Leiomyomas and Leiomyosarcomas

Leiomyomas

• Commonly known as fibroids
• These are benign masses of uterine smooth muscle cells
• They are the most common tumor in women
• Leiomyomas can be asymptomatic or manifest with:
  • Abnormal uterine bleeding
  • Pain
  • Urinary bladder disorders
  • Impaired fertility
• Malignant transformation is extremely rare

Morphology

• Tumors are sharply circumscribed, discrete, round, firm, and gray-white nodules
• They occur within the:
  • Myometrium (intramural)
  • Serosa (subserosal)
  • Endometrium (submucosal)
• Lesions show characteristically whorled bundles of relatively uniform smooth muscle cells with rare mitoses
• Variants can exhibit increased cellularity or atypical, bizarre cells

Leiomyosarcomas

• These are uncommon malignant tumors
• Form bulky, fleshy masses in the uterine wall or project into the lumen
• Histologically, there is a wide range of atypia
• Features that distinguish these from benign leiomyomas include:
  • Increased numbers of mitoses (5 to 10 per 10 high-power fields)
  • Cellular atypia
  • Necrosis
• These tumors disseminate throughout the abdominal cavity and aggressively metastasize

Fallopian Tubes Inflammations

• Suppurative salpingitis is typically a component of PID (pelvic inflammatory disease)
• Gonococcal infections account for 60% of cases
  • Any of the pyogenic organisms can be involved
  • Chlamydia is less often a factor

Tumors and Cysts

• Paratubal cysts are the most common primary lesions in the fallopian tube
• They are benign, 1 to 2 mm translucent cysts filled with serous fluid
• Larger versions near the fimbria are called hydatids of Morgagni
• Primary tubal adenocarcinoma is rare and can be associated with germline BRCA mutations
• Even early-stage tumors have a 40% 5-year mortality
  • Prognosis worsens with higher stages

Ovaries

• Contains several follicles and corpora albicantia
• Follicles contain germ cells

Non-Neoplastic and Functional Cysts

• Follicle and Luteal Cysts are extremely common findings
• Typically multiple and usually less than 2 cm
• Lined by follicular or luteinized cells with a clear, serous fluid
• Cysts derive from unruptured Graafian follicles, or follicles that have resealed after rupture
• Typically asymptomatic, but they can rupture with ensuing peritoneal inflammation and pain
• Most common in non-pregnant women of reproductive age, especially near menarche or menopause
• May occur at any age, including neonates and children

Size

• Range in size up to 2 cm in diameter called cystic follicles
• Larger cysts exceeding 2 cm (follicle cysts) can be diagnosed by palpation or ultrasonography and may cause pelvic pain

Microscopic Features

• Inner layers of granulosa cells with or without luteinization composed of uniform round nuclei
• Moderate amounts of eosinophilic cytoplasm
• Outer layer of theca cells with or without luteinization
• Luteinized cells have eosinophilic to clear cytoplasm and round nuclei with central nucleoli

Ovarian Tumors

• Can arise from the epithelium, germ cells, or sex cord stroma
• Overall, 80% are benign and most occur in women aged 20 to 45 years
• Malignant tumors typically occur in older women (45 to 65 years) and represent 3% of all female cancers
  • Most are detected only after spreading beyond the ovary

Tumors of Surface (Mullerian) Epithelium: Serous Tumors

• Serous tumors account for 30% of all ovarian tumors
• 70% are benign or borderline
• Serous carcinomas are the most common ovarian malignancy (40% of the total)
• Prognosis is linked to stage and tumor grade
  • Even with extensive extra-ovarian spread, low grade tumors can progress slowly

Pathogenesis

• Risk factors include:
  • Nulliparity (a woman who hasn't given birth to a child)
  • Gonadal dysgenesis
  • Family history
  • Hereditable mutations
• Most intriguing risk factors are genetic
• Inherited germline mutations in both BRCA1 and BRCA2 increase susceptibility to both ovarian and breast cancer
• BRCA1 and -2 mutations incur a risk of ovarian cancer development by age 70 years in 20% to 60% of patients; most are high-grade
• Low-grade tumors tend to arise in serous borderline tumors and have KRAS and BRAF mutations
• Conversely, high-grade tumors have a high frequency of BRCA and p53 mutations

More on Serous Tumors

• Many tumors (especially high-grade serous) appear to arise from the fimbriated end of the fallopian tube (serous tubal intraepithelial carcinoma)

Morphology

• Grossly: Typically large cystic masses filled with serous fluid
• Benign cystadenomas have a smooth and glistening inner lining
• Cystadenocarcinomas can have small mural nodularities or papillary projections
• Bilaterality is common

Microscopic Features

• Benign cystadenomas are lined by a single layer of tall columnar, ciliated epithelial cells that occassionally form microscopic papillae
• Cystadenocarcinomas have multilayered epithelium with many papillary areas and large, solid epithelial masses that focally invade the stroma
• Borderline tumors demonstrate mild atypia with complex micropapillary epithelial architecture without invasion

Mucinous Tumors

• Account for roughly 30% of all ovarian neoplasms
• 80% are benign or borderline
• Primary mucinous carcinomas amount to less than 5% of all ovarian malignancies
• Smoking is a risk factor and KRAS mutations are a common feature
• These tumors can seed the peritoneum with numerous implants that produce extensive mucinous ascites, called pseudomyxoma peritonei
  • Can be due to primary appendiceal tumors

Morphology

• Grossly: Tumors tend to produce large multiloculated cystic masses filled with sticky, gelatinous fluid
• Less than 10% are bilateral

Microscopically

• Benign lesions are lined by tall, columnar non-ciliated epithelium with apical mucin similar to benign cervical or intestinal epithelium
• Cystadenocarcinomas usually exhibit intestinal-type epithelium
  • Display solid tumor growth, necrosis, and stroma invasion
• Borderline mucinous tumors exhibit complex growth analogous to serous tumors but lack solid growth or stromal infiltration

Endometrioid Tumors

• Endometrioid carcinomas account for 20% of all ovarian cancers
• Show epithelium resembling benign or malignant endometrium
• About 15% to 20% of cases occur in the setting of concurrent endometriosis, although direct origin from the ovarian surface is also possible
• PTEN, KRAS, and b-catenin mutations occur frequently, as well as p53 mutations

Morphology

• Grossly: Lesions are a combination of solid and cystic masses
• 40% are bilateral
• Microscopically: The glandular patterns bear a strong resemblance to endometrial adenocarcinoma

Clear Cell Adenocarcinoma

• Uncommon; it is considered a variant of endometrioid adenocarcinoma
• Tumors can be cystic or solid
• Large epithelial cells contain abundant clear cytoplasm
• Patients with cancer confined to the ovary have 5-year survivals of 65%
  • With extra-ovarian spread, 5-year survival is unusual (poor prognosis)

Brenner Tumor

• Variably sized (1 to 30 cm) solid tumor
• Characterized by dense fibrous stroma and nests of epithelium resembling urinary transitional epithelium
• Usually unilateral; the vast majority of these tumors are benign

Clinical Course, Detection, and Prevention of Surface Epithelial Tumors

• These tumors tend to have similar manifestations: lower abdominal pain and enlargement
  • Symptoms are secondary to bowel or bladder compression
• Benign lesions are readily resected
  • Malignant lesions are associated with progressive cachexia
  • Dissemination beyond the capsule can cause massive ascites and/or diffuse peritoneal studding
• Most patients are diagnosed only after the tumor has become large or disseminated, leading to poor overall survival statistics
• Fallopian tubal ligation and oral contraceptive use reduce risk of developing ovarian malignancy

Detection

• CA-125 (a high-molecular-weight glycoprotein marker of ovarian cancer) is present in the serum of more than 80% of patients with serous or endometrioid carcinomas
  • More useful as a tool in monitoring disease progression than in primary diagnosis
  • Non-specific peritoneal inflammation also increases the serum levels
• Elevated osteopontin levels may allow earlier ovarian cancer detection

Germ Cell Tumors

• Germ cell tumors represent 15% to 20% of all ovarian tumors
• Most are benign cystic teratomas
• Similar to male germ cell tumors
• Arise from neoplastic transformation of totipotential germ cells capable of differentiating into the three germ cell layers

Teratomas

• Mature (benign) teratomas (dermoid cysts) typically arise in young women during their active reproductive years
• Karyotype of virtually all benign teratomas is 46XX; likely arise from an ovum after the first meiotic division
• Tumors are bilateral in 10% to 15% of cases
• Vast majority of such tumors are cured by excision
• 1% undergo malignant transformation, most commonly as squamous cell carcinoma

Morphology

• Mature teratomas are characteristically cystic masses lined by squamous epithelium with adnexal structures
• Including hair shafts and sebaceous glands
• Tooth structures and tissues from other germ cell layers can often also be identified (e.g., cartilage, bone, thyroid, and neural tissues)

Monodermal or Specialized Teratomas

• Differentiate along the line of a single abnormal tissue
• Most common is struma ovarii, composed entirely of mature thyroid tissue
• Ovarian carcinoid is another variant

Immature (Malignant) Teratomas

• Rare tumors composed of embryonic elements resembling immature fetal tissues
• These occur chiefly in adolescents and young women
• Although they grow rapidly and frequently penetrate the capsule, low-grade tumors have an excellent prognosis
  • Even high-grade malignancies can respond well to chemotherapy

Dysgerminoma

• Ovarian counterpart of testicular seminoma
• Most occur between ages 20 and 40 years; most have no endocrine function
• All dysgerminomas are malignant, but only about one-third are highly aggressive
• Because they are chemosensitive, overall survival exceeds 80%

Morphology

• Grossly: Tumors are solid, yellow-white to gray-pink, and fleshy; 80% to 90% are unilateral
• Microscopically: Lesions consist of sheets and cords of large vesicular cells separated by scant fibrous stroma

Endodermal Sinus (Yolk Sac) Tumor

• Rare malignancy resulting from differentiation of germ cells toward yolk sac structures
• The tumors occur in children and young women
• Grow aggressively, although they are chemoresponsive

Morphology

• Histologically, there are glomerulus-like structures with a central vessel enveloped by germ cells within a cystic space lined by additional germ cells (Schiller-Duvall body)
• Intracellular and extracellular hyaline droplets are conspicuous and can contain a-fetoprotein (AFP)

Choriocarcinoma

• Extra-embryonic differentiation of malignant germ cells
• Most tumors exist in combination with other germ cell tumors
• They are identical to placental malignancies and elaborate chorionic gonadotropins
• Ovarian choriocarcinomas are highly malignant, metastasize widely, and are much more resistant to chemotherapy than their placental counterparts

Sex Cord Stromal Tumors: Granulosa-Theca Cell Tumors

• 5% of all ovarian tumors and composed of various combinations of theca and granulosa cells
• Two-thirds occur in postmenopausal women
• Tumors can elaborate large amounts of estrogen & produce precocious sexual development & endometrial hyperplasia
• Predispose patients to endometrial carcinoma
• Occasionally, granulosa cell tumors product masculinizing androgens
• 5% to 25% of granulosa cell tumors are malignant
• Most have an indolent course; 10-year survival rates of 85%

Morphology

• Grossly: Usually unilateral, solid, and white-yellow
• Microscopically: Granulosa cell component consists of small cuboidal-to-polygonal cells growing in cords, sheets, or strands
• Can be occasional gland-like structures with acidophilic material (Call-Exner body)
• Thecal cell components are composed of sheets of plump spindle cells often containing lipid droplets

Fibromas, Thecomas, and Fibrothecomas

• Account for 4% of all ovarian neoplasms
• The vast majority of these are benign
• Curiously, 40% of tumors are associated with ascites and occasionally right-sided hydrothorax (Meigs syndrome)
• Gross: Usually unilateral, solid, hard, gray-white masses
• Microscopic: The fibroma component is composed of well-differentiated fibroblasts and scant collagenous connective tissue
  • The thecoma portion contains plump spindle cells with lipid droplets

Sertoli-Leydig Cell Tumors (Androblastomas)

• Recapitulate the cells of the testes and commonly produce masculinization or defeminization
• Usually unilateral and consist of tubules composed of Sertoli cells and/or Leydig cells interspersed with stroma

Metastatic Tumors

• Common site for metastases
• 5-10% of ovarian tumors are metastases
• Usually bilateral, small, multinodular surface tumors with extensive extraovarian spread
• Most common metastases are from endometrium, appendix (adenocarcinoid or mucinous adenocarcinoma), breast, colon, carcinoid, pancreas and stomach
• Metastatic mucinous carcinomas are most difficult to distinguish from primary mucinous ovarian neoplasm
• Krukenberg tumors are ovarian cancers (often bilateral) caused by metastatic mucin-producing signet cells, usually originating from the stomach