Lecture 7.1: Body of th Uterus and Endometrium Flashcards
Which autosomal dominant disorder is due to germline mutations of PTEN and is associated with high incidence of endometrial carcinoma and breast cancers?
Cowden syndrome
Why is it important to make the distinction between adenosarcomas and large benign polyps of the endometrium?
Adenosarcoma is estrogen-sensitive and responds to oophorectomy
Type II endometrial carcinomas are by definition what grade of tumor?
Poorly differentiated (grade 3) tumors
An inactivating mutation of which tumor suppressor gene is a common genetic alteration in both endometrial hyperplasia and endometrial carcinomas; which pathway does this regulate?
- PTEN important regulator of PI3K/AKT pathway
- Loss of PTEN leads to overactivation of this pathway
Between which days of the menstrual cycle will you see dilation of gland which appear tortuous and serrated or “saw-toothed?”
Glands dilate days 18-24
When the lesions of endometriosis are extensive, organizing hemorrhage causes what?
Fibrous adhesions btw tubes, ovaries and other structures and obliterates the pouch of Douglas
What is the appearance of endometrial polyps?
- Exophytic masses which may be single or multiple and usually sessile
- Occasionally large and pedunculated
What is the gross morphology and size of malignant mixed müllerian tumors?
Often bulky and polypoid, and may protrude through the cervical os
Ascending infection by which organism is a common cause of both acute and chronic endometritis?
Chalmydia trachomatis
Women with endometriosis have a 3x greater risk for development of what 2 cancers?
Ovarian and clear cell types
Briefly describe what stage I-IV indicate for both type I and II endometrial adenocarcinoma and malignant mixed mullerian tumors?
- Stage I: confined to corpus uteri
- Stage II: involves corpus AND cervix
- Stage III: extends outside the uterus, but NOT outside true pelvis
- Stage IV: extends outside the true pelvis or involves mucosa of bladder or rectum
Distinction of leiomyosarcoma from leiomyoma is based on what cellular features?
Nuclear atypia + mitotic index + zonal necrosis
Based on histology what must be present for the diagnosis of endometriosis to be readily made?
When both endometrial GLANDS and STROMA are present, with or without the presence of hemosiderin
The sarcomatous component of malignant mixed müllerian tumors may mimic what tissues?
Striated muscle, cartilage, adipose tissue, and bone
Based on the anatomy why do leiomyosarcomas often metastasize to the lung?
Tumor invades uterine vein and goes straight to lungs
Endometriotic lesions bleed periodically in response to extrinsic (ovarian) and intrinsic hormonal stimulation producing what?
Nodules w/ red-blue to yellow-brown appearance on or just beneath the mucosal and/or serosal surfaces at site involved
What are 5 disorders associated with development of endometrial carcinoma?
- Obesity
- Diabetes (abnormal GTT in 60%)
- HTN
- Infertility
- Unopposed estrogen stimuulation
What is the histology of the glands seen in the endometrium during the proliferative phase of the menstrual cycle?
Straight, tubular structures lined w/ regular, tall, pseudostratified columnar cells
What is the most frequent cause of dysfunctional uterine bleeding; resulting from what?
Anovulation (failure to ovulate); due to subtle hormone imbalances
What is the behavior and prognosis of leiomyosarcomas like?
- OFTEN recur after surgey
- More than 1/2 metastasize hematogenously —> lungs, bone, and brain; may also disseminate throughout abdominal cavity
- Overall 5-year survival = 40%, but anaplastic lesions = 10-15%
What is the likelihood of non-atypical hyperplasia of the endometrium progressing to adenocarcinoma; what may be seen morphologically when estrogen is withdrawn?
- Rarely progress to cancer (1-3%)
- May evolve into cystic atrophy when estrogen is withdrawn (after menopause)
In sporadic endometrioid carcinomas, loss of expression of DNA mismatch repair genes is commonly caused by what?
Epigenetic silencing (via promoter hypermethylation)
Endometrial hyperplasia is an important cause of abnormal bleeding and is also important due to what?
Frequent precursor to the most common type of endometrial carcinoma
What makes serous endometrial intraepithelial carcinoma a pre-malignant lesion if the cells are the same as serous carcinoma?
Lack of identifiable stromal invasion (are confined to epithelial surface)
When their is failure of ovulation what hormonal imbalance occurs?
Excessive endometrial stimulation by estrogen that is unopposed by progesterone
What is the peak age range for type I endometrial carcinoma and what is an early sign?
- Age = 55-65 y/o = post-menopausal
- Vaginal bleeding in older women = early sign
What is necessary for establishing the diagnosis of endometrial carcinoma?
Histological examination of tissue obtained by biopsy or curettage
What are the morphological and cellular features (chromatin and nucleoli) which encompass atypical hyperplasia (EIN) of the endometrium?
- Complex patterns of proliferating glands displaying nuclear atypia
- Glands are commonly back-to-back and branching
- Nuclei w/ open (vesicular) chromatin and conspicuous nucleoli
Which chromosomal translocation has been linked to low-grade endometrial stromal sarcomas?
JAZF1-SUZ12
Endometrial stromal neoplasms are divided into what 2 categories?
1) Benign stromal nodules
2) Endometrial stormal sarcomas: either high- or low-grade
What is the metaplastic theory in relation to the pathogenesis of endometriosis?
Endometrium arises from coelomic mesothelium or mesonephric remnant that undergo endometrial differentiation giving rise to ectopic tissue
Of the 2 classifications of endometrial carcinoma, which is the most common type accounting for 80% of cases?
Type I
What stromal changes are seen in the late secretory phase of the menstrual cycle?
- Prominent spiral arterioles appear by day 21-22 accompanied by ↑ ground substance and edema btw stromal cells
- Stromal hypertrophy –> ↑ cytoplasmic eosinophilia (predecidual change) + resergence of stromal mitoses
- Sparse infiltrate of neutrophils and lymphocytes appear
Defects in what are associated with a higher prevalence of endometrial carcinomasa arising in women from families w/ HNPCC (aka Lynch Syndrome)?
DNA mismatch repair genes
What is the morphology of type I endometrial carcinoma?
- Endometrioid –> most are well-differentiated
- Can take form of localized polypoid tumor or one that diffusely infiltrates the endometrial lining
Mutation in which gene encodign a component of Mediator allowing uncontrollable cell division has been implicated in 70% of leiomyomas?
MED12
Activating mutations in which gene associated with endometrial carcinomas seems to play a role in invasion?
PIK3CA
What is the behavior of type II (serous) endometrial carcinomas and how does it spread?
- Aggressive
- Intraperitoneal –> travel through fallopian tubes and implants on peritoneal surfaces and lymphatic spread
What are the 2 distinct patterns by which leiomyosarcomas grow within the uterus?
1) Bulky, fleshy masses that invade uterine wall
2) Polypoid masses that project into uterine lumen
List the 8 most common sites of endometriosis in descending order of frequency.
- Ovaries
- Uterine lig.
- Rectovaginal septum
- Cul de sac
- Pelvic peritoneum
- Large and small bowel and appendix
- Mucosa of cervix, vagain, and fallopian tubes
- Laparotomy scars
What is the likelihood of a leiomyoma undergoing malignant transformation to a leiomyosarcoma?
Extremely rare
What is the most common invasive cancer of the female genital tract?
Endometrial carinoma
How does the location and histology of the secretory vacuoles change over the course of the secretory phase (post-ovulation) during the menstrual cycle?
- Marked by the appearance of secretory vacuoles
- Subnuclear vacuoles –> supranuclear vacuoles
- Glands dilate when secretion is maximal –> tortuous and serrated or “saw-toothed”
Diagnosis of adenosarcomas of the endometrium is dependent on the finding of a tumor composed of what?
Malignant-appearing stroma, which coexists w/ benign but abnormally shaped endometrial glands
What finding does the diagnosis of chronc endometritis depend on?
Plasma cells in the stroma of the endometrium
Which genes are involved in malignant mixed müllerian tumors?
Same genes mutated in endometrial carcinomas, such as PTEN, TP53, and PIK3CA
What is the recurrence rate of low- and high-grade stromal sarcomas?
About 50% recur; also prone to late recurrences (years later)
Adenosarcomas of the endometrium are considered what grade of malignany?
Generally low-grade
Endometriosis is principally a disorder affecting women during what time period?
Active reproductive/childbearing years; 3rd-4th decade
What plays a role in the increased estrogen production by endometriotic stromal cells which enhances survival and persistence of endometriotic tissue?
Due to high levels of the enzyme aromatase (not present in normal endometrium)
Morphology of atypical hyperplasia of the endometrium has considerable overlap with well-differentiated endometrioid adenocarcinoma; how can the distinction be made?
May not be possible without hysterectomy
What is adenomyosis?
Presence of endometrial tissue WITHIN the uterine wall (myometrium)
Endometrial polyps have been observed in association with what drug?
Tamoxifen, used in breast cancer therapy due to its anti-estrogenic activity on the breast; has weak pro-estrogenic effects on endometrium
How do adenosarcomas of the endometrium most typically present and what is the principle diagnostic dilemma w/ these tumors?
- Large broad-based endometrial polypoid growths that may prolapse thru the cervical os
- Dilemma = distinguishing these tumors from large benign polyps
What is the cardinal morphological feature of non-atypical hyperplasia of the endometrium?
- ↑ in gland-to-stroma ratio
- May be back-to-back glands, but usually intervening stroma is retained
What is the underlying cause of endometrial hyperplasia?
Prolonged ESTROGENIC stimulation of the endometrium
Which benign neoplasm of the myometrium is perhaps the most common tumor in women?
Leiomyomas (commonly called fibroids) = Smooth m. neoplasm
What is the most common cause of abnormal uterine bleeding in the pre-puberty age group?
Precocious puberrt (hypothalamic, pituitary, or ovarin origin)
Is the loss of PTEN seen in endometrial hyperplasia predictive of progression to carcinoma?
NO
What is the 5-year prognosis for stage I (grade 1 or 2) endometrial carcinomas following surgery +/- irradiation?
90% = excellent
What is the common presentation and in whom for malignant mixed müllerian tumors?
Postmenopausal female w/ bleeding
What are the clinical signs/sx’s of endometriosis?
- Severe dysmenorrhea (aka cramps)
- Dyspareunia (pain w/ sex)
- Bleeding
- Colicky pelvic pain
- 30-40% present w/ infertility
What are the 2 major categories of endometrial hyperplasia recommended by the WHO?
- Non-atypical hyperplasia
- Atypical hyperplasia (aka endometrial intraepithelial neoplasia)
Well differentiated endometrial carcinomas may be differentiated from hyperplasia by what?
Lack of intervening stroma btw glands
Anovulation leading to dysfunctional uterine bleeding is most common during what 2 periods of a woman’s life?
Menarche and peri-menopausal period
What is the benign metastases theory in relation to the pathogenesis of endometriosis?
Endometrial tissue spreads via blood and lymph to distant sites
Why might a patient with endometriosis present with pain on defecation or dysuria?
- Rectal wall involvement = pain on defecation
- Involvement of bladder serosa = dysuria
What is the extrauterine stem/progenitor cell theory in relation to the pathogenesis of endometriosis?
Bone marrow derived stem/progenitor cells differentiate into endometrial tissue
Metastases from malignant mixed müllerian tumors usually contain which component of the tumor?
Only EPITHELIAL components
What is the peak age of incidence for leiomyosarcomas?
40-60 y/o so occur before and after menopause
Epigenetic alterations seen in endometriosis lead to what kind of response to estrogen and progesterone?
↑ responsivness to estrogen and ↓ responsivness to progesterone
What are chocolate cysts or endometriomas in the setting of endometriosis?
When ovaries become distorted by large cystic masses filled with brown fluid as a result of previous hemorrhage
Mutations in what gene are seen in at least 90% of type II (serous) endometrial carcinomas; what does this mutation cause?
- TP53; majority being missense mutations
- Mutations results in accumulation of the altered protein in the nucleus
Endometrial polyps may become hyperplastic in association with what; what is their response to hormones?
- In assoc. w/ generalized endometrial hyperplasia
- Responsive to estrogen but show little or no response to progesterone
What are the characteristic microscopic features which distinguish leiomyomas?
- Bundles of smooth m. cells in characteristic whorled pattern
- Uniform in size and shape, oval nucleus + long bipolar processes
- RARE mitosis
Type II endometrial carcinoma typically arises in what age group and typically in the setting of what?
- In women 10 years older than that of type I; peak age = 65-75 y/o
- Usually arise in the setting of endometrial atrophy
What is the typical clinical presentation of leiomyomas?
- Even when large or numerous, may be asymptomatic
- Common sx’s: abnormal bleeding + urinary frequency + sudden pain from infarction of a large or pedunculated tumor and impaired fertility
Acute endometritis is uncommon and caused by what?
- Bacterial infections that arise after delivery or miscarriage
- Group A hemolytic strep, staphylococci, and others
What are malignant mixed müllerian tumors (aka carcinosarcomas)?
Endometrial adenocarcinomas w/ a malignant mesenchymal component
Which ethnicity has a higher frequency of type II (serous) endometrial cancer accounting for a 2-fold higher mortality rate?
African Americans
Endometrial hyperplasia is defined as an increase in the proliferation of what?
↑ proliferation of glands relative to the stroma = ↑ gland:stroma ratio
What is the relation of the PI3K/AKT pathway to estrogen?
PI3K/AKT signaling enhances the ability of the estrogen receptor to turn on the expression of its target genes
Which hormone is responsible for driving the proliferation of glands and stroma during the proliferative phase of the menstrual cycle?
Estrogen
The outcome/prognosis of malignant mixed müllerian tumors is dependent on what?
- Depth of invasion AND stage
- Also the differentiation of the mesenchymal component
- Heterologous mesenchymal components = worse prognosis
What are the complications which may arise due to leiomyomas in a pregnant woman?
- ↑ frequency of spontaneous abortion
- Fetal malpresentation
- Uterine inertia (failure to contract w/ sufficient force)
- Post-partum hemorrhage
Rearrangements of what chromosomes and involving what genes implicated in other benign neoplasms are seen in about 40% of leiomyomas?
Cr. 12q14 –> HMGIC and 6p –> HMGIY
Loss-of-function in which gene that is a regulator of chromatin structure has been implicated in both type I endometrial carcinoma, ovarian endometroid and clear cell carcinomas?
ARID1A
What is the significance of atypical endometriosis?
Likely precursor to endometriosis-related ovarian carcinoma
What is seen on microscopic examination of adenomyosis?
Irregular nests of endometrial stroma, w/ or w/o glands, arranged within myometrium, separated from basalis by at least 2-3mm
How does the karyotype of leiomyosarcomas differ from that of leiomyomas?
- Have complex, highly variable karyotypes that frequently include deletions; subset contains MED12 mutations
- Majority of leiomyomas have normal karyotypes
What is the regurgitation theory in relation to the pathogenesis of endometriosis?
Retrograde flow of menstrual endometrium through fallopain tubes leads to implantation at ectopic sites (occurs in 90% of women)
What is the most common appearance of the endometrium during anovulation?
Contains pseudostratified glands and scattered mitotic figures
What are some of the conditions associated with excess estrogen production which can lead to endometrial hyperplasia?
- Anovulation
- Obesity = peripheral conversion of androgens –> estrogens
- Menopause
- Prolonged administration of estrogenic substances (estrogen replacement therapy)
- Polycystic ovarian syndrome
- Functioning granulosa cell tumor of the ovary
- Excessive ovarian cortical function (cortical stromal hyperplasia)
What is the gross morphology of leiomyomas; can occur in which layers?
- Sharply circumscribed + discrete + round; firm + gray-white tumor
- Vary in size from barely visible to massive
- Occur within myometrium (intramural), beneath endometrium (submucosal) or beneath the serosa (subserosal)
What is the precursor of type II (serous) endometrial carcinoma and what can be this lesion be stained for immunohistochemically?
- Serous endometrial INTRAepithelial carcinoma (pic top left)
- Can stain forTP53 (pics on right)
Some type II (serous) endometrial carcinomas will have a predominantly glandular growth pattern; how can they be distinguished from type I (endometrioid) carcinoma?
Marked cytologic atypia
What is the hallmark mutation associated with type I endometrial carcinoma?
Mutations that ↑ signaling through PI3K/AKT pathway
How do leiomyomas most often present and there is an increased incidence in which ethnic group?
- Most often presents as multiple discrete tumors
- ↑ incidence in African Americans
What are the 3 morphological subtypes of type II endometrial carcinoma and which is most common?
- Serous = most common
- Clear cell
- Mixed müllerian tumor
The epithelial and stromal components of malignant mixed müllerian tumors are derived from what?
The same founding cell
