L8 - Gynaecopathology: endometrial cancers, hormonally driven tumours of the uterus and new molecular histological classification (Dr Francesca Maggiani) Flashcards
- revising the anatomy and histology of the uterus - understanding the pathogenesis of endometrial cancer - Describing the different cancers as by the recently reviewed classification
Which part of the uterus is specifically discussed in relation to tumours?
The epithelial lining of the uterine cavity is the primary site discussed.
How does hormonal stimulation influence uterine tumours?
Most uterine tumours have a specific connection with oestrogen stimulation, which plays a key role in their development and progression.
What two classification methods are integrated in current practice for uterine tumours?
Histological classification and genetic classification are now used together for uterine tumours.
What are the major changes the uterus undergoes during a woman’s lifespan?
The uterus changes enormously in size, shape, and configuration, especially with the cyclical growth and shedding of the endometrial lining under hormonal influence (across the menstrual cycle)
Which hormones are primarily responsible for endometrial growth and shedding?
Oestrogen stimulates growth, while progesterone prepares the lining and, when withdrawn, leads to menstrual shedding.
How does the development of the uterus relate to embryology?
The proper development of the uterine cavity depends on the correct formation of the mullerian duct.
What is the most common symptom associated with uterine cancer?
linked to abnormal bleeding, which may be more obvious in menopausal or perimenopausal women, is the most common symptom.
How can irregular bleeding be interpreted?
It may be due to benign conditions, precursors of endometrial cancer such as hyperplasia, or other factors like hormonal imbalance.
What is the issue with irregular bleeding being a symptom for endometrial cancer
not every woman has regular perioids and we aren’t completely sure when menopause starts - different for different women
What is menopause
Menopause signifies the end of a long biological process marked by a gradual decline in estrogen and progesterone levels. During the transition known as perimenopause, menstrual cycles can become irregular, varying in frequency and flow making it difficult to pinpoint. Menopause itself is officially recognized when a person has not had a period for 12 consecutive months, indicating the end of reproductive capability.
What is the myometrium
specialised smooth muscle that we find in the uterus (where one might find fibroids)
Which structural layers make up the endometrium?
The endometrium comprises the stratum basalis (basal layer) and the stratum functionalis (functional layer).
What is the role of the stratum basalis?
It contains the reserve of immature cells that persist through menstruation and regenerate the stratum functionalis layer each cycle.
What occurs to the stratum functionalis during the menstrual cycle?
It increases in thickness and complexity under hormonal stimulation and is shed at the end of menstruation
is it normal to have inflammatory cells in the endometrial lining
it can be completely normal and can be found during different phases of the cycle or they can signify other things e.g. infection
Which additional components are present in the functional layer?
The functional layer includes glandular elements, stromal tissue, vascular components, and occasionally inflammatory cells.
What is the common precursor lesion for endometrial carcinoma?
Endometrial hyperplasia, often with atypia, is recognised as a precursor to endometrial carcinoma.
What regions seem to have the highest incidence of uterine carcinomas
North America, China, Russia, australia (data in Africa is less reliable)
How is the incidence of endometrial carcinoma affected by age?
It typically affects women over 50, with a higher incidence in postmenopausal or perimenopausal women.
why might Africa appear to have a lower incidence rate of uterine carcinoma
could be due to under-reporting or the fact that they have a younger population
What are the three most common genital malignancies in women ( ranked most to 3rd common)
- cervical cancer
- Ovarian cancer
- Cancer of the endometrium
(these tumours affect postmenopausal women in the largest majority of cases)
Why are ovarian cancers typically only found once it has progressed to the later stages
because its early symptoms are vague and easily mistaken for common, non-serious conditions, there is no routine screening, they spread rapidly
What percentage of endometrial carcinoma cases occur in women under 40?
Approximately 5% of cases may occur in younger women, although this may change with trends such as rising obesity rates.
How is obesity linked to endometrial carcinoma?
Obesity increases oestrogen levels through peripheral conversion, thereby heightening the risk of endometrial hyperplasia and carcinoma.
apart from carcinomas, what are other reasons that could cause postmenopausal bleeding?
- atrophic vaginitis (59% of women with this condition)
- Endopmetrial polyp (12% of women with this condition)
- Endometrial hyperplasia ( 10% of women with this condition)
- Hormonal effect (7% of women with this condition) e.g. hormonal replacement therapy
- other (less than 1% of women with this condition) e.g. random ruptured gland, infection
what percentage of post menopausal women who experience bleeding have this because of endometrial carcinoma or cervical carcinomas
- Endometrial carcinoma –> 10% of women with this condition
- Cervical carcinoma –> 2% of women with this condition
What is the significance of tamoxifen in uterine tumours?
Tamoxifen, used in breast cancer treatment, can increase oestrogenic stimulation in the uterus, elevating the risk of endometrial pathology.
What does normal functional endometrium look like? (histological features)
exhibits regularly spaced glands, bland cellular features, and a uniform stromal background (dense)
What phase is characterized by secretory endometrium?
Secretory endometrium is seen after ovulation, during the secretory phase. In this phase, estrogen peaks and then declines, and progesterone becomes the predominant hormone. The glands in the endometrium appear more coiled and swollen stroma
What is endometrial hyperplasia?
Endometrial hyperplasia is a condition where there is clonal proliferation of the endometrial glands.
What histological changes indicate endometrial hyperplasia?
Focal glandular crowding, an increased number of glands compared to nornal, potential epithelial atypia, and architectural disorganisation are seen in hyperplasia ( e.g. tend to be rounder rather than columnar and have multiple nuclear foci)
How is endometrial hyperplasia linked to treatment?
Progesterone therapy, including intrauterine devices e.g. Marina coil releasing progesterone, can reverse hyperplasia, supporting the role of oestrogen in its development.
What distinguishes endometrial carcinoma from hyperplasia on histology?
Endometrial carcinoma shows more complex glandular architecture, pronounced cytological atypia, and often loss of the normal stroma-to-gland ratio. whilst endometrial hyperplasia is characterised by glandular crowding, irregular architecture and cytological atypia.
What is the typical histological pattern of endometrioid carcinoma?
Endometrioid carcinoma presents with crowded glandular structures interspersed with thin stroma, sometimes with squamous metaplasia and increased mitotic activity.
How does the presence of mitotic activity aid in the diagnosis of carcinoma?
Increased mitotic activity, particularly in a menopausal patient where the endometrium should be quiescent, supports a diagnosis of carcinoma.
What is the importance of grading in endometrial carcinoma?
Grading helps determine the aggressiveness of the tumour, although it is based on the sampled tissue and might not reflect the entire tumour.
What staging system is commonly used for endometrial cancer?
The FIGO staging system is used, with stages determined by the depth of myometrial invasion, cervical involvement, and extra-uterine spread.
what is myometrium invasion
The extent that a tumor, typically in the uterus, has grown into the muscular middle layer of the uterine wall called the myometrium
What is the significance of myometrial invasion in staging?
The extent of myometrial invasion (less than or greater than 50%) is a key factor in determining the stage and guiding treatment.e.g.
Stage :
1A –> Tumour confined to uterus <50% myometrial invasion
1B –> Tumour confined to uterus >_ 50% myometrial inversion
II - cervical stromal invasion (there is access to the lymphatics that are around the cervix )
…..
Why is cervical extension of the tumour critical in staging?
Cervical involvement indicates a higher stage due to access to pelvic lymphatics, increasing the risk of metastasis.
What is the significance of the tumour invading into the serosa
means the cancerous cells have reached the outer lining of an organ which greatly increases the risk of the cancer spreading to the peritoneal cavity, leading to peritoneal metastases, and generally indicates a poor prognosis for the patient
What does lymphovascular invasion indicate in endometrial carcinoma?
Lymphovascular invasion is associated with a more aggressive tumour and may necessitate additional therapies such as radiotherapy following surgery …. ( we know that if we see more than 5 areas where there is lymphovascular invasion, it can behave more aggressively)
Which two main types of endometrial carcinoma are described?
Type one (endometrioid carcinoma) and type two (serous carcinoma and clear cell carcinoma) are the main categories.
What characterises type one endometrial carcinoma?
It is typically low grade, oestrogen-related endometrioid carcinoma which occurs in perimenopausal or early menopausal women, is associated with obesity, and often presents with irregular bleeding.
What percentage of endometrial carcinomas are type I
75-80% ( most common type)
What would the typical patient for type I tumours be
perimenopausal or early menopausal ( 60-70) typically found in women with increased BMI, caucasian
How is type II endometrial carcinoma different?
Type two tumours usually affect older women (around 70–80 years), are not linked to oestrogen (hormonal) stimulation or BMI (obesity), and tend to be high grade, atypical and aggressive.
What histological subtypes are included under type two endometrial carcinoma?
Serous carcinoma and clear cell carcinoma are the primary subtypes in type two.serous papillary carcinoma 5-10% and clear cell carcinoma 3-5%, affecting postmenopausal women (70-80)
Why was the traditional histological classification insufficient for endometrioid carcinomas?
Because both type I and type II endometrioid carcinomas has identical histological appearances / characteristics (age, distribution, patient type), although they behave very differently morphologically e.g. some low-grade tumours may act much more aggressively than expected (so typical treatment wouldn’t be sufficient), while some high-grade tumours, which are typically treated more aggressive may not manifest as anticipated. This variability highlights the importance of genetic classification in determining the appropriate treatment approach.
What are risk factors for Leiomyosarcoma (smooth muscle cancer) / endometroid carcinoma
higher concentration of oestrogen with early menarche, late menopause, nulliparity (anovulatory cycles) tamoxifen therapy, and polycystic ovarian syndrome are risk factors.
What is tamoxifen
A pharmacological treatment for breast cancer when it is caused by the expression of HER2
What role does P53 play in uterine tumour classification?
P53 status helps differentiate high-grade endometrioid carcinomas from serous carcinomas, with mutated P53 being a hallmark in serous carcinoma.
How is P53 mutation identified in serous carcinoma?
Immunohistochemical staining shows either diffuse strong positivity or complete absence of staining, indicating a mutated pattern.
Which other molecular pathways are implicated in serous carcinoma?
Abnormalities in the PI3K/AKT /mTOR and MAPK pathway and other oncosuppressors may also be present.
What are the main features of clear cell carcinoma?
Clear cell carcinoma is characterised by sheets of large cells with clear or pale cytoplasm and often lacks oestrogen and progesterone receptor expression. Clear cell carcinomas are typically solid rather than growing in glands
How do immunohistochemical markers aid in diagnosing clear cell carcinoma?
Markers that show positive for napsin A and AMACR help distinguish clear cell carcinoma from other clear cell tumours, for instance from metastatic renal cell carcinoma. They also need to be negative for oestrogen and progesterone
What is the genetic profile of endometrioid carcinoma typically like?
Endometrioid carcinomas usually exhibit a poly-mutational profile with accumulation of multiple small mutations, which is generally associated with a better prognosis with the immune system being able to spot them more easily, responding better to treatment and presenting at an earlier stage
What can POLE wildtype show abnormalities in
in the MMR system –> either being MMR deficient who tend to have a better response to treatment (EC, MMRd) or MMR proficient with p53 wildtype (EC, NSMP) or p53 mutant (EC, p53mut)
What is meant by “poly-mutational” in the context of endometrioid carcinoma?
It refers to the accumulation of several small genetic mutations rather than a single dominant mutation.
How does the immune response differ in poly-mutational tumours?
These tumours tend to be more antigenic and are more readily recognised by the immune system, which can lead to a better response to treatment.
What is the significance of mismatch repair (MMR) deficiency in endometrial cancer?
MMR deficiency indicates abnormalities in the DNA repair system, is linked to Lynch syndrome, and may confer a better treatment response.
How is Lynch syndrome related to endometrial carcinoma?
Lynch syndrome, a hereditary condition associated with defective MMR, increases the risk of endometrial cancer, along with colorectal and gastric cancers.
What are the different molecular subtypes in the current classification of endometrial carcinoma?
The current classification includes POLE-mutated, MMR-deficient, copy number low with wildtype P53, and copy number high with mutated P53.
What characterises POLE-mutated endometrial carcinoma?
It is typically low grade, highly antigenic with a strong immune response, and associated with a good prognosis.
What does “copy number low” refer to in endometrial carcinoma?
It describes tumours with fewer genetic alterations overall and generally wildtype P53, which are usually less aggressive.
What is the prognosis for copy number high tumours with mutated P53?
These tumours tend to have a poorer prognosis and are more aggressive.
Why is combining histological and genetic classifications beneficial?
It provides a more accurate prediction of tumour behaviour and guides personalised treatment strategies.
What is the main reason histology is still performed despite the advent of genetic testing?
Histology is relatively easier and more cost-effective to obtain and confirms the presence of tumour tissue before further genetic testing is carried out.
How is an endometrial biopsy obtained?
Samples may be obtained by inserting a device into the uterine cavity to aspirate tissue or by taking a directed biopsy from a suspicious polyp.
What challenges can arise during endometrial sampling?
Inadequate sampling, scanty tissue, and incorrect clinical information can all complicate the diagnosis.
What does a normal functional endometrium look like
consists of regular spaced glands and bland cells ( characteristic of a healthy endometrial phase)
How is ultrasound utilised in evaluating the endometrium?
Ultrasound helps measure endometrial thickness, which is correlated with the likelihood of pathology in postmenopausal women. ( one can determine the phase of the menstrual cycle by examining its histological features e.g. gland spacing and cellular appearance)
What does an increased endometrial thickness on ultrasound suggest in a 65-year-old woman?
It suggests the possibility of endometrial pathology, warranting further investigation and biopsy.
Why can clinical details sometimes be problematic in sample evaluation?
Incomplete or incorrect clinical details can lead to difficulties in correlating the biopsy findings with the patient’s presentation.
What does the term “two week wait referral” imply in the context of endometrial cancer?
It indicates an urgent referral for patients with suspicious symptoms, ensuring prompt evaluation and tissue sampling.
How does the stage of endometrial cancer influence treatment?
The stage determines the extent of surgical intervention and the need for adjuvant treatments such as radiotherapy or chemotherapy.
What is the significance of lymph node involvement in endometrial cancer?
Lymph node involvement, particularly in the pelvis and para-aortic regions, indicates advanced disease and a worse prognosis.
What is the rationale behind using radiotherapy in endometrial cancer treatment?
Radiotherapy may be used post-surgery to control local disease, especially in cases with lymphovascular invasion or deep myometrial involvement.
Which type of endometrial carcinoma is often associated with a better survival rate?
Endometrioid carcinoma (type one) generally has a better survival rate compared to type two tumours.
What is the clinical importance of identifying precursors to endometrial carcinoma?
Early detection of precursor lesions like hyperplasia allows for timely intervention, reducing the progression to full-blown carcinoma.
How does hormonal replacement therapy affect the endometrium?
Hormonal replacement therapy prolongs exposure to oestrogen, which can lead to an increased risk of endometrial hyperplasia and carcinoma.
What role does progesterone play in managing endometrial hyperplasia?
Exogenous progesterone can induce regression of hyperplasia by counteracting the proliferative effects of oestrogen e.g. seen in patients with the marina coil, progesterone therapy as exogenous progesterone
what is Endometrial intraepithelial neoplasia (EIN)
American name for endometrial hyperplasia - a clonal proliferation of endometrial glands, considered to be a premalignant condition due to its strong association with concurrent and / or subsequent endometroid ( type I) adenocarcinoma of the endometrium
What are the basic criteria required for diagnosing endometrial intraepithelial neoplasia?
The diagnosis requires the identification of glandular crowding and cytological atypia in lesions that are typically larger than 1mm
What architectural criteria are used to diagnose endometrial intraepithelial neoplasia?
The architectural criteria specify that the area of the glands must exceed the area of the endometrial stroma. This disorganization in the glandular arrangement is a key feature in identifying neoplastic changes.
What cytological criteria are important in diagnosing endometrial intraepithelial neoplasia?
Cytological criteria involve assessing the differences in nuclear and cytoplasmic characteristics between the abnormal areas and the background endometrium. These differences help identify potential neoplastic lesions.
What is the significance of architectural disorder in endometrial lesions?
Architectural disorder, such as abnormal gland crowding, is an important criterion in distinguishing benign hyperplasia from neoplastic lesions.
Why might a repeat biopsy be necessary in endometrial sampling?
A repeat biopsy may be needed if the initial sample is inadequate or does not correlate with imaging findings.
How do clinical management decisions change based on the patient’s reproductive desires?
Younger patients wishing to conceive may be managed with conservative, pharmacological treatments rather than hysterectomy. (with that said pharmacological treatments might still reduce their chances of conceiving and requires following up)
what is the architecture for endometrioid carcinomas
- Confluent or back to back glands lacking intervening stroma
- Cribriform or microacinar pattern
- Complex papillary, micropapillary or villoglandular structures
what are the cytological features of an endometroid carcinoma
- Resembles proliferative type endometrium with varying degrees of atypia (mitotic activity)
- Cellular and nuclear enlargement
- Nuclear rounding ( not elongated ) with nucleoli with loss of polarity
should the endometrium show signs of mitotic activity in perimenopausal / penopausal women?
No
What surgical treatment might be considered for endometrial carcinoma in postmenopausal women?
A hysterectomy, often with removal of the ovaries and assessment of lymph nodes, is a common surgical treatment.
How does serous carcinoma typically present in the uterine cavity?
Serous carcinoma may present as a mushroom-like or polypoid mass, often with associated bleeding
what type of patients typically present with serous carcinoma
postmenopausal ( older than type I), nonobese women, oestrogen independent. There seems to be a high incidence in black women with a history of pelvic radiation or tamoxifen use
Where do serous carcinomas often arise within
endometrial polyps (background endometrium often atrophic)
What is the cellular appearance of serous carcinoma compared to endometrioid carcinoma?
Serous carcinoma cells are typically more pleomorphic, have prominent nucleoli, and display a higher degree of atypia.
How can serous carcinoma be distinguished immunohistochemically from high-grade endometrioid carcinoma?
P53 immunostaining is crucial, with serous carcinoma showing either diffuse strong positivity or complete absence of staining.
What challenges exist when diagnosing serous carcinoma on small biopsy samples?
Serous carcinoma can be patchy or focal, indicating that only small areas of the tumor may be present in a biopsy. If the sampled tissue includes only a small portion of the tumor, the full extent and severity of the disease may remain unclear. When the entire uterus is removed through a hysterectomy, the tumor may become invisible, suggesting that it was only a tiny focus.
What morphological challenges exist when diagnosing serous carcinomas
The cellular structure of serous carcinoma tends to be more aggressive and atypical compared to other types of endometrial cancer. The cells are often highly pleomorphic, meaning they vary in shape and size being solid or glandular ( in architecture) similar to ovarian / tubal high grade serous carcinomas. They also exhibit hyperchromatic characteristics, with dark-staining nuclei, and are mitotically active, indicating rapid cell division. These pronounced features can sometimes complicate diagnosis, especially in small samples, as they may closely resemble other high-grade malignancies.
What is the significance of squamous metaplasia in endometrial lesions?
Squamous metaplasia may be present in endometrioid carcinoma and can complicate the morphological assessment.
How does the current genetic classification improve prognostication in endometrial cancer?
It provides additional markers that correlate with tumour behaviour and potential response to targeted therapies.
Why is the assessment of the genetic profile important even when histological findings are clear?
The genetic profile may reveal underlying aggressive behaviour that is not obvious on morphology alone.
What does POLE (p261) endode
the DNA polymerase E which is a heterotetramer (p261,p59,017,p12) responsible for the leading strand DNA replication. It contains the proof reading exonuclease domain to ensure low mutation rates in replicating cells.
What is the role of DNA polymerase E (POLE) mutations in endometrial cancer?
POLE mutations are associated with a strong immune response, earlier presentation, and a better prognosis despite high mutation rates.
what did early studies demonstrate about POLE mutations
that they were observed in colorectal cancer, pancreatic cancer, ovarian cancer, ultra-mutated giant cell high grade glioma and endometrial cancer.
what two things base treatment for endometrial carcinomas
histology and genetic classification ( we know this is more accurate)
What is the more modern classification for endometrial cancers
TCGA - cancer genome atlas
- Group 1 POLE mutation ( good prognosis) - usually endometrail
- Group 2 - MMRd (intermediate prognosis )
- Group 3 - low copy number alteration (intermediate prognosis)
- Group 4 -p53 mutant (poor prognosis)
How does the molecular classification impact treatment strategies?
It helps tailor treatment decisions, including the use of adjuvant therapies, by identifying tumours that may respond better to immunotherapy or targeted treatments.
What are the main criteria for a diagnosis of invasive endometrioid carcinoma?
The diagnosis is based on complex glandular architecture, cytological atypia, and evidence of stromal invasion.
What is the importance of correlating clinical information with histological findings in endometrial biopsies?
Accurate correlation ensures that the biopsy is representative and that any potential malignancy is not missed.
How do discrepancies between clinical details and biopsy findings complicate diagnosis?
Inaccurate or incomplete clinical details can lead to under- or overdiagnosis, making it challenging to decide if further sampling is necessary.
What imaging modality is commonly used to assess endometrial pathology?
Transvaginal ultrasound is commonly employed to measure endometrial thickness and detect abnormalities.
What is the relationship between menstrual irregularity and endometrial pathology?
Irregular menstrual bleeding can be an early sign of endometrial hyperplasia or carcinoma, especially when deviating from a woman’s normal cycle.
Why might bleeding be a less specific symptom in postmenopausal women?
Postmenopausal bleeding can have various causes including polyps, infections, or hormonal therapy, not just carcinoma.
How does the lecture illustrate the progression from normal endometrium to carcinoma?
It outlines a sequence from normal secretory endometrium to hyperplasia (with atypia) and finally to carcinoma, highlighting the role of unopposed
What is secretory endometrium?
Secretory endometrium occurs after ovulation, with declining oestrogen levels and predominant progesterone influence.
What is the impact of inadequate sampling on the management of endometrial lesions?
Inadequate samples may delay diagnosis, necessitate repeat biopsies, and complicate treatment planning.
How does endometrial carcinoma typically differ in presentation between younger and older patients?
Younger patients (often with obesity) usually present with type one, low-grade endometrioid carcinoma, while older patients are more likely to develop type two, high-grade carcinomas.
What additional information can immunohistochemistry provide in endometrial cancer diagnosis?
It can identify specific molecular markers such as P53, oestrogen receptors, and mismatch repair proteins, which aid in tumour classification and prognosis.
How has the integration of genetic testing influenced endometrial cancer management?
It allows for more precise prognostication and personalised treatment plans, potentially improving survival rates.
What is the overall significance of combining histological and genetic data in the management of endometrial carcinoma?
This combined approach enhances diagnostic accuracy, guides therapeutic decisions, and ultimately contributes to improved patient outcomes by identifying tumours that might otherwise be misclassified based solely on morphology.
What type of biopsy will most diagnoses be done through
Pipelle/ endometrial biopsy ( the amount of tissue received will affect the accuracy of the diagnosis)
what are Pipelle/ endometrial biopsy
a medical procedure where a small tissue sample is taken from the lining of the uterus (endometrium) using a specialized instrument called a Pipelle, allowing a doctor to examine the tissue for abnormalities like cancer. It also allows for direct biopsies e.g. removal of polyps
