Pathology Of The Ovary PDF

August 29, 2023 Pathology of the Ovary Page 1 of 11 Pathology of the Ovary Instructor: Lucy Ma, MD; email: [email protected] Block 5: Urology/Endocrine/Reproduction Thread: Pathology Learning Objectives By exam time, you should be able to do the following: 1. Categorize the major types of ov...

August 29, 2023 Pathology of the Ovary Page 1 of 11 Pathology of the Ovary Instructor: Lucy Ma, MD; email: [email protected] Block 5: Urology/Endocrine/Reproduction Thread: Pathology Learning Objectives By exam time, you should be able to do the following: 1. Categorize the major types of ovarian tumors by tissue of origin (epithelial, germ cell, sex cord–stromal). 2. Classify ovarian epithelial tumors based on both histologic features (serous, mucinous, endometrioid, etc.) and malignant potential (benign, borderline, and malignant). 3. Discuss the associations between BRCA mutations, TP53, and highgrade serous carcinoma. 4. Describe and identify the major subtypes of germ cell tumors. 5. Describe and identify the major subtypes of sex cord–stromal tumors. 6. Discuss the most common primary tumor types that metastasize to the ovary. Further Reading Prat J, Mutter GL. The Female Reproductive System and Peritoneum. In: Strayer DS, Saffitz JE, Rubin E. Rubin’s Pathology Mechanisms of Human Disease. Eighth edition. Wolters Kluwer; 2020. (Available online to students via the Scott Library) Study Questions 1. A 37-year-old patient presents with anovulation and clitoromegaly. They have also noticed worsening acne and coarse facial hair. Pelvic exam demonstrates an adnexal mass. Assuming their adnexal mass is causing her symptoms, what is the most likely diagnosis? August 29, 2023 Pathology of the Ovary Page 2 of 11 2. A 19-year-old patient is at their family medical doctor for a new patient visit. On their intake form, they note that their grandmother died young from “some kind of ‘lady’ cancer” and three of their aunts had breast cancer. Based on the family history, which type of ovarian neoplasm are they most at risk for? What sort of prophylactic measures might be considered? 3. A 32-year-old patient presents to their OB-GYN with a positive home pregnancy test. Office ultrasound is notable for an adnexal mass and an unremarkable uterus with no evidence of intrauterine pregnancy. Based on this clinical history, what is the most likely diagnosis? What is the most likely neoplastic diagnosis? 4. A 54-year-old patient with a history of endometriosis presents to their OB-GYN with increased abdominal discomfort and a sensation of “pelvic fullness.” An exploratory laparotomy and hysterectomy with bilateral salpingo-oophorectomy shows a large left ovarian mass. Histologic exam reveals back-to-back tubular endometrioid-like glands with cribriform architecture, nuclear atypia with stromal invasion, as well as foci of benign endometrial type glands with endometrial stroma. What is the most likely diagnosis? What genetic alterations, if any, would you expect to see in their tumor? 5. A 70-year-old patient presents with melena and pelvic fullness. Abdominal and pelvic imaging reveals bilateral ovarian masses as well as a diffusely thickened gastric lining. An upper GI endoscopy study reveals gastric carcinoma. What histology do you expect to see in the ovaries? Ovarian cycle a. First ovarian cycle at puberty is called menarche; cessation of ovarian cycle is called menopause b. Length of cycle is ~21-35 days (on average 28 days) c. Divided into two phases: a. Follicular phase  follicle development to ovulation i. Ovarian follicle consists of an oocyte surrounded by inner layer of granulosa cells and outer layer of theca cells August 29, 2023 Pathology of the Ovary Page 3 of 11 ii. During follicular phase, ovaries produce single dominant follicle (termed Graafian follicle) selected for ovulation b. Luteal phase  ovulation to menses i. Following ovulation, the remaining granulosa cells of the follicle luteinize transform into corpus luteum d. Ovulation (egg released from ovary) is stimulated by LH surge e. Generally, theca cells secrete androgens (under the influence of LH) while granulosa cells secrete estrogen (under the influence of FSH) Polycystic Ovarian Syndrome (PCOS) a. One of the most common endocrine/metabolic disorders in reproductive age b. Principal features  androgen excess, ovulatory dysfunction, and polycystic ovaries c. Clinical presentation: infertility, oligomenorrhea, hirsutism, acne, obesity d. Etiology: not entirely clear; quite complex with multiple potential etiologies e. Pathophysiology: cardinal finding is elevated LH (or elevated LH:FSH level) a. Persistently elevated LH leads to absence of LH surge, and therefore, absence of ovulation. LH acts on theca cells to secrete androgens. In turn, androgens are converted to estrogen. i. Excess androgens lead to clinical presentation of hirsutism, acne, etc. ii. Excess estrogens lead to increased risk of endometrial hyperplasia/carcinoma iii. Impaired ovulation leads to infertility and oligomenorrhea August 29, 2023 Pathology of the Ovary Page 4 of 11 b. Insulin resistance and hyperinsulinemia i. Increased risk of type 2 diabetes f. Histology: bilaterally enlarged ovaries with multiple/numerous follicle cysts and thick fibrous capsule, absence of corpus luteum Endometriotic Cyst a. Also known as “endometrioma” or “chocolate cyst” clinically b. Etiology & pathophysiology : endometriosis involving ovary a. Repeated cycles of hemorrhage leads to brown, “chocolate” color c. Histology: evidence of endometriosis lining a cyst a. Endometriosis: 1) endometrial glands, 2) endometrial stroma, 3) hemosiderin-laden macrophages (from accumulation of old blood) Ovarian Neoplasms a. Epidemiology: i. In the US, ovarian cancer is 2nd most common gynecologic malignancy following uterine cancer, but it is the most common cause of death from gynecologic cancer ii. 5th leading cause of cancer death in natal females (following lung, breast, colorectal, and pancreatic cancers) b. Categorization: By ovarian component i. Surface/fallopian tube epithelium  surface epithelial tumors ii. Germ cells germ cell tumors iii. Sex cord/stromal cellssex cord-stromal tumors iv. Extraovarian  metastasis Surface Epithelial Ovarian Neoplasms a. Classified by epithelial type and malignant potential b. Classification by malignant potential i. Benign 1. Minimal to mild cytologic atypia August 29, 2023 Pathology of the Ovary Page 5 of 11 2. Minimal epithelial proliferation 3. 80% of ovarian tumors ii. Borderline 1. Mild to moderate cytologic atypia 2. Increased epithelial proliferation with complex architecture 3. NO INVASION iii. Malignant/Carcinoma 1. Marked cytologic atypia 2. Marked epithelial proliferation with complex architecture 3. Invasive c. Classification by epithelial type i. Three major histologic types 1. Serous 2. Mucinous 3. Endometrioid ii. Rare subtypes 1. Brenner/Transitional cell 2. Clear cell d. Serous ovarian tumors i. Most common ovarian neoplasm ii. Histology: Fallopian tube-like epithelium (ciliated columnar) iii. 30% are malignant (Serous ovarian carcinoma) 1. Malignant low-grade (Type 1) 2. Malignant high-grade (Type 2) iv. Low-grade serous ovarian carcinoma 1. Progress from benignborderlinecarcinoma 2. Mutations: KRAS, BRAF, ERBB2 v. High-grade serous ovarian carcinoma 1. No association with benignborderlinecarcinoma tumor pathway 2. Arise from Fallopian tube epithelium via intraepithelial precursors 3. Associated with BRCA1 and BRCA2 germline mutations 4. Mutations: TP53 August 29, 2023 Pathology of the Ovary Page 6 of 11 5. Accounts for majority of ovarian carcinoma diagnoses and related deaths e. Mucinous ovarian tumors i. Usually benign or borderline 1. Primary mucinous ovarian carcinomas are rare ii. 20-25% of ovarian epithelial neoplasms iii. Histology: Columnar epithelial cells with cytoplasmic mucin iv. Mutations: KRAS f. Endometrioid ovarian tumors i. Malignant (carcinoma) more common than benign and borderline ii. 10-15% of all ovarian carcinomas iii. 15-20% associated with endometriosis iv. Mutations: PTEN, CTNBB1, ARIDA1 v. Histology is identical to that of endometrial endometrioid carcinoma Germ Cell Tumors a. 15-20% of all ovarian tumors; comprise second largest group of ovarian neoplasms b. Similar to germ cell tumors of the testis c. Four main types i. Teratoma ii. Dysgerminoma iii. Yolk sac iv. Nongestational choriocarcinoma d. Rare Subtypes i. Embryonal ii. Mixed germ cell e. Teratoma i. Most common germ cell tumor ii. Three categories 1. Mature “benign” teratoma a. Also known as “dermoid cyst” b. Comprises ~95% of germ cell tumors August 29, 2023 Pathology of the Ovary Page 7 of 11 c. Contains components of mature tissue types (ectoderm, mesoderm, and endoderm) i. Although usually benign, mature tissue type can undergo malignant transformation; i.e., squamous cell carcinoma! d. Associated with anti-NMDA receptor encephalitis 2. Immature (malignant) teratoma a. Contains immature fetal tissue, typically immature neuroepithelium 3. Monodermal/specialized teratoma a. Mature teratomas made up of entirely one type of tissue b. Classic examples: i. Struma ovarii: Mature thyroid tissue only, can be functional (hyperthyroidism), can be site of origin of papillary thyroid carcinoma ii. Ovarian carcinoid: Neuroendocrine tumor, can also be functional f. Dysgerminoma i. Ovarian counterpart to testicular seminoma ii. Malignant potential: considered malignant but variable levels of aggressiveness iii. Histology: Similar to testicular seminoma, large vesicular cells with clear cytoplasm, well-defined cell borders, and centrally-placed nuclei, arranged in nests/cords, separated by fibrous septa containing lymphocytes or granulomatous inflammation iv. May show elevated serum LDH g. Yolk sac (endodermal sinus tumor) i. Derived from extraembryonic yolk sac structures ii. Malignant potential: Malignant iii. Histology: Characteristic for Schiller-Duval bodies and hyaline globules iv. May show elevated serum alpha feta protein (AFP) August 29, 2023 Pathology of the Ovary Page 8 of 11 h. Nongestational choriocarcinoma i. Derived from extraembryonic trophoblastic structures  composed of cytotrophoblasts and syncytiotrophoblasts ii. Extremely rare; most commonly seen as a component in mixed germ cell tumors iii. Histology: Resembles gestational choriocarcinomas with sheets of atypical trophoblasts. iv. May show elevated serum beta-hCG Sex-Cord Stromal Tumors a. Derived from ovarian stroma and sex cords of the embryonic gonad b. Can have hormonal effects c. Three main types i. Granulosa cell ii. Fibroma/thecoma/fibrothecoma iii. Sertoli-Leydig d. Granulosa cell tumor i. Resemble developing ovarian follicle ii. Adult and juvenile subtypes iii. May have elevated serum estrogen, systemic symptoms of hyperestrogenic state (endometrial hyperplasia/carcinoma, or precocious puberty in children) iv. Adult granulosa cell tumor 1. Recurrent FOXL2 mutations 2. Histology: nuclear grooves, Call-Exner bodies (small follicle-like structures filled with eosinophilic material) 3. May have elevated serum inhibin e. Fibroma/Thecoma/Fibrothecoma i. Derived from ovarian stromal cells 1. Fibroblasts  Fibroma 2. Theca cells  Thecoma 3. Mixture of both  Fibrothecoma ii. Malignant potential: Mostly benign, rare incidences of sarcoma iii. Histology: Low grade spindle cells with collagenous/fibromatous stroma August 29, 2023 Pathology of the Ovary Page 9 of 11 iv. Associated with multiple syndromes, including: 1. Meigs syndrome: hydrothorax, ascites, and ovarian fibroma 2. Basal nevus (Gorlin) syndrome: Basal cell carcinoma, keratocystic odontogenic tumors, bilateral ovarian fibromas f. Sertoli-Leydig i. Derived from sex cords of embryonic gonad, composed of various amounts of Sertoli and Leydig cells ii. Often androgen-secreting 1. Virilization, hirsutism, voice changes iii. Histology: Sertoli tubules and groups of Leydig cells (polygonal pink cells) Metastasis to Ovary a. Ovary is most common site of metastasis within the gynecologic tract b. Often BILATERAL ovarian involvement c. Common sites of origin: GI tract (most common), breast, and other Müllerian organs d. Krukenberg Tumor i. Refers to bilateral ovarian masses composed of mucinous signet ring cells, usually of gastric origin Answers to Study Questions These answers are not meant to be all encompassing; rather they are examples of the types of thought processes needed for application of the material. 1. A 37-year-old patient presents with anovulation and clitoromegaly. They have also noticed worsening acne and coarse facial hair. Pelvic exam demonstrates an adnexal mass. Assuming their adnexal mass is causing her symptoms, what is the most likely diagnosis? Answer: The clinical symptoms are indicative of virilization, suggestive of a testosterone-secreting lesion. The ovarian tumor most commonly associated with virilization is a Sertoli-Leydig tumor. 2. A 19-year-old patient is at their family medical doctor for a new August 29, 2023 Pathology of the Ovary Page 10 of 11 patient visit. On their intake form, they note that their grandmother died young from “some kind of ‘lady’ cancer” and three of their aunts had breast cancer. Based on the family history, which type of ovarian neoplasm are they most at risk for? What sort of prophylactic measures might be considered? Answer: The family history is strongly suggestive of a BRCA1 or BRCA2 mutation, which has an estimated risk of ovarian cancer of 20-60% by age 70. Because the most commonly associated ovarian cancer is high-grade serous carcinoma, a bilateral salpingo-oophorectomy may be a considered a prophylactic measure. They will require counseling regarding fertility and the hormonal impact of a bilateral oophorectomy. 3. A 32-year-old patient presents to their OB-GYN with a positive home pregnancy test. Office ultrasound is notable for an adnexal mass and an unremarkable uterus with no evidence of intrauterine pregnancy. Based on this clinical history, what is the most likely diagnosis? What is the most likely neoplastic diagnosis? Answer: The most likely diagnosis of an adnexal mass in a patient with an increased hCG and no evidence of intrauterine pregnancy is an ectopic pregnancy. However, assuming that they are not pregnant, one possible neoplastic cause is a mixed germ cell tumor with a choriocarcinoma component. 4. A 54-year-old patient with a history of endometriosis presents to their OB-GYN with increased abdominal discomfort and a sensation of “pelvic fullness.” An exploratory laparotomy and hysterectomy with bilateral salpingo-oophorectomy shows a large left ovarian mass. Histologic exam reveals back-to-back tubular endometrioid-like glands with cribriform architecture, nuclear atypia with stromal invasion, as well as foci of benign endometrial type glands with endometrial stroma. What is the most likely diagnosis? What genetic alterations, if any, would you expect to see in their tumor? Answer: The tumor description of marked nuclear atypia and stromal invasion is diagnostic of an adenocarcinoma. The background showing foci of benign endometrial glands and endometrial stroma is compatible with endometriosis; therefore, this is consistent with an endometrioid carcinoma of the ovary. The most common genetic mutations are CTNNB1, PIK3CA, KRAS, ARID1A, and PTEN. 5. A 70-year-old patient presents with melena and pelvic fullness. August 29, 2023 Pathology of the Ovary Page 11 of 11 Abdominal and pelvic imaging reveals bilateral ovarian masses as well as a diffusely thickened gastric lining. An upper GI endoscopy study reveals gastric carcinoma. What histology do you expect to see in the ovaries? Answer: Bilateral ovarian masses in the setting of diffuse gastric cancer is suggestive of metastatic gastric carcinoma involving the ovaries (or Krukenberg tumors), in which the histology would appear as diffuse infiltration of mucinous signet-ring cells.