Neoplasms of the Ovary and Normal Histology Pincas Bitterman, MD 2019

 Epithelial ovarian tumors  Sub-types  Brenner tumor  BRCA1/BRCA2  Borderline tumors  Tumors with "coffee-bean" nuclei  Pseudomyxoma peritonei  Germ cell tumors  Benign and malignant  Mature cystic teratoma (Dermoid cyst)  Dysgerminoma  Schiller-Duval bodies  Sex Cord-Stromal Tumors  Fibroma  Granulosa cell tumor  Call-Exner bodies  Metastatic tumors to the ovary  Most common sites  Krukenberg tumor

 OVARIES ● Most common lesions are functional cyst which are benign, and non-malignant neoplasms. ● Functional cysts include Follicular cysts and Luteal Cysts. Patients may present with or without symptoms, or vaginal bleeding with or without a pelvic mass. ● The incidence of ovarian cancer increases with age. Early detection is problematic as generally the patients have no symptoms and present at high stage (II-III) where the tumor has spread to other sites inside or outside the pelvis. ● Ovarian cancer is the #1 killer among female genital malignancies in the US ● Inflammation ○ Oophoritis . Associated with PID . Autoimmune, rare

● Non-Neoplastic and Functional Cysts ○ Follicular and luteal cysts . Very common: physiologic? . Unruptured graafian follicles . Ruptured follicles which sealed immediately . Usually multiple, about 2cm in diameter . Lined by granulosa and thecal cells  Theca cells may be luteinized ○ Corpora lutea . Lined by luteinized granulosa cells ○ Polycystic Ovaries (former name: Stein Leventhal syndrome). . May be associated with stromal hyperthecosis . Stromal hyperplasia is not unusual ▪ Affects 3% - 6% of reproductive-age women ▪ Very conspicuous luteinized thecal cells . estrogen production . Endometrial hyperplasia on occasion . Most common in postmenopausal women . Numerous follicle cysts  Subcortical . Enlarged ovaries  Twice the normal size . Thickened cortex . Absence of corpora lutea . Clinical presentation  Oligomenorrhea  Anovulation  Obesity  Hirsutism  Virilism (rarely) . Microscopic appearance  Concordant with the gross view: Cysts etc . Clinical course  Persistent anovulation  Obesity  Hirsutism, virilization

● Neoplastic Processes ○ Review of histology is absolutely necessary for understanding and diagnosis ○ Malignant tumors represent 6% of all cancers in females in the USA ▪ Incidence ranks below uterine and cervical cancers ▪ Not commonly detected at early stage ▪ Risk factors include  Nulliparity or low parity  Gonadal dysgenesis in children  Family history  Heritable mutations (BRCA – 5% of patients < 70 years old- and BRCA2) • These increase the susceptibility to ovarian cancer, but not borderline tumors • 20% to 60% by the age of 70 • Most cancers are Serous  Better than 90% of serous carcinomas show mutations in the tumor-suppressor gene p53  Oral contraceptives and tubal ligations appear to be protective ○ The majority of ovarian tumors are benign . Once removed, the patient is “cured” ○ The incidence of malignancy increases with age ○ The size of the tumor is generally unrelated to its behavior, (benign versus malignant ○ Behavior of malignant tumors depends primarily on the grade and stage of the tumor . Borderline (Atypical proliferative) Tumors  No destructive stroma invasion  Implants which are not clear cut malignant  Chemotherapy only with metastatic carcinoma  About 5% die from disease metastatic carcinoma is not present . Malignant  Destructive stromal invasion  Metastasis ▪ Risk factors for malignant tumors include: . Nulliparity . Family history . Gonadal dysgenesis in children . Genetic  BRCA1 and BRCA2 mutations  Lynch syndrome II ○ The classification of ovarian tumors is based on the most probable tissue/cell of origin . Surface coelomic epithelium  Serous (Serous intraepithelial carcinoma, (STIC).  Mucinous, etc. . Germ cells  These migrate to the ovary from the yolk sac at the 5th to sixth week of gestation . Ovarian stroma . Metastatic

○ The majority of tumors are nonfunctional ○ Most become symptomatic because of their size ○ Many have spread prior to surgery ○ Some epithelial tumors tend to be bilateral – review table ○ Metastatic tumors have a tendency to be bilateral ○ Stroma tumors are generally unilateral ○ Malignant germs cell tumors are most often unilateral ○ Occasional symptoms include: . Abdominal/pelvic pain . Abdominal distention – ascites . Urinary and gastrointestinal symptoms . Vaginal bleeding ○ Prognosis is determined by type of tumor, STAGE and GRADE

○ Epithelial tumors . Most common . Size: small or massive ○ Histologic types . Serous (lined by tall columnar ciliated cells-tubal-like)  Filled with clear fluid  All types of serous tumors (benign, borderline, and malignant) account for 30% of all ovarian tumors. 75% are benign or borderline. Of the 25% malignant, 40%-50% are serous  Benign tumors are generally cystic, with a smooth and glistening cut surface.  Borderline tumors show a range of papillary projections. Malignant tumors show multifocal solid areas which may be associated with cysts.  Bilaterality: 20% in cystadenomas; 30% of borderlines and approximately 65% in carcinomas  Generally originate from the surface epithelium  Cystadenomas  Cystadenofibroma  Benign ▫ Variant with more proliferation of the fibrous stroma associated with the epithelium ▫ Benign, small, multilocular with small, simple fibrotic, papillary processes. ▫ Depending on the lining epithelium, they may be serous, mucinous, endometrioid, transitional (Brenner), or rarely clear ▫ Borderline or malignant types are extremely rare  Adenofibromas  Carcinoma (STIC). ○ Morphology . Serous . Benign: cuboidal/columnar epithelium with cilia without nuclear stratification . Borderline: Complexity of papillae, nuclear stratification, nuclear atypia, few mitotic figures, but NO DESTRUCTIVE STROMAL INVASION; Microinvasion . Calcifications (psammoma bodies on occasion). . Malignant: Destructive stromal invasion associated with marked nuclear atypia, numerous mitotic figures, large, edematous papillary structures . Borderline and malignant tumors may involve the ovarian surface  Micropapillary tumors: areas of borderline and carcinoma, but low grade.  Implants/metastasis; large intra-abdominal masses.  5-year survival rates range from 100%-70% if confined to the ovary, and 25% to 95% with peritoneal involvement, in carcinomas and borderline tumors respectively.  Borderline tumors may recur after several years  Mucinous  Lines by mucinous epithelium similar to the cervix or colon without cilia.  They represent 20%-25% of all ovarian tumors  Mostly occur in middle adult life  > 90% are benign or borderline  Mucinous carcinomas account for < 5% of ovarian cancers  Grossly: numerous cysts and rare surface involvement  The majority show abundant gland-like or papillary structures with nuclear atypia and stratification if borderline or malignant. Carcinomas contain solid areas, marked nuclear atypia, numerous mitotic figures and necrosis plus INVSION OF THE STROMA • Intraepithelial carcinoma  Some originate in endometriosis and are rarely carcinomas  10-year survival rate in borderline, noninvasive and invasive is about 95%, 90% and 55% respectively  Endometrioid  20% of all ovarian cancers  The great majority are carcinomas  Occasionally benign: cystadenofibromas  30% associated with endometrial cancer  >25% coexist with endometriosis  Grossly: combination of solid and cystic areas  Morphology: Lined by cells resembling endometrium  40% are bilateral  5-year survival in stage I is around 75%  Clear Cell Adenocarcinoma  Less common than the others  May occur in association with endometriosis or endometrioid carcinoma  May be solid or cystic  Characterize by epithelial cells with abundant clear cytoplasm arranged in sheets, tubules, or cysts  5-year survival rate of approximately 60% when confined to the ovary. If not, survival is generally < 20%  Transitional cell tumors  Benign transitional cell tumor (Brenner).  Rare adenofibromas  Solid or cystic tumors  Unilateral (90%)  From microscopic lesions up to 30 cm. Small lesions (1cm -2cm) are more common  Transitional epithelium resembling the epithelium of the urinary tract with ‘coffee bean’ nuclei  Tumor nests in a fibrous stroma  The nests may show glandular spaces lined my mucinous epithelium  Rarely contain a plum cellular stroma with hormonal activity  Greater than 95% are benign with rare borderline and malignant counterparts  If malignant without a classic Brenner tumor component, they are characterized as TRANSITIONAL CELL CARCINOMA  ○ Clinical Course, Detection, and Prevention of Surface Epithelial Tumors . Benign tumors are cured with resection . Characteristic symptoms when the tumors are large include:  Lower abdominal pain  Abdominal enlargement  Gastrointestinal complains  Urinary symptoms (frequency, dysuria)  Pelvis pressure and pain etc.  If malignant, additional symptoms may include weakness, weight loss and cachexia, particularly as the tumors progresses  Ascites: Accumulation of fluid If the tumor has infiltrated the peritoneal cavity: • Malignant cells may be present in the fluid  Advanced tumor show lymph node involvement and metastasis to the pelvis, abdomen, thorax, and other sites  Generally diagnose when the tumor has spread with a consequent guarded prognosis  Early detection is the key to achieve a better prognosis, however, blood markers have been somewhat elusive up to this point ▫ CA-125: high molecular weight glycoprotein is elevated in 80% of patients with serous and endometrioid cancer, however, its elevation is non-specific as benign tumors and other conditions may cause elevation of CA-125  Prevention remains an elusive goal  Prophylactic oophorectomy in patients with BRCA mutations are currently standard

● Germ Cell Tumors

● ● Histogenesis and interrelationship of tumors of germ cell origin. (Modified from Teilum, ref. 198.) ● Germ Cell

Seminoma, dysgerminoma Tumors of totipotential cells

Embryonal carcinoma Embryonal carcinoma

Extraembryonic structures Embryonic ectoderm, mesoderm,

Endodermal sinus tumor (yolk sac tumor) Choriocarcinoma Teratoma ● ● ●

●

● ○ 15% to 20% of all ovarian tumors ○ Majority are benign cystic teratomas (dermoid cysts) ○ Remainder are more common in children and young adults with a higher incidence of malignant tumors ○ Morphologically very similar to testicular germ cell tumors ○ Teratomas . Mature (benign)  They appear to originate from an ovum after the first meiotic division, with a 46XX karyotype for all benign cases  Cystic, dermoid cyst (most common type)  They present in all ages, but more commonly in women in the reproductive years  Bilateral in 15% of cases  Characteristically they consist of a unilocular cyst containing hair and cheesy sebaceous material  Teeth and/or tooth-like structures are common  Elements from all germ cells layers may be present such as cartilage, bone, thyroid tissue, respiratory epithelium, etc.  Skin is commonly present  1% or less undergo malignant transformation: squamous cell carcinoma, thyroid carcinoma, etc.  The solid variant is uncommon (Mature Solid Teratoma). ○ Monodermal (specialized) ▪ The great majority are unilateral ▪ Struma ovarii is only composed of mature thyroid tissue • It is the most common and may be functional ▪ Carcinoid: may be functional as well, particularly if large (> 7 cm) ▪ Metastatic intestinal carcinoid is usually bilateral ▪ Strumal carcinoid is very rare, and composed of a combination of struma and carcinoid . Immature (malignant)  Rare  Immature fetal like components  In pre-pubertal adolescents and young women: 18 is the mean age  Gross: Solid and cystic with hemorrhage and necrosis and areas of cheesy material and/or hair  Most common immature component is neural tissue  Less likely are cartilage, glands, bone, etc.  Extraovarian spread is directly related to the amount of immature component which determines the grade of the tumor (Low vs. high grade)  Tendency to grow rapidly with capsular invasion, and local spread or metastasis.  Low grade tumors have an excellent prognosis. o Dysgerminoma . Very similar to testicular seminoma . 2% of all ovarian malignant tumors, but 50% of malignant germ cell tumors . Most common malignant germ cell tumor . 75% in the second and third decades . The great majority have no endocrine function. Few produce elevated HCG (stromal syncytiotrophoblasts) . Better than 80% unilateral . Lobulated large mass . Usually solid, with occasional cysts, yellow-white, and fleshy . Characteristic dispersed sheets of large vesicular cells with clear cytoplasm, and large central nuclei, separated by fibrous cord containing a lympho-plasmacytic infiltrate with occasional granulomas . One third are aggressive . Tumors without a broken capsule or spread have a 96% cure rate with salpingo-oophorectomy . Extremely radiosensitive

○ Yolk Sac Tumors ▪ Endodermal sinus is the most common type  Mostly in children, or young women  May present with abdominal pain, and a rapidly growing pelvis mass  Rare, but the second most common malignant germ cell tumor after seminoma  Derived from differentiation of malignant germ cells towards extra-embryonic yolk sac structures  Generally unilateral  Rich in alpha-fetoprotein and alpha-antitrypsin  Morphology: ▫ Schiller Duval bodies (glomerulus-like structures), are characteristic ▫ Hyaline droplets  Most common additional component in dysgerminoma  Elevated AFP serum levels  Combination chemotherapy has improved the outcome

○ Choriocarcinoma . Identical to the gestational trophoblastic disease counterpart where it is most common . Originates from extra-embryonic differentiation of malignant germ cells . “Common” in the first decade . ↑ HCG serum level which aids in the diagnosis and to detect recurrences . Most often mixed with other germ cell tumors. The pure form is extremely rare . Aggressive tumors that generally have metastasized widely through the blood stream by the time of diagnosis . They are generally unresponsive to chemotherapy and often fetal

● Other Germ Cell Tumors ○ Embryonal carcinoma-highly malignant ○ Polyembryoma ○ Mixed germ cell tumor: Any mixture of the above

● Sex Cord-Stromal Tumors ○ Derived from ovarian stroma which originates from the sex cords of the embryonic gonad ○ Usually unilateral ○ The gonadal mesenchyme produces male (Sertoli and Leydig) and female (granulose and theca) structures ○ The tumors resemble the cell types mentioned above ○ Tumors may be feminizing due to the secretion of estrogen such as Granulosa and Theca cells ○ Tumors may be masculinizing due to androgens, such as Leydig and Sertoli cells

● Granulosa –Theca Cell tumors ○ Composed of granulose and theca cells in varying proportions ○ 5% of all ovarian tumors ○ Two thirds occur in postmenopausal women ○ Usually unilateral ○ They may be microscopic to large solid and cystic encapsulated masses commonly with hemorrhage ○ The granulosa cells are small, cuboidal, elongated, and somewhat polygonal with grooves (‘coffee bean nuclei’) ○ Multiple histological patterns: ▪ Small gland-like structures with luminal pink material (acidophilic): Call-Exner bodies ▪ Anastomosing cords ▪ Sheets or strands ▪ Cells forming islands-Insular type ▪ Multiple small follicles: Microfollicular ▪ Large cystic follicles: Macrofollicular

○ The thecoma component shows clusters or sheets of tumor cells ○ Gross: Yellow appearance on cut surface suggests hormonal activity ○ Pure thecomas are solid, firm, and yellowish ○ They may elaborate large amounts of estrogens: ▪ Associated with endometrial hyperplasia or carcinoma ▪ Cystic disease of the breast ○ Functioning active tumors in young girls (Juvenile Granulosa Cell Tumor) may produce precocious sexual development ○ Granulosa Cell tumors are potentially malignant with recurrences described several years after removal of the primary tumor ○ Differential diagnosis includes poorly differentiated carcinoma and carcinoid ○ The ten-year survival with GCT is > than 85% ○ Elevated serum levels of inhibin are associated with GCT and other sex cord stromal tumors. ○ Inhibin is also useful for monitoring therapy

Granulosa cell tumor Carcinoma

Bilateral, less than 5% Bilateral, more than 25% Stage I in 90% of cases Stage III or IV in most cases Nuclei round to angular, pale and Nuclei hyperchromatic, often bizarre commonly grooveda with atypical mitoses Mucin occasionally in follicles, Intracellular droplets or extracellular (Mainly in juvenile type) pools of mucin, psammoma bodies or Good prognosis glands may be present Indolent course, when clinically Poor prognosis Malignant Rapid course aException: dark, un-grooved nuclei of juvenile granulosa cell tumor. bException: rare juvenile granulosa cell tumors.

○ Fibroma-Thecoma ▪ From ovarian stroma ▪ Generally large pelvic masses that present with pain ▪ Meigs syndrome: ascites, right sided hydrothorax, and an ovarian tumor > than 6cm in diameter. Ascites is much more common than the other clinical findings ▪ May also be associated with the basal cell nevus syndrome ▪ Composed of fibroblasts (fibromas), or plump spindle cells with lipid (thecomas) ▪ 4% of all ovarian tumors ▪ If both types of cells are present: Fibro-thecoma ▪ 90% Unilateral, spherical, white to yellow, encapsulated, hard, covered by glistening ovarian serosa ▪ Pure fibromas are hormonally inactive and represent the majority of the tumors ▪ The vast majority are benign with rare exceptions

○ Sertoli-Leydig Cell Tumors (Androblastomas) . Unilateral, < than 1% of ovarian tumors, but occur in all age groups, but most often in the second and third decades . Associated with masculinization, or defeminization, and rarely estrogenic effect  Atrophy of the breasts, amenorrhea, sterility, loss of hair.  Virilization . Cut surface is golden brown . Cells similar to developing testicular cells featuring tubules, with or without Leydig cells. On occasion a sarcomatous pattern is characteristic . May have heterologous elements . Regarded as low grade malignancy (5% recur or metastasize) ○ Other Sex Cord-Stromal Tumors ▪ Leydig cell tumors originating in the ovarian Hilus  Unilateral  Leydig cells show Reinke crystalloids  Laboratory: Elevated 17-ketosteroids . Pregnancy luteoma: associated with virilization . Gonadoblastoma: Rare. Composed of germ and sex- cord cells

● Metastatic Tumors ○ Most common from the gynecologic tract and pelvic peritoneum ○ Bilateral in 75%-80% of cases . Breast . Gastrointestinal tract (colon, stomach, biliary tract, pancreas) . Krukenberg: Bilateral metastases composed of cells fill with mucin (signet-ring) . Metastic tumors to the ovaries from several other organs have been reported.