Pathology of the Ovaries and Fallopian Tubes, Part 1

Cheryl A. Hanau, M.D.

Click Here for Video
Learning Objectives
• Discuss the various cell types that comprise the ovary and be able to link each tumor
type back to the cell of origin
• Discuss benign conditions of the ovary including cystic diseases
• Discuss ovarian tumors in terms of cell of origin, epidemiology, morphology and the
criteria for determining malignancy, likelihood of malignancy and bilaterality, clinical
consequences, approaches to treatment
• List tumor markers that can be helpful in identifying various ovarian tumors
• Discuss benign fallopian tube conditions including salpingitis

Total Abdominal Hysterectomy – Bilateral Salpingo-oophorectomy (TAH-

BSO) specimen from patient of reproductive age
TAH-BSO from perimenopausal patient
 Non-Neoplastic and Functional Cysts
• Most common lesions of the ovary
• Surface Inclusion Cysts
• Secondary to invagination of surface epithelium
• Follicle Cysts (AKA Cystic Follicles)
• Arise from unruptured follicles or follicles that rupture, then seal and undergo
atresia
• Lined by surface epithelium that may be leuteinized
• Often multiple, can see increased estrogen and ensuing endometrial hyperplasia
• May rupture and cause abdominal pain
• Corpus Luteum Cysts – seen in ovaries of repro age women – may rupture

Non-neoplastic Cysts
Surface Inclusion Cysts

Corpus Luteum Cyst Hemorrhagic Corpus Luteum

Polycystic Ovarian Syndrome (PCOS)

• Affects 6-10 % of reproductive age women
• See hyperandrogenism, menstrual abnormalitites, polycystic ovaries, chronic
anovulation, decreased fertility
• See insulin resistance and altered adipose tissue metabolism that contributes to
association with obesity and Type 2 Diabetes
• Also associated with premature atherocsclerosis
• Appears to be related to defective regulation of enzymes involved in androgen
biosynthesis
• Linked to insulin resistance; administration of insulin mediators has been associated
with resumption of ovulation
PCOS
• Morphology of ovary
• Numerous cystic follicles or follicle cysts enlarge the ovaries; but can see these in
20-30% of all women
• PCOS patients are also at increased risk for endometrial hyperplasia and carcinoma

Polycystic Ovarian Syndrome

Stromal Hyperthecosis (Cortical Stromal Hyperplasia)

• Usually in postmenopausal women who present with symptoms similar to polycystic
ovarian disease
• Gross exam shows uniform enlargement of both (usually) ovaries with white/tan
appearance on sectioning
• Microscopic exam shows hypercellular stroma with luteininzation of stromal cells
Ovarian Stroma – Can see
stromal hyperplasia Hyperthecosis

Ovarian Tumor Overview

• 80% of ovarian tumors are benign
• Benign tumors more common in young women (20-45), malignant tumors more
common at later age (45-65)
 • Ovarian cancer is 3% of all cancer in females; fifth most common cause of cancer death
in US women
• Higher mortality rate than other genital CA, often discovered after spread beyond the
ovary
• Most are non-functional
• Some tend to be bilateral
• Symptoms: With large tumors get abdominal distension and discomfort, GI and urinary
sx

Risk Factors For Ovarian Carcinoma

• Increased risk in women who are nulliparous or have low parity
• Estimated risk of ovarian cancer in women with BRCA1 or BRCA2 mutation is is 20% to
60% by the age of 70 years and most of these cancers are serous cystadenocarcinomas
• Use of oral contraceptives appears to lower the risk of ovarian carcinoma

Ovarian Tumors
• WHO - Classify according to cell type of origin
• Surface/fallopian tube eptihelium & endometriosis
• Germ cells – pluripotent, migrate to ovary from yolk sac
• Ovarian stroma
• Can also see metastatic tumors to the ovary
Tumors of Surface (Muellerian) Epithelium
• Three major histologic types of epithelium
• Serous
• Mucinous
• Endometrioid
• Each can be benign, borderline or malignant depends on whether epithelial tumor cells
invade ovarian stroma
• Next can subclassify by other components
• Cystic areas (Cystadenomas)
• Cystic and fibrous areas (Cystadenofibromas)
• Mostly fibrous areas (adenofibromas)

Tumors of Surface Epitheilum

• Benign lesions
• Usually show flat epithelium and cystic areas
• Malignant lesions
• Usually show papillary projections and solid areas
• Carcinomas can extend through the capsule of the tumor and seed the
peritoneal cavity, resulting in ascites
• Tumors grow slowly, but by the time of diagnosis the malignancy is
usually quite large and has spread beyond the ovary
• CA-125 is a marker for some ovarian cancers
• Borderline lesions
• Neither clearly malignant nor clearly benign, are in a ‘borderline’
category
Tumors of Surface Epithelium: Most common cell of origin for ovarian tumors
• Serous tumors (30% of all ovarian tumors)
• Benign – serous cystadenoma
• Borderline (low malignant potential)
• Malignant – serous (+/- papillary) cystadenocarcinoma
• Most common ovarian cancer – about 40% of them
• 65% are bilateral
• Mucinous tumors
• Benign – mucinous cystadenoma
• Borderline (low malignant potential)
• Malignant – mucinous cystadenocarcinoma
• Endometrioid Tumor of Surface Epithelium
• Clear Cell Adenocarcinoma
• Brenner Tumor

Two Types of Ovarian Carcinoma

• Type I
• Low grade tumors – often arise in association with borderline tumors or
endometriosis
• Many histologic subtypes – low grade serous, endometrioid, mucinous
• Type II
• High grade serous carcinoma
• Arises from serous intraepithelial carcinoma
• Low grade serous ovarian CA – less nuclear atypia and better survival
• May arise in association with serous borderline tumors
• High grade serous ovarian CA – arises from in situ lesions in fallopian tube fimbriae or
from serous inclusion cysts within ovary
• Saw that BRCA1/2 women had prophylactic removal of tubes/ovaries
• Noticed marked epithelial atypia in tubes – called it ‘Serous Tubal Intraepithelial
Carcinoma’ ISTIC)
• Also see this in sporadic high grade serous ovarian tumors
• Where do others come from? Either cortical inclusion cysts of ovary or
implanation of detached fallopian tube epithelium where ovulation has
disrupted ovarian surface

Serous Tumors
• 30% of all ovarian tumors
• 25% are malignant, this makes up 40% of all ovarian malignancies, i.e. #1 ovarian
malignancy (50% if we count borderline)
• Often large, many are bilateral, especially if malignant
• Lined by serous (tubal-like) epithelium
• Benign and borderline most common ages 20-45; malignant later (unless familial)
 Serous Tumors - Pathogenesis
• Unsure of risk factors for benign and borderline
• Risk factors for malignant serous tumors
• Nulliparity
• Family history
• Heritable mutations – germline mutations in
• BRCA1 (5% of ovarian CA patients under 70)
• BRCA2
• Women with either of these have 20-60% ovarian CA risk by age 70

Features of Benign Serous Tumors

• Composed of one or several cysts with smooth inner as well as outer surfaces
• Cysts are lined by a layer of tall columnar, serous secreting, ciliated or non-ciliated cells
with no atypia
• Occasional short papillary projections, lined by same kind of cells may be present
• Outer surface of tumor is covered by mesothelial cells.
• When there is abundant fibrous stroma, the benign serous tumor can be called a
cystadenofibroma Serous Cystadenoma
Serous Cystadenoma
Serous Papillary Cystadenoma

Serous Tumor of Borderline

Flat lining of serous cystadenoma
Malignancy (Low Malignant
Potential)
 Serous Tumor of Borderline Serous Tumor of Borderline Serous Borderline Tumor – Not
Malignancy (Low Malignant Malignancy (Low Malignant definitely invasive – you’ll see invasive
Potential) Potential) in a moment!

Features of malignant serous tumors

• Depends of degree of differentiation
• Composed of numerous cysts with many papillary projections and solid areas.
• Epithelium piles up so there is more than one layer over the surface of the cysts
• See solid masses of epithelial cells are present that invade into wall of the cysts
• Cells are atypical with features of malignancy
Serous Papillary Serous Cystadeno- Serous Papillary More Psammoma Bodies
Cystadenocarcinoma carcinoma – We see Cystadenocarcinoma-
This one is invasive definite invasion into Can you find the
ovarian stroma here Psammoma Body?

Serous Tumor Biologic Behavior

• Depends on degree of differentiation – low grade versus high grade, even if if has
extended to the peritoneum
• Borderline serous tumors
• May arise from or extend to the peritoneal surfaces as noninvasive implants,
remain localized & be asymptomatic
• OR, can slowly spread, producing intestinal obstruction or other complications
after many years.
• OR, may develop into low-grade carcinoma – but even then will usually progress
slowly

Serous Tumor Biologic Behavior

• High-grade serous tumors
• Often widely metastatic throughout the abdomen at the time of presentation;
patient can experience rapid clinical deterioration.
The 5-year survival rate from diagnosis of:
• Borderline serous tumor confined to ovary: 100%
• Malignant serous tumor confined to ovary: 70%
• Borderline serous tumor involving peritoneum: 90%
• Malignant serous tumor involving peritoneum: 25%
• Note: Borderline tumors may have protracted course and recur so 5-year survival is not
synonymous with cure.

Mucinous Tumors
• 20-25% of all ovarian tumors; mid adult life
• Few are malignant, makes up about 3% of all ovarian CA
• Less often bilateral than serous tumors (only 5%)
• Rarely involve surface of ovary
• Many show nutation of KRAS proto-oncogene
• See tall columnar, mucin-secreting cells
• Are often very large tumors
• Can be malignant, benign or borderline, like serous tumors
• Pseudomyxoma peritoneii is a complication in 2-5% of patients
 Mucinous cystadenoma

Mucinous Borderline Tumors

• Distinguished from cystadenomas by:
• Epithelial stratification, tufting, and/or papillary intraglandular growth
• May look similar to adenomas or villous adenomas of the intestine
Borderline Mucinous Tumor Borderline Mucinous Tumor
(Mucinous tumor of low malignant
potential)

Mucinous Carcinoma
• See confluent glandular growth - “expansile” invasion
• Some authors use the term intraepithelial carcinomas for tumors with marked epithelial
atypia that lack invasive features – these can have 95% 10-year survival rate if Stage I
• Even if invasive – if Stage I can have 90% 10-year survival rate
• BUT - Mucinous carcinomas that have spread beyond the ovary are usually fatal, but are
rare
Mucinous Cystadenocarcinoma Benign/ Malignant areas of These ovarian tumors can get
Solid areas generally indicate Mucinous Tumor really BIG!!!
malignant areas
Endometrioid Ovarian Tumors
• 10-15% of all ovarian cancer
• Most are malignant – see solid and cystic growth
• 40% are bilateral
• Histologically similar to endometrial carcinoma
• 5-year survival for stage I is 75%
• About 15-20% of patients also have endometriosis – these tumors show up about 10
years earlier than without endometriosis
• Up to 30% are of these patients also have an independent endometrial carcinoma in the
uterus – still a good prognosis – so appears not to be a metastasis

Endometrioid Ovarian Tumors

• See similar molecular similarities to endometrial endometrioid carcinoma
• Mutations in PTEN, PIK3CA, ARIDIA and KRAS that increase PIEK/AKT pathway
signaling
• Mutations in mismatch DNA repair genes and CTNNB1 (Beta-catenin)
• The PTEN mutations are also seen in atypical endometriosis
• Can see TP53 mutations in poorly differentiated tumors, just like in endometrioid
CA of endometrium
Endometrioid Carcinoma Endometrioid Carcinoma

Clear Cell Adenocarcinoma

• Uncommon - Variant of endometrioid carcinoma
• Can see similar neoplasm in endometrium, cervix, uterus and vagina
• May be solid or cystic
• Micro – large cells with clear cytoplasm or hobnail type cells, arranged in solid, tubular
or papillary configuration
• Aggressive tumor, poor prognosis if beyond ovary

Cell Carcinoma of the Ovary Clear Cell Carcinoma of the Ovary