Lecture 7.1: Body of th Uterus and Endometrium Flashcards
1
Q
Which autosomal dominant disorder is due to germline mutations of PTEN and is associated with high incidence of endometrial carcinoma and breast cancers?
A
Cowden syndrome
2
Q
Why is it important to make the distinction between adenosarcomas and large benign polyps of the endometrium?
A
Adenosarcoma is estrogen-sensitive and responds to oophorectomy
3
Q
Type II endometrial carcinomas are by definition what grade of tumor?
A
Poorly differentiated (grade 3) tumors
4
Q
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?
A
- PTEN important regulator of PI3K/AKT pathway
- Loss of PTEN leads to overactivation of this pathway
5
Q
Between which days of the menstrual cycle will you see dilation of gland which appear tortuous and serrated or “saw-toothed?”
A
Glands dilate days 18-24
6
Q
When the lesions of endometriosis are extensive, organizing hemorrhage causes what?
A
Fibrous adhesions btw tubes, ovaries and other structures and obliterates the pouch of Douglas
7
Q
What is the appearance of endometrial polyps?
A
- Exophytic masses which may be single or multiple and usually sessile
- Occasionally large and pedunculated
8
Q
What is the gross morphology and size of malignant mixed müllerian tumors?
A
Often bulky and polypoid, and may protrude through the cervical os
9
Q
Ascending infection by which organism is a common cause of both acute and chronic endometritis?
A
Chalmydia trachomatis
10
Q
Women with endometriosis have a 3x greater risk for development of what 2 cancers?
A
Ovarian and clear cell types
11
Q
Briefly describe what stage I-IV indicate for both type I and II endometrial adenocarcinoma and malignant mixed mullerian tumors?
A
- 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
12
Q
Distinction of leiomyosarcoma from leiomyoma is based on what cellular features?
A
Nuclear atypia + mitotic index + zonal necrosis
13
Q
Based on histology what must be present for the diagnosis of endometriosis to be readily made?
A
When both endometrial GLANDS and STROMA are present, with or without the presence of hemosiderin
14
Q
The sarcomatous component of malignant mixed müllerian tumors may mimic what tissues?
A
Striated muscle, cartilage, adipose tissue, and bone
15
Q
Based on the anatomy why do leiomyosarcomas often metastasize to the lung?
A
Tumor invades uterine vein and goes straight to lungs
16
Q
Endometriotic lesions bleed periodically in response to extrinsic (ovarian) and intrinsic hormonal stimulation producing what?
A
Nodules w/ red-blue to yellow-brown appearance on or just beneath the mucosal and/or serosal surfaces at site involved
17
Q
What are 5 disorders associated with development of endometrial carcinoma?
A
- Obesity
- Diabetes (abnormal GTT in 60%)
- HTN
- Infertility
- Unopposed estrogen stimuulation
18
Q
What is the histology of the glands seen in the endometrium during the proliferative phase of the menstrual cycle?
A
Straight, tubular structures lined w/ regular, tall, pseudostratified columnar cells
19
Q
What is the most frequent cause of dysfunctional uterine bleeding; resulting from what?
A
Anovulation (failure to ovulate); due to subtle hormone imbalances
20
Q
What is the behavior and prognosis of leiomyosarcomas like?
A
- 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%
21
Q
What is the likelihood of non-atypical hyperplasia of the endometrium progressing to adenocarcinoma; what may be seen morphologically when estrogen is withdrawn?
A
- Rarely progress to cancer (1-3%)
- May evolve into cystic atrophy when estrogen is withdrawn (after menopause)
22
Q
In sporadic endometrioid carcinomas, loss of expression of DNA mismatch repair genes is commonly caused by what?
A
Epigenetic silencing (via promoter hypermethylation)
23
Q
Endometrial hyperplasia is an important cause of abnormal bleeding and is also important due to what?
A
Frequent precursor to the most common type of endometrial carcinoma
24
Q
What makes serous endometrial intraepithelial carcinoma a pre-malignant lesion if the cells are the same as serous carcinoma?
A
Lack of identifiable stromal invasion (are confined to epithelial surface)
25
When their is failure of ovulation what hormonal imbalance occurs?
Excessive endometrial stimulation by **estrogen** that is **unopposed** by **progesterone**
26
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
27
What is necessary for establishing the diagnosis of endometrial carcinoma?
**Histological examination** of tissue obtained by **biopsy** or **curettage**
28
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**
29
Which chromosomal translocation has been linked to low-grade endometrial stromal sarcomas?
***JAZF1-SUZ12***
30
Endometrial stromal neoplasms are divided into what 2 categories?
1) **Benign** stromal nodules
2) **Endometrial** stormal **sarcomas**: either **high**- or **low-grade**
31
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**
32
Of the 2 classifications of endometrial carcinoma, which is the most common type accounting for 80% of cases?
**Type I**
33
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
34
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**
35
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**
36
Mutation in which gene encodign a component of Mediator allowing uncontrollable cell division has been implicated in 70% of leiomyomas?
***MED12***
37
Activating mutations in which gene associated with endometrial carcinomas seems to play a role in invasion?
***PIK3CA***
38
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
39
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**
40
List the 8 most common sites of endometriosis in descending order of frequency.
1. **Ovaries**
2. Uterine lig.
3. Rectovaginal septum
4. Cul de sac
5. Pelvic peritoneum
6. Large and small bowel and appendix
7. Mucosa of cervix, vagain, and fallopian tubes
8. Laparotomy scars
41
What is the likelihood of a leiomyoma undergoing malignant transformation to a leiomyosarcoma?
**Extremely rare**
42
What is the most common **invasive** cancer of the female genital tract?
**Endometrial carinoma**
43
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**
- **Sub**nuclear vacuoles --\> **supra**nuclear vacuoles
- Glands **dilate** when **secretion is maximal** --\> **tortuous and serrated** or **"saw-toothed"**
44
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**
45
What finding does the diagnosis of chronc endometritis depend on?
**Plasma cells** in the stroma of the endometrium
46
Which genes are involved in malignant mixed müllerian tumors?
Same genes mutated in endometrial carcinomas, such as ***PTEN, TP53***, and ***PIK3CA***
47
What is the recurrence rate of low- and high-grade stromal sarcomas?
About **50%** recur; also **prone to late recurrences** (years later)
48
Adenosarcomas of the endometrium are considered what grade of malignany?
Generally **low-grade**
49
Endometriosis is principally a disorder affecting women during what time period?
**Active reproductive/childbearing** years; **3rd-4th decade**
50
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)
51
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**
52
What is adenomyosis?
Presence of **endometrial** tissue WITHIN the **uterine wall (myometrium)**
53
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
54
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**
55
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
56
What is the underlying cause of endometrial hyperplasia?
Prolonged **ESTROGENIC** stimulation of the endometrium
57
Which benign neoplasm of the myometrium is perhaps the most common tumor in women?
**Leiomyomas** (commonly called **fibroids**) = **Smooth m. neoplasm**
58
What is the most common cause of abnormal uterine bleeding in the pre-puberty age group?
Precocious puberrt (hypothalamic, pituitary, or ovarin origin)
59
Is the loss of *PTEN* seen in endometrial hyperplasia predictive of progression to carcinoma?
**NO**
60
What is the 5-year prognosis for stage I (grade 1 or 2) endometrial carcinomas following surgery +/- irradiation?
**90% = excellent**
61
What is the common presentation and in whom for malignant mixed müllerian tumors?
**Postmenopausal female** w/ **bleeding**
62
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**
63
What are the 2 major categories of endometrial hyperplasia recommended by the WHO?
1. **Non-atypical** hyperplasia
2. **Atypical** hyperplasia (aka endometrial intraepithelial neoplasia)
64
Well differentiated endometrial carcinomas may be differentiated from hyperplasia by what?
**Lack** of **intervening stroma** btw glands
65
Anovulation leading to dysfunctional uterine bleeding is most common during what 2 periods of a woman's life?
**Menarche** and **peri-menopausal** period
66
What is the benign metastases theory in relation to the pathogenesis of endometriosis?
Endometrial tissue spreads via blood and lymph to distant sites
67
Why might a patient with endometriosis present with pain on defecation or dysuria?
- **Rectal wall involvement** = pain on defecation
- **Involvement** of **bladder serosa** = dysuria
68
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
69
Metastases from malignant mixed müllerian tumors usually contain which component of the tumor?
**Only EPITHELIAL components**
70
What is the peak age of incidence for leiomyosarcomas?
**40-60 y/o** so occur **before** and **after** menopause
71
Epigenetic alterations seen in endometriosis lead to what kind of response to estrogen and progesterone?
**↑** responsivness to **estrogen** and **↓** responsivness to **progesterone**
72
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
73
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
74
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**
75
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**
76
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**
77
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**
78
Acute endometritis is uncommon and caused by what?
- **Bacterial infections** that arise after **delivery** or **miscarriage**
- **Group A hemolytic strep**, **staphylococci**, and others
79
What are malignant mixed müllerian tumors (aka carcinosarcomas)?
**Endometrial adenocarcinomas** w/ a **malignant** **mesenchymal** component
80
Which ethnicity has a higher frequency of type II (serous) endometrial cancer accounting for a 2-fold higher mortality rate?
African Americans
81
Endometrial hyperplasia is defined as an increase in the proliferation of what?
↑ proliferation of **glands** relative to the **stroma** = **↑ gland:stroma ratio**
82
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
83
Which hormone is responsible for driving the proliferation of glands and stroma during the proliferative phase of the menstrual cycle?
Estrogen
84
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**
85
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**
86
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***
87
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***
88
What is the significance of atypical endometriosis?
Likely **precursor** to **endometriosis-related ovarian carcinoma**
89
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**
90
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**
91
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)
92
What is the most common appearance of the endometrium during anovulation?
Contains **pseudostratified glands** and **scattered mitotic figures**
93
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)
94
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)
95
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 for***TP53*** (pics on **right**)
96
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**
97
What is the hallmark mutation associated with type I endometrial carcinoma?
Mutations that **↑ signaling** through **PI3K/AKT** pathway
98
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**
99
What are the 3 morphological subtypes of type II endometrial carcinoma and which is most common?
- **Serous** = most common
- **Clear cell**
- **Mixed müllerian tumor**
100
The epithelial and stromal components of malignant mixed müllerian tumors are derived from what?
The **same** founding cell
