Pathology and Diagnostics - Testis Tumors PDF

Pathology and Diagnositcs Renne - Lesson 06 Testis Tumors 14/11/2024 – Group 22 (Galbiati, Darwiche) Gross Anatomy of the Testis The testis is the main gonad made up of tubules. When looking at...

Pathology and Diagnositcs Renne - Lesson 06 Testis Tumors 14/11/2024 – Group 22 (Galbiati, Darwiche) Gross Anatomy of the Testis The testis is the main gonad made up of tubules. When looking at microscopy be aware of the boundaries of the testis. The testis ends with the tunica albuginea and is covered by peritoneum. During embryogenesis the gonads move outside from the peritoneum and you have the retroperitoneum that is the wolffian ducts that descends and then goes inside the inguinal canal. So you have the parietal and visceral peritoneum, which are called the tunica vaginalis. So it's a mesothelium that covers the gonad. The visceral part is on the testis and the parietal part is on the scrotum. This is important for staging, because if there is a tumor that infiltrates the tunica albuginea the staging won't change, but if it infiltrates the tunica vaginalis the staging will change. The gonads are the organs for reproduction. There are two components inside the testis: 1. Stromal component: responsible for mechanical support and hormone production. The main cell type are leydig cells. Vimentin typically highlights connective tissue. Stromal tumors exist but they are very rare compared to germ cell tumors. 1  2. Parenchymal components: consists of the seminiferous tubules and main cell type are sertoli cells. Spermatogenesis occurs in the seminiferous tubules and the male gametes are stored in the epididymis. ST:Sertoli Cells SG:Spermatogonia Sertoli cells are recognized by their oddly shaped nucleus and nucleolus, while spermatogonia are the undifferentiated germ cells that will mature into spermatozoa and during this process they migrate upwards. Testicular Tumors: Prevalence It's a very rare cancer making up 1% of male cancers but is mostly common between puberty and young adulthood. Most prevalent is germ cell tumor. The main symptoms include palpable mass, metastasis (retroperitoneal masses) and blood during ejaculation. Fortunately there is a kind of chemotherapy that is proven to be very effective. With time the death rate has decreased and incidence rate has increased. About 95% of these tumors are germ cell tumors, while the remaining are due to sex-cord stromal tumors. Between puberty and adulthood we mostly have germ cell tumors, but after the 50s we have mostly lymphomas. 2 Germ cell Tumors Two main categories: Seminomas, which peak during adulthood, and non seminomatous tumors, which peak during adolescence. Risk Factors Cryptorchidism: failure of one or both testis to descend into the scrotum Prior testicular tumor: due to genetic predisposition or exposure to damaging agents which may affect one or both testes. Family history Gonadal dysgenesis Androgen insensitivity syndrome 3 Some important terminology: Yolk Sac The yolk sac is a membranous structure that develops during early embryogenesis and plays a crucial role in the nutrition and development of the embryo. Its primary functions include the production of the first blood cells and vessels, the formation of primordial germ cells, and providing initial nutrition before the placenta is fully functional. The placenta is a specialized organ that forms later in pregnancy to establish a connection between the mother and the fetus. It facilitates the exchange of oxygen, nutrients, and waste products between maternal and fetal blood, produces hormones essential for maintaining pregnancy, and acts as a protective barrier against certain infections and harmful substances. 4 Germ cell tumor classification: Based on origin: Derived from germ cell neoplasia in situ (GCNIS-related tumors) Unrelated to germ cell neoplasia in situ (non-GCNIS-related tumors) Note: Teratoma type 1 vs type 2 under the microscope look the same. They can only be differentiated because type 1 is not related to germ cell neoplasia in situ while type 2 (GCNIS-related tumor) is derived from germ cell neoplasia in situ. Based on morphology: Seminoma (Sem) Non-Seminoma a. Teratoma (Tera) – resemble somatic cells b. Embryonal carcinoma (EC) – resemble embryonic stem cells c. Yolk sac tumor (YST) – resemble yolk sac cells d. Choriocarcinoma (CC) – resemble placental cells 5 In the image below, we can clearly see on the right GCNIS, characterized by large abnormal nucleated cells. In addition, spermatogenesis cannot be seen and the heterogeneity of the general tissue is absent. On the other hand, on the left part of the image we can see a normal seminiferous tubule with all associated cells. Spermatogenesis is also observable as maturing spermatids which are characterized by their small nuclei. Physiological role of OCT4 and c-KIT Immunochemistry is an important diagnostic method to recognize GCNIS and non-GCNIS related tumors, performed by analyzing specific molecular markers which are OCT4 in the nucleus and c-KIT on cellular membranes. These markers are crucial to distinguish seminomas and embryonal carcinomas. While seminomas are immunoreactive to OCT4 and c-KIT, embryonal carcinomas are only reactive to OCT4. Primordial germ cells express OCT4 and c-KIT during normal maturation, but eventually the gene expression of these molecules is suppressed. If there were to be a failure of this mechanism, carcinogenic outcomes could arise. Risk factors linked to this mechanism include environmental stress (hormonal imbalances) and genetic predesposition. This can lead to the totipotency survival pathway which can lead to a 12p gain (isochromosome presence or elongation of pre- existing chromosome 12). Studies have shown that 80% of patients that have germ cell neoplasia will develop invasive tumors after 7 years. 6 GCNIS-Related Tumors From the slide above we can deduce that Choriocarcinoma (CC) produces HCG while Yolk Sac Tumor (YST) produces AFP. Also, some seminomas produce HCG but not as much as CC. Some seminomas can produce HCG but less that choriocarcinoma Which of the following is the most likely risk factor for these carcinomas ? a. Gonadal dysgenesis b. HPV infection c. Torsion d. Hydrocele Answer: a) gonadal dysgenesis Seminoma It is the only cancer that comes in a pure form. It is the most common germ cell tumor, hence if a 30 year old comes with a testicular mass, you bet on a seminoma. LDH is the specific immunohistochemical serological marker. 7 Gross appearance: Whitish appearance with clear demarcation and a somewhat nodular appearance and can be seen bulging out. Below you can also see another tumor which needs further sampling. Microscopic appearance: multinodular surface. True capsule can’t be observed containing suspected neoplastic mass. Thin connective tissue layer corresponding to the compressed stromal tissue. At higher magnifications this tumor is composed of two elements: firstly the neoplastic cells (germ cells of the seminoma). Tile-like, non overlapping nuclei. Clear cytoplasm filled with glycogen. Secondly we can see the lymphocytic infiltrate. The lymphocytes are those which don’t have a clear cytoplasm, are dark stained and are present in the fibrous septum. 8 Embryonal Carcinoma Majority of embryonic carcinomas are not pure, always found with something else (one of the other five). Age range is shifted for young patients. Importantly not associated with AFP and hCG. Associated with elevated serum LDH. Gross Appearance: Poorly circumscribed, gray-whitish coalition, nodular mass, prominent areas of hemorrhage and necrosis. In the below picture, we can see the EC on the right and a teratoma on the left. Microscopic appearance: Large cells with a prominent nucleus. Looks like a high grade neoplasm. Neoplastic cells, nucleus larger than cytoplasm and you can see them overlapping, thus suggesting it's not a seminoma. 9 NOTE: Seminoma and embryonal carcinoma don't have specific markers. They can show LDH increase but it isn’t a specific marker. Yolk Sac Tumor Divided into post-pubertal and prepubertal. Both are associated with high AFP. Immunohistochemical markers are AFP and Glypican 3. Gross Appearance: has a gray-whitish/yellowish appearance. With a gelatinous, myxoid or mucoid surface. Hemorrhagic, necrotic and cystic areas might be present. 10 Microscopic Appearance: Two main variations present: 1. Endodermal sinus-like structure in which vessels are covered by neoplastic cells forming a ring, usually associated with pre-pubertal types. 2. Microcystic appearance: usually seen in adults. NOTE: Morphologically prepubertal and postpubertal are the same. Differentiate because prepubertal are pure while post-pubertal are mixed. Choriocarcinoma Very rare and almost never pure. It mimics placenta. If it is metastatic you have the choriocarcinoma syndrome in which you have multi organ hemorrhagic metastasis. 11 Gross Appearance: Multinodular hemorrhagic lesions. Microscopic Appearance: Blood and Multinucleated giant cells resembling placental cells. Seminoma + Syncytiotrophoblastic Elements: seminoma with giant syncytiotrophoblast cells, considered to be pure tumors. There is not a huge elevation of serum hCG. The presence of syncytiotrophoblasts has no prognosis value. Teratoma Subdivided into prepubertal and postpubertal. In relation to testis, teratoma is not a benign disease. Important to note because ovarian teratomas are benign. a. Prepubertal teratoma: benign and non-GCNIS- related tumor; no i12p b. Postpubertal teratoma: Displays mature features, and sometimes there are malignant transformations within the teratoma (sarcomas or carcinomas), this is known as Teratoma with somatic type malignancy. Teratomas are least responsive to chemotherapy. 12 Gross appearance: Cystic appearance. Cartilage that has a whitish appearance. Microscopic Appearance: Somatic cells represented by cartilaginous tissue nodules and an epithelium lined by cysts. Atypical epithelial cells indicate a teratoma with somatic type malignancy. Mixed Germ Cell Tumors Most non seminomatous tumors are mixed and usually display the following combinations: a. Embryonal Ca + Teratoma - 25-30% b. Embryonal Ca + Seminoma - 16% c. Embryonal Ca + YST + Teratoma - 11% d. Other combinations… 13 Question: A 28-year-old man has noticed increasing enlargement and a feeling of heaviness in his scrotum for the past year. On physical examination, the right testis is twice its normal size, and it is firm and slightly tender. An ultrasound examination shows a 3.5-cm solid right testicular mass. Abdominal CT scan shows enlargement of the para-aortic lymph nodes. Multiple lung nodules are seen on a chest radiograph. Laboratory findings include markedly increased serum levels of chorionic gonadotropin and a-fetoprotein. Which of the following neoplasms is the most likely diagnosis? a. Choriocarcinoma b. Large diffuse B-cell lymphoma c. Leydig cell tumor d. Metastatic prostatic adenocarcinoma e. Mixed germ cell tumor f. Pure seminoma Answer: e) mixed germ cell tumor Non-GCNIS Related Tumors 14 Spermatocytic Tumor: Older age group affected (average age 52 yrs; 19-92 range). Not associated with GCNIS/ITGCN, cryptorchidism, 12p abnormalities. Associated with gains of Chr 9 and 1: FGFR3 & HRAS mutations or gene amplifications. Not associated with other germ cell components. No ovarian counterpart or extragonadal location. Clinically benign, rare metastasis. Deadly if associated with sarcomatous transformation. Immunoreactive with respect to c-KIT. Sex Cord Stromal Tumors: Non-GCT, representing 5% of all testicular tumors. Leydig Cell Tumor: Most common sex cord stromal tumor. Two age peaks: 20% in children and 80% in adults. In children early detection of androgen production. In adults, 30% of patients develop gynecomastia. Bilateral involvement occurs in 3% of cases and it can be malignant (10%). Gross Appearance: Yellow masses that resemble adrenal glands. 15 Histological Appearance: Resemble Leydig cells with Reinke crystals which are diagnostic of leydig cells because only they produce these crystals. Staging System What's the difference seen in relation to each stage ? There is no stage 4. The “S” stands for serum which is important for diagnosis and staging. It ranges from S0 to S3 and the higher the serum marker concentration the higher the metastasis. 16 Opposed to many parenchymatous organs the staging is not determined by the size but by the structures that are invaded. pT2= invasion of adjacent structures: epididymis, hilar soft tissue tunica vaginalis, vascular/lymphatic structures). 17 Question: A 37-year-old man has noticed bilateral breast enlargement over the past 6 months. On physical examination, both breasts are enlarged without masses. His right testis is firm and 1.5 times larger than his left testis. His serum estrogen is increased. An ultrasound scan shows a circumscribed 2-cm mass in the body of the right testis. A right orchiectomy is performed, and grossly the mass has a uniform, brown cut surface. The microscopic appearance is shown in the figure. With electron microscopy, the cells have rod-shaped crystalloids of Reinke. What is the most likely diagnosis? Options: a. Choriocarcinoma b. Embryonal carcinoma c. Gonadoblastoma d. Leydig cell tumor e. Seminoma f. Teratoma g. Yolk sac tumor Answer: d) leydig cell tumor Summary: 18