Educational Case: Endometrial carcinoma types I and II

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A 57-year-old nulligravid morbidly obese woman presents to the office with abnormal vaginal bleeding for the past three weeks. She denies any other symptoms including pain, constipation, dyspareunia, fatigue, weight change, or any urinary symptoms. The patient's last menstrual period was seven years ago. Her past medical history is negative for sexually transmitted infections and positive for well-controlled hypertension and type II diabetes mellitus. She had a normal Papanicolaou (Pap) smear earlier this year and has no history of any abnormal Pap screenings. She denies tobacco, alcohol, and illicit drug use. She denies surgical history except wisdom teeth extraction at age 18.

FU1.2 Endometrial carcinoma. Compare and contrast the precursors, clinical setting, risk factors, pathologic findings, and prognosis for type I and type II carcinomas of the endometrium. Competency 2: Organ system pathology; Topic FU: Female reproductive—Uterus; Learning goal 1: Uterine neoplasia

• Women with postmenopausal vaginal bleeding should be evaluated for EC and possible precancerous lesions, regardless of risk factors. • Evaluation should include a transvaginal ultrasound to check for endometrial stripe thickness and/or endometrial biopsy for histological evaluation. • EC is the most common gynecologic cancer and the fourth most common female cancer behind breast, lung, and colon cancers. • Presentation at an early age should prompt possible evaluation for genetic and/or hereditary causes such as Lynch Syndrome. • Estrogen-containing drugs increase the risk of EC. HRT's risk, however, can be reduced by concurrently prescribing progesterone. • Type I EC is more common, estrogen-dependent, indolent, with a good prognosis, and usually remains intrauterine. PTEN mutations are common. The associated precursor lesion is endometrial intraepithelial neoplasia (atypical hyperplasia). • Type II EC is less common, estrogen-independent, aggressive, with a worse prognosis with respect to type I, and commonly spreads outside the uterus. TP53 mutations are common. The associated precursor lesion is endometrial intraepithelial carcinoma. • Regardless of cancer staging, almost all treatments will involve surgery, usually in the form of a hysterectomy with bilateral salpingo-oophorectomy. • As the stage of cancer increases, the prognosis continues to worsen and the associated treatment becomes more complex and invasive. Women with postmenopausal vaginal bleeding should be evaluated for EC and possible precancerous lesions, regardless of risk factors. Evaluation should include a transvaginal ultrasound to check for endometrial stripe thickness and/or endometrial biopsy for histological evaluation. EC is the most common gynecologic cancer and the fourth most common female cancer behind breast, lung, and colon cancers. Presentation at an early age should prompt possible evaluation for genetic and/or hereditary causes such as Lynch Syndrome. Estrogen-containing drugs increase the risk of EC. HRT's risk, however, can be reduced by concurrently prescribing progesterone. Type I EC is more common, estrogen-dependent, indolent, with a good prognosis, and usually remains intrauterine. PTEN mutations are common. The associated precursor lesion is endometrial intraepithelial neoplasia (atypical hyperplasia). Type II EC is less common, estrogen-independent, aggressive, with a worse prognosis with respect to type I, and commonly spreads outside the uterus. TP53 mutations are common. The associated precursor lesion is endometrial intraepithelial carcinoma. Regardless of cancer staging, almost all treatments will involve surgery, usually in the form of a hysterectomy with bilateral salpingo-oophorectomy. As the stage of cancer increases, the prognosis continues to worsen and the associated treatment becomes more complex and invasive.

After answering the patient's questions, and further discussion on risks, benefits, and alternative treatments, she desires surgical management and elects for a total laparoscopic hysterectomy with bilateral salpingo-oophorectomy. During surgery, the uterus is removed and is sent for pathological examination for depth of carcinoma invasion into the myometrium. Examination reveals invasion less than 30% into the myometrium. No sentinel lymph node biopsy is indicated since the depth of invasion is less than 50%. The final pathological examination reveals type I endometrioid carcinoma, Stage 1.

The authors report no conflicts of interest.

For postmenopausal bleeding, there are various possible diagnoses that could include vaginal atrophy (most common in elderly female patients), cervical or endometrial polyps, uterine fibroids, adenomyosis, pelvic organ prolapse, or even bleeding from other sources such as the rectum, vulva, and urethra. Other more concerning differentials include endometrial hyperplasia, endometrial carcinoma (EC), cervical carcinoma, trauma, or sexual assault.

The International Federation of Gynecology and Obstetrics (FIGO) has created three histopathologic grades, which are used to describe the degree of similarity between abnormal and normal tissue. 22 , 23 FIGO grades are: GX: Grade cannot be assessed G1: Well-differentiated, less than or equal to 5% solid growth pattern G2: Moderately-differentiated, less than 50% solid growth pattern but greater than 5% G3: Poorly-differentiated, greater than 50% solid growth pattern A large majority of type I endometrioid carcinomas are grades 1 and 2, with a minority being grade 3. Type II non-endometrioid cancers are always grade 3. 22 FIGO and the American Joint Committee on Cancer (AJCC) have separate but very similar staging systems, both of which account for uterine and extrauterine tumor involvement. The AJCC and FIGO EC staging ranges from Stage I to Stage IV. Stage I/T1 tumors are confined to the uterine body. Stage II/T2 tumors involve cervical stroma without extending beyond the uterus. Stage III/T3 tumors begin to extend to the adnexa, vagina, and/or local lymph nodes (pelvic and paraaortic). Stage IV/T4 have more distant spread including the bladder, bowel, other intra-abdominal organs, inguinal lymph nodes, etc. 22 , 23 FIGO remains a more surgical-based staging system due to ECs treatment typically involving surgery. These stages can vary slightly over time, so it is important to compare them to the latest guidelines when determining cancer stage. This is an extremely broad topic as patients with the same staging can have drastically different treatment plans depending on comorbidities, prior surgeries, age, ability to undergo the surgery, desire for children (especially if diagnosed at a young age), etc. However, based on the staging, there are general treatment plans that each stage will follow. Regardless of EC stage, however, surgical management is normally first line treatment with subsequent removal of the uterus and, most likely, the fallopian tubes and ovaries. For Stage I tumors, total hysterectomy with bilateral salpingo-oophorectomy is usually the only treatment needed with subsequent follow up to monitor for return of the cancer. Stage II expands upon the above surgery and is sometimes paired with removal of the upper part of the vagina as well (radical hysterectomy). This is normally paired with pelvic and para-aortic lymph node dissection or sampling. After recovery from surgery, the patient undergoes post-operative radiation therapy (usually external pelvic radiation and brachytherapy). If too frail for surgery, radiation alone can be the treatment of choice. If the lymph nodes are negative for cancerous cells on sampling/dissection, then the tissue remains at Stage II. If cancerous cells are found within the lymph nodes, the cancer is considered Stage III. For Stage III tumors, if visible, suspicious tissue is seen during surgery, these sections may be removed (debulking procedures), and then paired with those post-operative radiation therapies as recommended for Stage II. During surgery, pelvic washing (an attempt to remove cancer cells dislodged during the procedure) and removal of the omentum can also be performed. At this stage, chemotherapy may also be added to the treatment plan. Stage IV combines all the above treatment options as well as more aggressive debulking procedures and sampling of tissue outside the pelvis. Hormone therapy, especially if detectable progesterone and estrogen receptors are found, can also be initiated. Newer methods might also include immunotherapy and targeted therapy in the future. 24 What is the prognosis of type I and type II EC? What is the mortality of EC types based on age and race? The SEER database tracks multiple data points for EC but does not group data based on cancer staging, so there is no direct translation of prognosis to stage—instead, one must look at their data based on the localization of the cancer, regional spread, or distant spread, and then correlate with the AJCC/FIGO staging systems. Relative five-year survival for all patients regardless of EC type, patient age, race, or stage is 81.2%. This survival rate increases to 95% if the cancer is localized, as was seen in this patient (Stage 1a, localized), but drops to 69.4% when associated with regional lymph node spread. This rate decreases further to 17.3% if associated with distant spread (i.e. metastasis), and 53.2% with an unknown or unstaged cancer. 8 With respect to age only: Approximately 86.8% of patients are diagnosed with EC at age 50 or greater with an associated mortality rate of 16.9%. However, the mortality rate drops to only 0.5% if women are diagnosed before age 50. The highest mortality rate for all patients based on age is found in those 85 years or older at 32.6 deaths per 100,000 women. The rate drops to 20.7 deaths per 100,000 women for ages 65–69, which is also the highest incidence age group. 8 With respect to race only: Black women have an overall five-year survival rate of 62.7%, which supports the fact that they are commonly diagnosed with the more aggressive type II EC. Even when examining those below age 50, the five-year survival rate is still only 79.1%. For patients 85 years and older, the mortality rate is 42.5 per 100,000 and an even higher rate of 44.0 per 100,000 for ages 65–69. Mortality rates for those 50 years and older are much higher at 30.2% though for those under age 50 the rate is 0.61%, which is closer to the 0.5% overall rate as discussed above. 8