A 44 year old woman complains of persistent itching of the vulva. Creams recommended by her pharmacist provided no relief. Healthy since her last pregnancy more than 15 years ago, not seen by a gynecologist since then. Patient does not drink or smoke. Slightly overweight female. Vital signs normal. Examination of the vulva shows multiple white verrucous patches surrounding the introitus. CBC within normal range. Urinalysis negative for protein or glucose. Where are warty lesions from HPV 6 and 11 typically found?
HPV typically affects the vulva, vagina and cervix. The oropharynx and perianal region can also be involved. Note that 90% of vulvar intraepithelial neoplasia cases are due to HPV, especially HPV 16. Other causes include HSV-2.
35 year old woman was referred for follow-up secondary to findings of cytologic atypia in repeated PAP smears. She reports no other health problems and is employed in a business office. Patient enjoys the Friday bar scene. Had numerous “unfaithful” boyfriends. Her hobby is scuba diving and she travels 2-3 times per year for short vacations in the Caribbean. CBC within normal range. Urinalysis negative for protein or glucose. Biopsy showed a low-grade intraepithelial squamous cell dysplasia. How does this get to squamous cell carcinoma? What is her prognosis?
Progression from low grade must go through high grade before it can become full carcinoma. Spontaneous regression occurs in a majority of low grade lesions (most often associated with productive viral infections that are self limited) and a minority of high grade lesions.
A 33-year-old female complains of increasing pain during menstruation. Menarche at age 12. She stopped using oral contraceptives years ago and has regular menstruation. The patient and her husband would like to start a family, but she has never become pregnant. Occasional dysuria and dyspareunia. The patient is slender. Bimanual examination discloses enlargement of the left ovary with a possible cyst. Anterior tenderness is noted during the rectal exam. Biopsy is shown below. What is likely causing her condition? What finding is required to make the diagnosis of endometriosis?
Retrograde menstruation can cause endometriosis. Histologically you must see ectopic endometrial glands and stroma that are located outside of the uterus. Hemosiderin and fibrosis also found often.
A 34 year old woman complains of excessive fatigue. She has not seen her gynecologist for 7 years. She has two daughters ages 5 and 7. Her last pregnancy was difficult and she experienced excessive post-partum bleeding. The patient appears tired and pale. Her pulse is 92. The pelvic exam reveals nodular uterine enlargement. HCT 28 with MCV 68. Ultrasound consistent with submucosal and intramural tumors of the uterus. What is likely causing her condition?
Leiomyomas. These are found in premenopausal women and are estrogen sensitive. Extended menses occur due to poor uterine contraction and account for her microcytic iron deficiency anemia.
A 60-year-old female presents with vaginal bleeding. She has been taking conjugated estrogen medication for osteoporosis for the past 8 years. An endometrial biopsy performed 6 years ago showed endometrial hyperplasia. At that time she failed to return for follow-up. What is the most likely cause of her condition?
Endometrial carcinoma is the most common invasive cancer in the female genital tract, with high incidence in post-menopausal women. She has already been diagnosed with endometrial hyperplasia, which is a risk factor.
If you have HPV in the setting of a condyloma and a squamous cell carcinoma, which condition presents as shown below?
Koilocytic change represents an active HPV viral infection within the cells. Note the perinuclear halo and enlarged, hyperchromatic nuclei.
Why does cervical cancer tend to arise in the transition zone?
It tends to infect immature squamous cells which are found in the zone of transformation.
Which part of this pap smear is abnormal?
The clumps of cells are endocervical cells that are normal, the large cells are exocervical squamous cells. Abnormal cells are shown below with an enlarged nucleus and clumpy chromatin.
How do you know where to biopsy on culposcopy?
Acid staining of the cervix
What defines low grade squamous intraepithelial lesions?
Lack of maturation in the lower third of the mucosa. Note the amount of black in the cells indicating lots of viral protein and active infection.
What defines high grade squamous intraepithelial lesions?
Lack of maturation in the upper third of the mucosa.
What would you expect histology of this lesion to look like?
This is an exophytic squamous cell carcinoma
Why is cervical carcinoma worse than vulvar or vaginal carcinoma?
There is easier spread into local organs (ureter, bladder) and can lead to obstruction of the urinary tract.
A 44-year old woman complains of fullness after meals with vague lower abdominal discomfort. She had an appendectomy at age 17. Routine PAP smears have been consistently negative. She married at age 38 and has not been able to conceive. A maternal aunt died of breast cancer. No specific GI symptoms. She has been urinating with increased frequency. The abdomen is slightly protuberant. A mass is palpated in the right pelvis. Mild microcytic hypochromic anemia. WBC and differential normal. Urinalysis neg. Ultrasound demonstrates complex bilateral cystic masses in the lower abdomen. At surgical debulking prior to chemotherapy both ovaries are enlarged with cystic and solid masses. Cancer had extended to the pelvic organs, omentum, small bowel and liver surfaces (Stage III). What is the likely diagnosis and what are risk factors for this condition?
Serous cystadenocarcinoma. Abdominal discomfort is a common presenting factor in women with ovarian neoplasms. Age 45-65 is at highest risk for malignant ovarian tumors. Appendectomy rules out appendicitis and pseudomyxoma peritonei. FH of BRCA 1/2 mutations put her at risk for high grade serous carcinomas in the ovary. Nulliparity is also a risk factor. Of all the malignant ovarian tumors these are the most common. A significant portion of these cancers present bilaterally,
4 types of ovarian neoplasms
Surface epithelium (most common), germ cell, stromal and metastatic tumors.
Types of surface epithelial ovarian neoplasms
Serous, mucinous, endometriod (includes clear cell) and Brenner (composed of urothelium)
Type of germ cell ovarian neoplasms
Teratoma (most common germ cell) and dysgerminomas
Type of sex cord-stromal ovarian neoplasms
Granulosa-theca, sertoli and Leydig tumors.
Are most ovarian neoplasms functional or non-functional?
Most are non-functional. This means that they present as a mass that presents late and have a high mortality rate.
What would you expect this papillary ovarian neoplasm to look like on histology?
Papillary ovarian neoplasms tend to be benign. Below is a benign serous epithelial neoplasm of the ovary. Note that the proportion of epithelium to stroma is LOW w/minimal amount of epithelial proliferation around the stroma. Also note that there are no solid areas of epithelial growth and structures surrounded by epithelium are very simple. Note that in the lower image there is much more robust
What 3 conditions share molecular abnormalities that can arise in the uterus and ovaries?
Endometriosis, endometrial carcinoma and endometriod epithelial ovarian cancer.
Ovarian surface epithelial tumors that can be classified as benign, borderline and malignant?
Serous and mucinous cystadenomas.
How do you differentiate a serous from a mucinous cystadenoma in the ovary?
Most mucinous tumors are benign or borderline, serous are much more likely to be malignant. Serous tend to have bilaterally. Mucinous tend to be unilateral. Mucinous tumors tend to be larger and have a multilocular appearance.
How do you tell a mucinous from a serous cystadenoma of the ovary on histology?
Mucinous has tall
What is your diagnosis of this biopsy of an ovarian mass?
Serous cystadenoma. Note the open glandular spaces, minimal mitotic activity and psammoma bodies (micro calcifications)
What determines if a serous ovarian cystadenocarcinoma is high grade?
> 50% sheets of atypical cells and mitosis. Note that stromal invasion is extensive.
Where did this ovarian tumor likely come from?
Stomach, note the signet ring cells indicating a Kruckenberg tumor.
A 54-year-old woman presents with increasing abdominal girth. Appendectomy at age 16. PAP smears consistently negative. Vital signs WNL. The patient is obese abdominal and gynecologic exams are difficult. No anemia. WBC wnl. Transvaginal ultrasound shows a multicystic mass. Biopsy of the mass and CT is shown below. What is the most likely cause of her condition? What is her prognosis?
Note the production of mucin in the cytoplasm of the columnar epithelium. Mucinous ovarian cystadenoma. These are typically benign and have a good prognosis.
A 20-year-old female presents with unilateral abdominal pain. A 10 cm adnexal mass is discovered on pelvic examination. Biopsy is shown below. What would you expect to see on histological examination?
This is a mature cystic teratoma (dermoid cyst). Note the semi-solid mixture of cheesy material and hair in Rokitansky’s tubercle. These appear because squamous epithelium is very common in cystic teratomas. On histology you would see the squamous epithelium, apocrine glands, thyroid tissue, cartilage etc.
What is the chance of malignancy in a dermoid cyst?
Dermoid cyst + encephalitis
Paraneoplastic syndrome that happens w/dermoid cysts (mature cystic teratomas)
Immature teratoma risk for malignancy
Much higher, they tend to be solid and harbor malignant cells.
What are the two most common monodermal teratomas?
Struma ovarii (thyroid tissue presenting w/hyperthyroidism) and carcinoid.
What differentiates carcinoid symptoms in the GI tract from carcinoid teratoma symptoms in the ovary?
GI must have liver metastasis before symptoms present because before that serotonin is inactivated by first pass metabolism. In the ovary you don’t need liver metastasis because the serotonin goes straight into systemic circulation.
What type of ovarian teratoma is this?
Immature. Note the naked cytoplasms forming neural structures and rosettes, this is neuroectoderm in the teratoma. Remember that the more neuroectodermal tissue you see in an immature teratoma, the higher the grade.
A 35-year-old female presents to the ER with a 12-hour history of lower abdominal pain. She had multiple genital tract infections and STD infections. Reconstructive surgery to repair both fallopian tubes previously damaged by salpingitis was performed two years ago. She was in a long term relationship and seeking to become pregnant. Appendectomy at age 22. Examination reveals a tender left adnexal mass. WBC slightly elevated with no left shift. Amylase WNL. A serum hCG was 6500 U/L. Ultrasound - the uterine cavity was empty. What is your differential diagnosis for this patient?
Choriocarcinoma or ectopic pregnancy. Note that out of choriocarcinoma, ectopic pregnancy, normal pregnancy and molar pregnancy, choriocarcinoma has the highest levels of hCG. She most likely has an ectopic pregnancy because of her history of obstruction in the fallopian tube and attempt to become pregnant.
What is the most common cause of chronic salpingitis?
STD (chlamydia or gonorrhea) that causes PID.
What are possible causes of ectopic pregnancy?
IUD, peri-tubal adhesions and PID.
Why do you need to terminate an ectopic pregnancy with MTX or salpingotomy?
Chorionic villi invade into the fallopian tube that can cause rupture, bleeding and hemorrhagic shock.
What are common sites of ectopic pregnancy.
Ovary, abdomen, intra-uterine portion of fallopian tube and extra-uterine portion of fallopian tube (most common site)
What causes this?
This is hydrosalpinx. Chronic salpingitis results in accumulation of inflammatory fluid, inflammation, fibrosis, adhesions and enlargement of both ovaries.
These are images of a normal uterine tube. What would it look like if the patient had chronic salpingitis?
Note lots of chronic inflammation, infused plicae and fibrotic tissue.
A 23-year-old female at 15 weeks gestation presents with vaginal spotting. The patient reported no fetal movements. The size of her uterus corresponds to an estimated gestational age (EGA) of 22 weeks. No fetal heart tones were auscultated. A serum hCG was 1.2 million U/L. There is no fetus present on ultrasound examination. What is the most likely diagnosis?
Note that the size of the uterus is larger than its gestational age, serum hCG is elevated and no fetal movements. These are all indications for a molar pregnancy.
What are the different types of molar pregnancies?
Hydatidiform mole, invasive mole, placental site trophoblastic tumor and choriocarcinoma.
What is this? How does it form?
Markedly dilated villi filled with chorionic fluid. This is a hydatidiform mole. Complete moles form by 2 sperms fertilizing and empty egg (46 XX or 46 XY). Note that complete moles are totally undifferentiated with no fetal parts.
This is an image of normal chorionic villi. What would this look like if it were a complete mole?
In a complete mole you have large chorionic villi full of fluid with no capillaries. You also see proliferation of trophoblasts that do not form knots discontinuously like normal villi, but they continuously cover each villi and proliferate.
What do you do after D&C in a patient who had a hydatidiform mole?
Continuously check hCG levels for a year. If they don’t go down you may have an invasive mole, placental site trophoblastic tumor or choriocarcinoma.
Why is it key that you recognize an invasive mole?
It can go to the lung and brain and cause problems there if not resolved.
What makes an incomplete mole? How is it different from a complete mole? What is risk for future choriocarcinoma?
It has an X chromosome in the ovum and 2 sperms enter the ovum to make a 69 XYY, XXY or XXX. With these fetal parts form, less trophoblastic proliferation. Note that there is no risk for choriocarcinoma, but invasive mole still can happen.
What is different about these two vulvar biopsies?
The one on the left is high grade VIN. Note acanthosis and lack of progressive cell maturation toward the surface. On the right it is differentiated VIN with basal cell layer atypia (arrow) and normal appearing squamous cells apically.
Two patient present, each has high grade VIN. One has a flesh-colored lesion and the other has a warty carcinoma. What would biopsy of their lesions reveal?
Basaloid = flesh colored. Eosinophilic = warty.
What cells would you see on higher power in this patient with vulvar CIS?
Atypical cells without normal squamous cell maturation as you approach the surface.
How do you detect HPV infection in the biopsy of this warty lesion?
Note the absence of kilobytes, increased N:C ratio, hyperchromatic atypical nuclei and lack of maturation toward the surface. This is a high-grade squamous intraepithelial lesion of the cervix and only DNA hybridization technique can recognize the infection because the DNA has integrated with the viral DNA at this point.
What features will help you differentiate invasive squamous cell carcinoma of the cervix from high grade intraepithelial lesions?
Sheets of tumor cells invading the stroma, eosinophilic cytoplasms, keratin production and intracellular bridges.
What is responsible for the overproduction estrogen and pelvic pain in people with endometriosis?
Pelvic pain: inflammatory mediators. Estrogen: stromal cell proliferation due to progesterone resistance. Note that the ectopic endometrial glands respond to hormonal cycling and pain can become cyclic. Secretory phase endometrial glands are shown below.
Gross features of leiomyoma vs. leiomyosarcoma?
Leiomyomas are well circumscribed, firm, neoplasms. Leiomyosarcomas have hemorrhage and necrosis.
What are common places leiomyomas arise?
Submucosal (pedunculated and circumscribed), intramural, subserosal
Histological features of leiomyoma vs. leiomyosarcoma?
Leiomyoma has bundles of uniform smooth muscle cells with an eosinophilic collagenous background. Leiomyosarcoma has atypical nuclei and mitoses.
Risk factors for endometrial carcinoma
Obesity, nulliparity, diabetes, HTN and unopposed estrogen
What people typically get type 2 (high grade) endometrial carcinoma?
Older patients often have the serous pattern which has greater chance for malignancy.
What are the different levels of endometrial hyperplasia?
Simple hyperplasia without atypia, simple with atypia, complex without atypia and complex with atypia. Note the crowding and back-to-back glands in complex hyperplasia.
Most common molecular alterations that occur in progression from simple endometrial hyperplasia to grade 1 uterine endometriod carcinoma.
PTEN -> hMLH1 -> KRAS + Microsatellite instability -> beta-catenin/PIK3CA
What characteristics differentiate complex endometrial hyperplasia with atypia from endometrial carcinoma?
Carcinoma will still have back-to-back glands with little fibrotic stroma. However, the nuclear atypia and mitosis will be increased and myometrial invasion is common.