphatic spread) Dyspnea, hemoptysis and chest pain with lung metastasis Jaundice with liver metastasis Hydronephrosis by para-aortic lymph nodes enlargement Pedal edema by IVC obstruction

PHYSICAL EXAMINATION: Enlarged testis (except choriocarcinoma) Nodular testis Loss of testicular sensation Flat and difficult to feel epididymis General examination for metastasis

CLASSIFICATION OF TESTICULAR TUMORS Germ Cell Tumors (%90) Seminomas (%60) Classical Spermatocystic Anaplastic Non-Seminomatous Tumors (%40) Embryonal Carcinoma Yolk Sac Tumor Choriocarcinoma Teratoma Mixed Tumors Non-Germ Cell Tumors Sex-Cord Stromal Tumors (%2) Leydig Cell Tumor Sertoli Cell Tumor Granulosa Cell Tumor Mixed Type Unclassified Mixed Germ Cell and Stromal Tumor Adnexal and Paratesticular Tumors Miscellaneous Tumors (%5) (Metastatic tumors, Carcinoid,Lymphoma)

GERM CELL TUMORS 1) Seminoma testicular cancer The commonest variety of testicular tumour Adults are the usual target (4th and 5th decade); never seen in infancy Patients present with painless testicular mass 30 % have metastases at presentation, but only 3% have symptoms related to metastases Serum alpha fetoprotein is normal Beta HCG↑30% of patients with Seminoma Highly sensitive to radiotherapy among testis tumors

SEMINOMA CLASSICAL (%85) Middle age (30-50) ↑BetaHCG(10%) Very slow growth Spermatocytic(2% - 12% ) Old age (> 50 yr) Most common GCT in men > 65 yrs Extremely low metastatic potential Good prognosis ANAPLASTIC (5% - 10) Middle age Aggressive - lethal Greater mitotic activity Higher local invasion Higher metastatic potential Higher rate of β-HCG production

2)NON-SEMİNOMATOUS GERM CELL TUMORS 2. a) Embryonal Carcinoma: 2nd most common germ cell tumor 90% of NSGCT Present in majority of mixed germ cell tumours Most men present in their 20s to 30s with a testicular mass Highly malignant tumours; may invade the cord structures epididymis High degree of metastasis Serum AFP is positive in 30%, beta HCG is elevated in 20% of cases

2)NON-SEMİNOMATOUS GERM CELL TUMORS 2.b) Choriocarcinoma: A rare and aggressive tumour (5years survival is 5%) Typically elevated B-Hcg > 99% Usually present with distant mets – lung and /or brain Primary is very small and often exhibit NO TESTICULAR ENLARGEMENT, small palpable nodule may be present. Hematogenous mets most common

2)NON-SEMİNOMATOUS GERM CELL TUMORS 2.c) Yolk sac tumor: Most common prepubertal GCT in children. Pure yolk sac tumor <2% of testicular tumors in adults 40% of mixed germ-cell tumors. AFP ↑ >90% of pts Testicular mass the most usual presentation Respond very well to chemotherapy, even if they have spread Microscopically, Schiller-Duval bodies are a characteristic feature

2)NON-SEMİNOMATOUS GERM CELL TUMORS 2.d) Teratoma: Teratoma in greek means “monster tumor” Contain all three germ layers with varying degree of diffrentiation Occurs in its pure form in pediatric age group with a mean age of diagnosis at 20 months In adults, occur as a component of mixed germ cell tumor Normal serum markers. Mildly elevated AFP levels

3)SEX CORD STROMAL TUMORS Sertoli cell: -Excess estrogen production -Gynecomastia in 1/3rd of cases -10 % are malignant  -Androgen insensitivity syndrome -Peutz-Jeghers syndrome Leydig cell: -Produces androgens -Reinke crystals  -Klinefelter’s syndrome  Granulosa cell Mixed types

METASTATIC TUMORS OF TESTIS Lymphoma -most common secondary tumor -most common testicular tumor in patients above 50 years  Leukemia Prostate cancer

SPREAD Direct Spread: This spread occurs by invasion. Tunica albuginea is rarely penetrated Scrotal skin involvement Spread to spermatic cord and epidedymis may occur : points towards bad prognosis Lymphatic spread: Seminoma metastasize exclusively through lymphatics They drain primarily to para-aortic lymph nodes Blood Spread NSGCT spread through blood route Lungs, liver, bones and brain are the usual sites usually involved

TUMOR MARKERS AFP (alpha-fetoprotein): Trophoblastic Cells -upper limit of normal serum AFP<10-15 microg/L -serum AFP concentrations >10,000 microg/L are found almost exclusively in patients with (NSGCTs) or hepatocellular carcinoma B-HCG: Syncytiotrophoblastic Cells -most commonly elevated tumor marker in testicular cancer -normal value in men is less than 5 to 10 IU/L -Increased levels of beta-HCG can be found in seminoma or nonseminoma

TUMOR MARKERS Lactate Dehydrogenase (LDH): -elevated in 40 to 60 percent of men with testicular germ cell tumors -less sensitive and less specific tumor marker than (beta-hCG) or (AFP) for men with NSGCTs - increased levels reflect tumor burden, growth rate, and cellular proliferation AFP, BHCG & LDH are included in TNM staging of testicular cancers

DIAGNOSIS Painless swelling or a nodule in one testicle is the most common presenting sign In any man with a solid, firm mass within the testis, testicular cancer must be the considered diagnosis until proven otherwise Physical examination Scrotal USG Blood test: CBC + AFP , B-HCG , LDH CT Scan, MRI, PET Scan Radical inguinal orchiectomy Contralateral testicular biopsy Retroperitoneal lymph node dissection

DDx Epididymo-orchitis Hematoma Torsion Paratesticular neoplasm (most commonly benign) Hernia Varicocele-spermatocele Tuberculosis and other testicular infections

STAGING(for all patients) Serum tumour markers -AFP -hCG -LDH Abdominopelvic CT Chest X-ray/ CT Testis ultrasound (bilateral)

TNM STAGING Testicular cancer is staged using the TNM system created by the American Joint Committee on Cancer (AJCC). T refers to how much the main (primary) tumor has spread to tissues next to the testicle. N describes how much the cancer has spread to regional (nearby) lymph nodes. M indicates whether the cancer has metastasized (spread to distant lymph nodes or other organs of the body). S indicates the serum (blood) levels of tumor markers that are made by some testicular cancers.

ROYAL MARSDEN CLASSIFICATION Stage I: Cancer is found only in the testicle. Stage II: Cancer has spread to the retroperitoneal lymph nodes in the belly. -IIA: <2 cm in size or < 6 positive nodes -IIB: 2-5 cm in size or > 6 positive nodes -IIC: large and bulky abdominal mass, usually > 5-10 cm Stage III: Cancer has spread beyond the lymph nodes in the belly. There may be cancer in parts of the body far away from the testicles such as the lungs, brain, bones and liver. Stage IV: Hematogenous spread

GENERAL MANAGEMENT After obtaining serum AFP & B-Hcg levels in suspected case of malignant germ cell tumour Radical inguinal orchietectomy with high ligation of spermatic cord is done, it is both diagnostic & therapeutic Further management depends on, pathology & stage of disease.

Radical inguinal orchietectomy Testicular tumors are diagnosed, staged and locally controlled by inguinal orchiectomy. Scrotal biopsy is irrelevant and contraindicated.

TREATMENT Radical Inguinal Orchiectomy Surveillance Retro Peritoneal Lymph Node Dissection(RPLND) Radiotherapy Chemotherapy

SEMINOMAS TX 1. Early Stage Radiation therapy (gold standard) Surveillance (selected cases) 2. Advanced Stage Chemotherapy

NONSEMINOMAS TX Early Stage (Stage I) Retroperitoneal Lymph Node Dissection Open / Laparoscopic Surveillance (low-risk patients) Chemotherapy (2 courses) (high-risk patients*) * angio-lymphatic invasion >%50 presence of embryonal cell carcinoma Absence of yolk sac component Advanced Stage (>IIB) Chemotherapy (BEP : Bleomycin/etoposide Cisplatin)

PROGNOSIS High-risk prognostic features include any of the following: Mediastinal primary tumor Nonpulmonary visceral metastases AFP > 10,000 ng/mL hCG > 50,000 IU/L LDH > 10 times the upper limit

A good prognosis can typically be expected in patients with the following: Testicular or retroperitoneal primary tumor No nonpulmonary visceral metastases Alpha-fetoprotein < 1000 ng/mL Human chorionic gonadotropin < 5000 IU/L Lactate dehydrogenase (LDH) < 1.5 times the upper limit

FOLLOW-UP At least 5 years with: -periodic x-rays -CT scans -blood tests for tumor markers Also, since there is an increased risk (about 2%) of a second tumor, it is important to continue monthly testicular self-exams.

REFERENCES "What Is Testicular Cancer?" American Cancer Society. N.p., n.d. Web. 01 Apr. 2017. <https://www.cancer.org/cancer/testicular-cancer/about/what-is-testicular- cancer.html>. "Testicular Cancer." Background, Pathophysiology, Epidemiology. N.p., 13 Mar. 2017. Web. 01 Apr. 2017. <http://emedicine.medscape.com/article/279007- overview>. "Testes and Epididymis Anatomy." Overview, Gross Anatomy, Microscopic Anatomy. N.p., 28 Oct. 2016. Web. 01 Apr. 2017. <http://emedicine.medscape.com/article/1949259-overview#a2>.