[PATH] Uterus and Endometrium [ROBBINS Ch 22] Flashcards
1
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
2
Q
How does the location and histology of the secretory vacuoles change over the course of the secretory phase (post-ovulation) during the menstrual cycle?
A
- Marked by the appearance of secretory vacuoles
- Subnuclear vacuoles –> supranuclear vacuoles
- Glands dilate when secretion is maximal –> tortuous and serrated or “saw-toothed”
3
Q
What stromal changes are seen in the late secretory phase of the menstrual cycle?
A
- 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
4
Q
Which hormone is responsible for driving the proliferation of glands and stroma during the proliferative phase of the menstrual cycle?
A
Estrogen
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
What is the most frequent cause of dysfunctional uterine bleeding; resulting from what?
A
Anovulation (failure to ovulate); due to subtle hormone imbalances
7
Q
Anovulation leading to dysfunctional uterine bleeding is most common during what 2 periods of a woman’s life?
A
Menarche and peri-menopausal period
8
Q
What is the most common cause of abnormal uterine bleeding in the pre-puberty age group?
A
Precocious puberrt (hypothalamic, pituitary, or ovarin origin)
9
Q
When their is failure of ovulation what hormonal imbalance occurs?
A
Excessive endometrial stimulation by estrogen that is unopposed by progesterone
10
Q
What is the most common appearance of the endometrium during anovulation?
A
Contains pseudostratified glands and scattered mitotic figures
11
Q
Acute endometritis is uncommon and caused by what?
A
- Bacterial infections that arise after delivery or miscarriage
- Group A hemolytic strep, staphylococci, and others
12
Q
What finding does the diagnosis of chronc endometritis depend on?
A
Plasma cells in the stroma of the endometrium
13
Q
Ascending infection by which organism is a common cause of both acute and chronic endometritis?
A
Chalmydia trachomatis
14
Q
List the 8 most common sites of endometriosis in descending order of frequency.
A
- 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
15
Q
What is the regurgitation theory in relation to the pathogenesis of endometriosis?
A
Retrograde flow of menstrual endometrium through fallopain tubes leads to implantation at ectopic sites (occurs in 90% of women)
16
Q
What is the benign metastases theory in relation to the pathogenesis of endometriosis?
A
Endometrial tissue spreads via blood and lymph to distant sites
17
Q
What is the metaplastic theory in relation to the pathogenesis of endometriosis?
A
Endometrium arises from coelomic mesothelium or mesonephric remnant that undergo endometrial differentiation giving rise to ectopic tissue
18
Q
What is the extrauterine stem/progenitor cell theory in relation to the pathogenesis of endometriosis?
A
Bone marrow derived stem/progenitor cells differentiate into endometrial tissue
19
Q
What plays a role in the increased estrogen production by endometriotic stromal cells which enhances survival and persistence of endometriotic tissue?
A
Due to high levels of the enzyme aromatase (not present in normal endometrium)
20
Q
Epigenetic alterations seen in endometriosis lead to what kind of response to estrogen and progesterone?
A
↑ responsivness to estrogen and ↓ responsivness to progesterone
21
Q
Women with endometriosis have a 3x greater risk for development of what 2 cancers?
A
endometriod and clear cell types
22
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
23
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
24
Q
What are chocolate cysts or endometriomas in the setting of endometriosis?
A
When ovaries become distorted by large cystic masses filled with brown fluid as a result of previous hemorrhage
25
What is the significance of atypical endometriosis?
Likely **precursor** to **endometriosis-related endometrial carcinoma**
26
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
27
Endometriosis is principally a disorder affecting women during what time period?
**Active reproductive/childbearing** years; **3rd-4th decade**
28
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**
29
Why might a patient with endometriosis present with pain on defecation or dysuria?
- **Rectal wall involvement** = pain on defecation
- **Involvement** of **bladder serosa** = dysuria
30
What is adenomyosis?
Presence of **endometrial** tissue WITHIN the **uterine wall (myometrium)**
31
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**
32
What is the appearance of endometrial polyps?
- **Exophytic** masses which may be **single** or **multiple** and usually **sessile**
- Occasionally **large** and **pedunculated**
33
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**
34
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
35
Endometrial hyperplasia is defined as an increase in the proliferation of what?
↑ proliferation of **glands** relative to the **stroma** = **↑ gland:stroma ratio**
36
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**
37
What is the underlying cause of endometrial hyperplasia?
Prolonged **ESTROGENIC** stimulation of the endometrium
38
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)
39
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
40
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
41
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
42
Is the loss of *PTEN* seen in endometrial hyperplasia predictive of progression to carcinoma?
**NO**
43
What are the 2 major categories of endometrial hyperplasia recommended by the WHO?
1. **Non-atypical** hyperplasia
2. **Atypical** hyperplasia (aka endometrial intraepithelial neoplasia)
44
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
45
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)
46
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**
47
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**
48
What is the most common **invasive** cancer of the female genital tract?
**Endometrial carinoma**
49
Of the 2 classifications of endometrial carcinoma, which is the most common type accounting for 80% of cases?
**Type I**
50
What are 5 disorders associated with development of endometrial carcinoma?
1. **Obesity**
2. **Diabetes** (abnormal GTT in 60%)
3. **HTN**
4. **Infertility**
5. **Unopposed estrogen** stimuulation
51
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**
52
What is the hallmark mutation associated with type I endometrial carcinoma?
Mutations that **↑ signaling** through **PI3K/AKT** pathway
53
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***
54
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
55
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**
56
Activating mutations in which gene associated with endometrial carcinomas seems to play a role in invasion?
***PIK3CA***
57
In sporadic endometrioid carcinomas, loss of expression of DNA mismatch repair genes is commonly caused by what?
**Epigenetic silencing** (via **promoter hypermethylation**)
58
Well differentiated endometrial carcinomas may be differentiated from hyperplasia by what?
**Lack** of **intervening stroma** btw glands
59
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**
60
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**
61
What are the 3 morphological subtypes of type II endometrial carcinoma and which is most common?
- **Serous** = most common
- **Clear cell**
- **Mixed müllerian tumor**
62
Type II endometrial carcinomas are by definition what grade of tumor?
**Poorly differentiated** (grade **3**) tumors
63
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
64
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**)
65
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
66
What is necessary for establishing the diagnosis of endometrial carcinoma?
**Histological examination** of tissue obtained by **biopsy** or **curettage**
67
What is the 5-year prognosis for stage I (grade 1 or 2) endometrial carcinomas following surgery +/- irradiation?
**90% = excellent**
68
Which ethnicity has a higher frequency of type II (serous) endometrial cancer accounting for a 2-fold higher mortality rate?
African Americans
69
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)
70
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**
71
What are malignant mixed müllerian tumors (aka carcinosarcomas)?
**Endometrial adenocarcinomas** w/ a **malignant** **mesenchymal** component
72
The epithelial and stromal components of malignant mixed müllerian tumors are derived from what?
The **same** founding cell
73
Which genes are involved in malignant mixed müllerian tumors?
Same genes mutated in endometrial carcinomas, such as ***PTEN, TP53***, and ***PIK3CA***
74
What is the gross morphology and size of malignant mixed müllerian tumors?
Often **bulky** and **polypoid**, and may protrude through the cervical os
75
The sarcomatous component of malignant mixed müllerian tumors may mimic what tissues?
**Striated muscle**, **cartilage**, **adipose tissue**, and **bone**
76
Metastases from malignant mixed müllerian tumors usually contain which component of the tumor?
**Only EPITHELIAL components**
77
What is the common presentation and in whom for malignant mixed müllerian tumors?
**Postmenopausal female** w/ **bleeding**
78
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**
79
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**
80
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**
81
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**
82
Adenosarcomas of the endometrium are considered what grade of malignany?
Generally **low-grade**
83
Endometrial stromal neoplasms are divided into what 2 categories?
1) **Benign** stromal nodules
2) **Endometrial** stormal **sarcomas**: either **high**- or **low-grade**
84
Which chromosomal translocation has been linked to low-grade endometrial stromal sarcomas?
***JAZF1-SUZ12***
85
Which benign neoplasm of the myometrium is perhaps the most common tumor in women?
**Leiomyomas** (commonly called **fibroids**) = **Smooth m. neoplasm**
86
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**
87
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***
88
Mutation in which gene encodign a component of Mediator allowing uncontrollable cell division has been implicated in 70% of leiomyomas?
***MED12***
89
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)
90
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**
91
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**
92
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**
93
What is the likelihood of a leiomyoma undergoing malignant transformation to a leiomyosarcoma?
**Extremely rare**
94
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**
95
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**
96
Distinction of leiomyosarcoma from leiomyoma is based on what cellular features?
**Nuclear atypia** + mitotic index + **zonal necrosis**
97
What is the peak age of incidence for leiomyosarcomas?
**40-60 y/o** so occur **before** and **after** menopause
98
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%**
99
Based on the anatomy why do leiomyosarcomas often metastasize to the lung?
Tumor invades **uterine vein** and goes **straight to lungs**
100
What is the recurrence rate of low- and high-grade stromal sarcomas?
About **50%** recur; also **prone to late recurrences** (years later)
