Today we welcome one of our colleagues, Dr. Deanna Glassman, current PGY-4 at Women and Infants / Brown University, but heading off to Houston, TX this summer to become a new fellow in gynecologic oncology at MD Anderson Cancer Center!
She shares with us her own story of applying into GynOnc and the essential facts of this field.
Today on the podcast we welcome Dr. Lindsey Beffa, clinical associate professor in the Division of Gynecologic Oncology at Women and Infants Hospital and the Warren Alpert Medical School at Brown University.
Endometrial cancer (or cancer of the endometrial lining) represents approximately 90% of uterine cancers overall. It’s the 4th most common cancer among US women and the most common GYN malignancy in the US. It has been increasing in incidence and has a peak incidence in women aged 60-70.
Type I Endometrial Cancer
These are low grade (1 or 2) cancers that generally have endometrioid histology. They overall have a favorable prognosis. When you think of endometrial cancer, this is probably what you imagine. They are estrogen-driven, have precursor lesions (EIN), and often present at an early stage.
Risk factors for type I cancers can be summarized with the type of tumor. These are estrogen-driven tumors. Thus, exogenous estrogen, or excess endogenous estrogen states, such as PCOS, chronic anovulatory states, obesity, diabetes mellitus, and rarely, granulosa cell tumors of the ovary that are estrogen secreting.
There are also genetic risk factors, including the Lynch syndrome, which is an autosomal dominant disorder of mismatch repair proteins. These are known as MLH 1, MSH 2, MSH 6, and PMS 2. Additionally, the Cowden syndrome is an autosomal dominant mutation of PTEN.
Type II Endometrial Cancer
On the other hand, these are high grade endometrioid or other aggressive histologies, such as clear cell or carcinosarcoma. These are fortunately much rarer but also have a less favorable prognosis. The risk factors for these are less clear, but do tend to appear in older, thinner patients; these tumors are additionally not estrogen-sensitive.
Presentation and Diagnosis
The most common presentation (75-90%) of endometrial cancer is abnormal uterine bleeding or postmenopausal bleeding. Additionally, abnormal Pap smears (AGC) or a thickened endometrial lining on ultrasound (>4mm postmenopausal) may prompt evaluation.
An endometrial biopsy is the simplest and very reliable way to achieve diagnosis, as long as >50% of the cavity is involved. If symptoms persist despite a negative biopsy, hysteroscopy and dilation and curettage should be performed.
Staging of Endometrial Cancer
(c) NCCN
On today’s podcast, we welcome Jenna Emerson, MD, the current 3rd year fellow in gynecologic oncology and alumnus of the residency at Brown University / Women and Infants! Jenna takes us today through the often confusing world of GTD (or GTN, or GTT).
GTD encompasses several distinct disease entities, including complete and partial molar pregnancy, invasive moles, gestational choriocarcinoma, and placental-site trophoblastic tumors (PSTT).
Molar Pregnancies are a form of non-invasive GTD, and will be encountered by the general OB/GYN. It’s estimated 1:600 TABs will pathologically be molar pregnancies. 20% will lead to malignant GTD and require treatment, with complete moles more often leading to malignancy than partial moles.
The distinction of complete versus partial moles make for great test questions, though the management is the same. There are two main distinctions:
Karyotype – partial is triploid, complete is diploid
Clinical features – complete is completely weird, while partial only partially weird. Though the ACOG PB 53 has since been retired, this table is helpful in going over the main differences:
ACOG PB 53
Moles generally present with first trimester bleeding or characteristic US findings (“snowstorm appearance”). Initial management requires a number of steps for evacuation or hysterectomy. Be sure to check out the NCCN guidelines (membership required, but free!) for review.
Malignant GTD occurs post-molar if bHCG plateaus, increases, or is persistently positive. This ultimately requires staging per FIGO criteria:
NCCN / FIGO
NCCN / FIGO
If disease is low risk and local disease only, management is hysterectomy vs repeat D&C. A second curettage for low risk cures 40% of patient, and avoids need for chemotherapy. This is a change from traditional teaching, based on a prospective trial published in 2016.
If this surgical management is unsuccessful while following bHCG, then it’s time to move to chemotherapy. Low risk disease is treated with single agent chemo (MTX or Actin-D). Per GOG174, Actin-D has a higher complete response rate, but is more toxic than MTX. High risk disease is treated with EMACO. Check out the NCCN guidelines for more information on these regimens.
Choriocarcinoma and Placental Site Trophoblastic Tumor
Choriocarcinoma can follow term pregnancies (50%), moles (25%), or non-term histologically normal pregnancies (25%). They have early systemic mets, and require chemotherapy. The staging system is the same as above to decide single vs. multi-agent therapy. These are very vascular, so the classic CREOG answer is that you should not biopsy a suspected choriocarcinoma!
PSTT, epithelioid trophoblastic tumor – both of these are very rare and can follow any pregnancy. These should be referred to specialized centers, and are most commonly treated with hysterectomy.
Diagnostic Dilemmas
We reviewed a number of scenarios that can pose diagnostic challenges. In brief:
Malignant GTD following non-molar pregnancies
In the case of persistent AUB for > 6weeks after pregnancy, a bHCG should be checked to rule out new pregnancy or GTD
Choriocarcinoma as malignancy of unknown primary
Mets have been reported in pretty much every body site.
Serum beta (which will almost certainly be above discriminatory zone) and pelvic US to r/o pregnancy allow for diagnosis.
Phantom hCG – heterophile antibodies
Positive serum hCG testing can result due to relatively non-specific circulating antibodies which bind to secondary antibody in a sandwich assay (antigen 🡪 primary antibody detects antigen-labeled secondary antibody, which detects primary antibody and has detectable indicator).
Several ways to identify: pos serum with neg urine (antibodies aren’t shed in the urine but bHCG glycoprotein is), value doesn’t decrease with serial dilutions, or can send to a separate lab which may use separate secondary assay.
Postmenopausal hCG
Baseline small amount of hCG produced by the pituitary – rises in peri- and post-menopausal, during chemo. Typically beta is 5 or less but can occasionally be higher. Confirm by checking LH – if LH is consistent with menopause, this confirms pituitary source.
Thanks for sticking with us until the end of this adnexal mass journey! Today we’re going to cover some rare tumors that always find themselves on CREOGs — the sex cord stromal tumors. These only comprise about 1.2% of primary ovarian cancers. Most people are fortunately diagnosed at an early stage due to the fact that symptoms tend to be much more overt with these types of tumors.
Granulosa Cell Tumors
There are two subtypes of granulosa cell tumors: adult and juvenile. Adult type comprises 95% of these neoplasms, and generally occur in women aged 50-54 years. Juvenile type typically develops before puberty. It has a higher proliferative rate, but lower risk for late recurrences. Regardless of type, these typically present as a large, unilateral mass clinically, with a mean diameter of 12cm. They can produce estrogen and/or progesterone, so symptoms can be related to hyperestrogenism particularly in juveniles (i.e., precocious puberty). The production of estrogen in adult types is also associated with concomitant endometrial hyperplasia or cancer; with EIN present in 25-50%, and endometrial carcinoma present in 5-10% of patients. Thus, it is important to perform endometrial sampling when one of these tumors is suspected or diagnosed.
The histopathology is classic: “Call-Exner bodies", where the pale, round, coffee-bean shaped nuclei characteristic of granulosa cells arrange themselves into rosettes around a central cavity.
Thecomas
Thecomas are solid, fibromatous, generally benign neoplasms. They are generally unilateral, and are comprised of theca cells. The theca cells appear in normal ovulation as follicles develop into secondary follicles, and under the influence of LH produce androgens. After ovulation, theca cells also help to form the corpus luteum with granulosa cells.
Because of this high production of androgen that will be converted, endometrial hyperplasia or cancer can also be found in these patients, and it is wise to perform endometrial sampling for that reason. Up to 20% of patients may have synchronous endometrial cancer.
Fibromas
These are the most common type of sex cord stromal tumor. They are benign, solid, unilateral neoplasms, generally occurring in postmenopausal women, and are not hormonally active. However these can be implicated in Meigs’ syndrome, where the tumor is associated with extensive ascites or a pleural effusion.
Sertoli / Leydig Cell Tumors
These two are the rarest of the sex cord stromal tumors, accounting for less than 0.5% of these. The histopathology of the hollow tubules (Sertoli) surrounded by fibrous stroma (Leydig) is classic. These will often produce androgens and be associated with virilizing symptoms. They also are unilateral and are often associated with large masses, with a mean size of 16cm at presentation. AFP is often another marker.
Germ cell tumors are our next foray into these adnexal masses. They comprise 20-25% of ovarian neoplasms, can be benign or malignant, and occur generally in younger women: between ages 10-30 years.
Many of these for CREOGs are distinguished by specific tumor markers and specific histopathology. We’ve put a brief table together here to help with the episode and get some of those visual references!
(C) CREOGs Over Coffee (2019)
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The views expressed herein represent those of the podcast authors personally, not of their institutions.
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