The functional unit of the ovary is the ovarian follicle, which is comprised of an oocyte surrounded by granulosa and theca cells. The theca cells respond to LH by producing androgens from cholesterol. The granulosa cells respond to FSH by converting the androgens produced by the theca cells into oestrogens like oestradiol. The enzyme used to perform this conversion is called aromatase.
Oestradiol stimulates the oocyte to mature. It also stimulates the proliferative phase of the endometrium, to prepare the endometrium for the egg to be implanted.
After ovulation the residual follicle becomes the corpus luteum, which now starts to secrete progesterone. Progesterone stimulates growth of the endometrial stroma while it inhibits secretion of FSH and LH from the anterior pituitary.
Follicular cysts: At any point in time there are many follicles in one ovary. One of these follicles can degenerate, forming follicular cysts. Most women will have one or more follicular cysts as it is very common. These cysts are normally asymptomatic, but they can rupture, causing acute abdomen with pain.
Corpus luteal cysts: When an egg isn’t fertilized the corpus luteum of that egg usually breaks down. Sometimes however, it fills with blood or serous fluid and becomes a cyst instead of degenerating. Like follicular cysts, these cysts are very common and are probably seen in most women. Also like follicular cysts these cysts can rupture, causing acute abdomen.
Chocolate cysts occur in women with endometriosis in the ovary. This produces menstrual products that form a chocolate-brown cyst in the ovary.
Polycystic ovary disease
Polycystic ovary disease (PCOD) is a poorly understood condition. It is more frequent in adolescent women. It is an endocrine disorder, caused by increased LH compared to FSH. It’s characterised by three things: ovulatory dysfunction, androgen excess and polycystic ovaries, although there is often oestrogen excess as well.
Etiology: The exact etiology is unknown. There is high concordance, so there is a genetic component. The disease can occur in the absence of ovaries, so the ovaries are probably not the cause but rather a symptom of the disease. The following are potential risk factors:
- Obesity/insulin resistance
- Positive family history
Women with PCOD often have much higher insulin resistance than their body weight would normally indicate.
Morphology: The ovaries are usually twice the normal size and filled with cysts around 1 cm in diameter.
Pathomechanism: The exact pathomechanism is unknown. Hyperinsulinism may be involved. Something causes the level of LH to increase. Extra LH causes theca cells to produce more androgens. As the FSH level is normal the granulosa cells won’t convert all these androgens to oestrogens, and the androgens will instead be released into the blood.
Some of these androgens will be converted into oestrogens by peripheral adipose tissue. These oestrogens will inhibit FSH secretion from the anterior pituitary, worsening the problem.
The abnormal LH:FSH ratio causes the maturation of ovarian follicles to be impaired, and instead of maturing properly the follicles will become cysts.
Clinical features: Excess androgens in the blood causes development of male characteristics like facial hair. As the follicles aren’t maturating properly these women have problems conceiving or are sterile. Abnormal uterine bleeding is common.
As these patients have high circulating oestrogen, they have increased risk for endometrial carcinoma.
We distinguish four types of ovarian tumors, including metastasis as one type. The ovary consists of three cell types, the surface epithelium, totipotent germ cells and the sex-cord stroma, which includes the theca and granulosa cells. Each of these cell types can give rise to tumors.
Most primary ovarian tumors are unilateral while most metastases are bilateral.
Many different types exist so ovarian tumors are very varied. These tumors frequently cause symptoms late, which delays diagnosis. Metastasis at the time of diagnosis is very common.
Malignant ovarian tumors frequently disseminate to the peritoneum, causing peritoneal carcinosis. This can cause ascites.
Symptoms: These can vary from specific type to type, but generally ascites and abdominal pain are seen. Due to the ascites affected women often notice that their clothes no longer fit properly around their waist.
- Surface epithelium tumors
- Germ cell tumors
- Sex cord tumors
- Ovarian metastases
Diagnosis: Transvaginal ultrasound is the gold standard. Several tumor markers can be detected in some types:
- Epithelial tumors – CA-125
- Yolk sac tumor – AFP
- Choriocarcinoma – hCG
Epidemiology: The peak incidence depends on the type of tumor:
- Younger reproductive women (15 – 30) – germ cell tumors
- Older reproductive women (35 – 40) – benign epithelial tumor
- Postmenopausal women (60 – 70) – malignant epithelial tumor
Surface epithelium tumors
Tumors that originate from the surface epithelium account for 70% of all ovarian tumors, but 90% of all malignant ovarian tumors. As is typical for ovarian tumors these tumors present with symptoms late and therefore carry a poor prognosis.
The pathogenesis is not taken from Robbins and is probably not important to know. I’ve included it because I found it interesting. It was taken from here.
Pathogenesis: The most prevalent theory is that these tumors develop from endometrium or fallopian tube epithelium that seeded to the ovary. The microenvironment of the ovary promotes neoplastic transformation. The following points support this theory:
- Dysplastic precursor lesions to these tumors can be found in fallopian tubes and not in ovaries. These lesions showed many molecular abnormalities that are also seen in these tumors
- Tubal ligation reduces the incidence of many ovarian epithelial tumors
- These tumors are highly associated with endometriosis
The old theory was that these tumors develop from the surface epithelium of the ovary. This epithelium would undergo metaplasia and form the neoplasm. However, many points argue against this:
- None of these neoplasms resemble ovarian surface epithelium histologically
- Most ovarian tumors don’t express ovarian surface epithelium proteins
- Tumors of the corresponding surface epithelium of the testis are rare
- Positive family history
- BRCA1 or BRCA2 germ-line mutation
We distinguish five subtypes of surface epithelium tumors. These are serous, mucinous, endometrioid, clear cell and transitional cell tumors. Each of these are further subdivided into benign, borderline and malignant types:
|Dignity||Serous tumors||Mucinous tumors||Endometrioid tumors||Clear cell tumors||Transitional cell tumors|
|Benign||Serous cystadenoma||Mucinous cystadenoma||Endometrioid cystadenoma||Benign clear cell tumor||Brenner tumor|
|Borderline||Serous borderline tumor||Mucinous borderline tumor||Endometrioid borderline tumor||Borderline clear cell tumor||Borderline Brenner tumor|
|Malignant||Serous cystadenocarcinoma||Mucinous cystadenocarcinoma||Endometrioid cystadenocarcinoma||Clear cell adenocarcinoma||Malignant Brenner tumor|
The “borderline” tumors are low-grade malignant tumors with low invasive potential. These carry better prognosis than the malignant form.
Prognosis: As these tumors are usually found late, the stage of the tumor rather than the histological subtype is the major determinant of the outcome.
Serous tumours are the most common subtype. These are cystic tumors and contain serous fluid. The serous cystadenoma is usually a single, simple cyst with simple squamous epithelial lining. They are most frequent in women 30 – 40 years old.
Serous cystadenocarcinomas are usually not simple cysts but rather complex, multiloculated cysts, containing serous fluid. Unlike the benign form these are lined by a thick epithelial lining. They are most frequent in postmenopausal women. As these are malignant the epithelial lining will invade nearby tissues. Serous cystadenocarcinoma is associated with mutations in BRCA1.
The borderline tumors have features in between the benign and malignant type. They are per definition malignant and have metastatic potential, but they don’t invade tissues.
The serous tumors often have psammoma bodies on histology. Serous tumors are very likely to be bilateral, which occurs in 25% of cases.
Mucous tumors are similar to the serous tumors in all aspects except that the tumor cells produce mucin instead of serous fluid. They are much less likely to be bilateral.
Endometrioid tumors are histologically similar to endometrium, hence the name. The malignant form (endometrioid cystadenocarcinoma) is more common than the benign and borderline forms. As can be imagined, this subtype is associated with endometriosis. This cancer sometimes co-exists with endometrioid carcinoma of the endometrium, so upon diagnosis of this tumor the endometrium should be tested for cancer. These tumors are bilateral in 30% of cases.
Clear cell tumors are rare. As the name suggests these tumors are comprised of clear cells. It is also associated with endometriosis.
Transitional cell tumors are more commonly called Brenner tumors. These are not cystic but rather solid, often unilateral tumors comprised of urinary-tract-like transitional epithelium. These tumors are most frequently benign.
Germ cell tumors
Germ cell tumors are the second most frequent ovarian tumors. These are more common in reproductive age, especially in younger women. These are similar to the germ cell tumors in males in many ways so most characteristics you remember from the testicular counterparts also apply here.
These are the important subtypes:
- Dermoid cyst (mature teratoma)
- Immature teratoma
- Struma ovarii
- Yolk sac tumor
- Embryonal carcinoma
Dermoid cyst accounts for 90% of all ovarian teratomas. These are benign. Dermoid cysts are mature teratomas and therefore can contain mature tissues, like hair, teeth or nests of gastrointestinal epithelium.
Immature teratomas account for only 10% of ovarian teratomas but are malignant. Instead of being cysts these tumors are bulky and solid. Histology reveals that the tissues that comprise these tumors are immature. The grade and therefore the prognosis depend on how much neuroepithelial tissue there is; the more, the higher the grade.
Struma ovarii is a rare type of teratoma composed entirely of mature thyroid tissue. This tumor is a rare but interesting cause of hyperthyroidism.
Dysgerminoma is the ovarian counterpart of the testicular seminoma. All are malignant, but like seminomas the dysgerminomas are very sensitive to irradiation therapy. The tumor cells have clear cytoplasm due to their glycogen content.
Yolk sac tumor produces AFP, an important tumor marker.
Embryonal carcinoma of the ovary are necrotic and haemorrhagic masses, like in the testis. These tumors are aggressive.
Choriocarcinoma produces hCG, an important tumor marker. Choriocarcinomas spread haematogenously very early.
Sex cord tumors
These tumors can be comprised of granulosa cells, theca cells, Sertoli cells and/or Leydig cells, or almost any combination thereof. Three tumors are important here:
- Granulosa-theca cell tumor
- Sertoli-Leydig cell tumor
Granulosa-theca cell tumors frequently produce oestrogen. These increase the risk for breast and endometrial carcinoma.
Thecofibromas are comprised of theca cells and fibroblasts.
Sertoli-Leydig cell tumors may produce androgens and cause symptoms of masculinization. The Sertoli cells may produce tubules.
Metastases to the ovary are most frequently from GI-tract, breast, lung or endometrium.
Krukenberg tumors are bilateral ovarian metastases that originate from the GI tract, most commonly from the diffuse type (signet ring) stomach carcinoma. These tumors are often mucinous and can be hard to distinguish from primary mucinous epithelial tumors.
57. Diseases of the uterus and fallopian tubes
59. Pathology of pregnancy I (implantation disorders, gestosis, trophoblastic tumours)