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Cervical & Uterine Neoplasms

Notes

Cervical & Uterine Neoplasms

Sections






Anatomy Review

The uterus comprises three layers: the perimetrium (aka, serosa), myometrium, and endometrium.

Deails of the cervix: the internal os (aka, orifice), opens into the uterus, the endocervical canal, and the external os, opens to the vagina. The ectocervix is the rounded surface of the cervix that bulges into the vagina.

The vagina and ectocervix comprise stratified squamous epithelia, and that the endocervical canal and uterus comprise columnar epithelia.

The squamous columnar junction is the location where these two tissue types meet; its anatomical location varies with hormonal influence, which changes with age and reproductive status.

In our diagram, we indicate the original squamous columnar junction (SCJ) and, above this, a new squamous columnar junction.

The area between these points is the "transformational zone" – this is an area of active squamous metaplasia, and is the origin of cervical carcinomas and high-grade epithelial lesions in 90% of cases.

Cervical Carcinoma

Cervical carcinoma is the 4th most common cancer among women globally.

In the United States, preventative measures and early diagnosis have decreased cervical cancer prevalence and mortality, but not uniformly – for example, the mortality rate among African Americans and Hispanic/Latina women remains significantly higher than that of Caucasians.

Signs and Symptoms:

Patients are asymptomatic in the early stages of cervical cancer, but, as lesions grow and invade deeper tissues, patients may present with abnormal uterine bleeding, pelvic and back pain, and obstructive uropathy.

Origins & Types:

More than 80% of cervical cancers are of the squamous cell subtype, and are preceded by low and high-grade squamous intraepithelial lesions.

Be aware that these lesions were formerly classified as cervical intraepithelial neoplasms grades 1-3.

Less common cervical cancer subtypes include:
Adenocarcinoma (the precursor lesion for HPV-dependent adenocarcinoma is "adenocarcinoma in situ")
Endometrioid adenocarcinoma
Adenosarcoma (comprises mixed epithelial and mesenchymal components)
Germ cell tumors (yolk sac tumors, choriocarcioma).

Cervical carcinoma spreads directly to the perimetrium, vagina, uterus, bladder, rectum, and to more distant organs via the lymph and blood vessels.

Risk Factor: HPV

The major risk factor for cervical cancer is infection by HPV types 16 and 18, which enter cervical cells through defects in the mucosa, usually at the transformation zone.
HPV reprograms the host cells to silence tumor suppressor factors and enhance tumor-promoting factors.

The availability of HPV vaccines and cancer screening with Pap smear tests have reduced the rates of cervical cancer incidence and mortality in the US and other wealthy countries.

Pap Smear Test

The Pap smear test allows us to inspect the cervical cells for abnormalities, including low- and high-grade squamous intraepithelial lesions and squamous cell cancer.

We show that the cells of a healthy cervix are heterogenous, and include superficial, intermediate, and basal cells that stain light to dark, respectively.

For comparison, we also draw an example of cells taken from a high-grade squamous intraepithelial lesion; notice the clusters of cells with enlarged, hyperchromatic nuclei.

High Grade:

High Grade Cervical Cancer
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Low Grade:

Low Grade Cervical Cancer
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Healthy cervical cells:

Healthy Cervical Cells
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See references at end.

Nonneoplastic variations in cervical cell samples include:
Squamous metaplasia
Hyperkeratosis
Parakeratosis

Be aware that we also changes during pregnancy (navicular cells, decidual cells, cytotrophoblast and synctiotrophoblast cells, etc.), and changes in different phases of the menstrual cycle or reproductive lifespan (atrophy, repair and regeneration with inflammation, perimenopausal cells, etc).

Malignant uterine neoplasms

Signs & Symptoms:

The most common manifestations are abnormal uterine bleeding and ovulatory dysfunction, and that larger masses can cause pain and pressure in the abdominopelvic cavity.

ENDOMETRIAL CANCER

The endometrium is the layer of the uterus that proliferates and sheds during menstrual cycles.

Endometrial cancer is the 4th most common cancer in US women.

Endometrioid cancer
Accounts for approximately 80% of all endometrial cancers; it is preceded by atypical hyperplasia (aka, endometrial intraepithelial neoplasia, EIN). Fortunately, most cases are caught in early stages with good prognosis.

Be aware that endometrioid cancers were formerly categorized as Type 1 endometrial cancers.

Endometrioid cancer is associated with elevated estrogen to progesterone ratios and several specific genetic mutations.

Recall that chronically elevated estrogen levels, which have mitogenic effects, are seen in patients with PCOS, obesity, and higher numbers of ovulatory cycles (early menarche/late menopause).

Mean age at diagnosis is 60 years old.

Genetic mutations associated with initiation and progression of endometrioid cancer: PTEN, CTNNB1, PIK3CA, ARID1A, and KRAS.

Elevated estrogen to progesterone ratios induce atypical hyperplasia in the endometrium, which can ultimately lead to endometrioid cancer.

The cancerous lesions fully invade the endometrium and tumors can form within the myometrium, the muscular layer of the uterus. These tumors can cause the uterus to become enlarged and tender.

Treatment includes hysterectomy with possible chemotherapy and radiation; combined hormonal contraceptives, which reduce estrogen levels, have protective effects.

Serous adenocarcinoma
The second most common endometrial carcinoma.

Though it accounts for only 10% of cases of endometrial cancer, it is responsible for 40% of deaths from endometrial cancer.

Patients are usually in their 70s or 80s.

Serous adenocarcinoma is aggressive, and quickly invades the deeper myometrium and extra-uterine tissues – in our drawing, we show lesions in the abdomen, peritoneum, retroperitoneum, and lymph nodes.

Unlike endometrioid carcinoma, serous adenocarcinoma is NOT estrogen-driven; it is associated with p53 mutations.

Unfortunately, it has a high recurrence rate.

Carcinosarcomas
Comprise a mixture of epithelial and connective tissues; these neoplasms were formerly referred to as Malignant Mixed Müllerian Tumors (MMMTs).

These tumors are rare, but aggressive.

UTERINE STROMA & MYOMETRIUM

Leiomyosarcomas
Arise in the smooth muscle of the myometrium.

These tumors are aggressive, and quickly spread to extra-uterine sites, most notably the lungs and liver.

Though rare, they respond poorly to treatment and are often deadly.

Adenosarcomas
Found in the uterine stroma.

Tumors comprise normal gland cells mixed with sarcoma cancer cells - we show typical glands surrounded by enlarged stromal cells with high mitotic activity.

These cancers are usually low-grade, with good prognosis.

Benign uterine neoplasms

Leiomyomas, aka, fibroids
Common neoplasms that arise from smooth muscle cells of the myometrium under the direction of estrogen and progesterone.

Fibroids can be asymptomatic, or they may present with abnormal uterine bleeding, pelvic and back pain; complications include infertility and spontaneous abortion.

Fibroid treatments include NSAIDs, hormonal therapies, and surgical interventions

Additional Details

Histopathological types of endometrial carcinoma:

Endometrioid carcinoma: adenocarcinoma, adenocarcinoma-variants. Historically categorized as Type 1 EC.

Can be all 4 molecular subtypes.

Associated with PTEN, CTNNB1, PIK3CA, ARID1A and KRAS mutations.

Tall columnar cells line glands, no intervening stroma.

Usually early-stage, favorable prognosis.

Associated with: High estrogen:progrestrone. (some estrogenic drugs, such as tamoxifen, PCOS, obesity, early menarche/late menopause), Lynch syndrome, diabetes.

Mean age = 60.

Pathogenesis: Elevated, chronic estrogen stimulation -> mitogenic effects on endometrial glands and stroma -> hyperplasia -> adenocarcinoma.

Non-endometrioid carcinomas:

Patients tend to be older (70-80 yo), more likely to have deep myometrial invasion with nodal and peritoneal involvement. Associated with endometrial atrophy.

Serous adenocarcinoma:
Majority are of p53 molecular subtype.
Histology: papillary structures, glands with serrated edges, prominent nucleoli, high mitotic rate. Possible psammoma bodies.

Clear cell adenocarcinoma:
Rare, usually older postmenopausal patients.
Can be any of the 4 molecular subtypes.
Usually negative for estrogen receptor protein but positive for Napsin A (helps differentiate from serous and serous endometrial cancer and secretory endometrioid carcinoma).
Various morphological patterns.

Mucinous adenocarcinoma – rare, mucinous differentiation in histology. Usually low-grade, good prognosis.

Others: Undifferentiated carcinoma, neuroendocrine tumors, mixed carcinoma.

Molecular classification system
Based on somatic copy number mutations & tumor mutational burden:

DNA polymerase epsilon (POLE) mutated subtype. POLE is a gene involved in DNA replication and repair. Younger, thinner patients; good prognosis.

Mismatch repair deficient subtype (MMRd). High tumor mutational frequency. Associated with Lynch syndrome.

No specific molecular profile (NSMP). Mostly endometrioid neoplasms. Younger women, estrogen exposure.

P53 abnormal. TP53 mutations. Older, thinner women. Often found in advanced stage, poor prognosis.

Former classification system - Types 1 and 2

Type I: more common, estrogen-dependent, younger women. Hyperplasia. Low grade, good prognosis. Mutations in PTEN, PIK3CA, KRAS, CTNNB1.

Type II: High-grade, can be endometrioid adenocarcinoma or others (serous, clear cell, mixed cell, etc.). Older, thinner women. Up to 10% have p53 mutations. Often found in advanced stage, poor prognosis.

These "Types" do not reflect complicated underlying biology, so they are less useful for diagnoses and treatment.

Board Review

Cervical Cancer

Getting ready for boards? Review these concise, bulleted high yield reviews for your exam.

USMLE & COMLEX-USA

Nurse Practitioner (NP)

Physician Assistant (PA)

Internal Medicine (ABIM)

Board Review

Endometrial Cancer

Getting ready for boards? Review these concise, bulleted high yield reviews for your exam.

USMLE & COMLEX-USA

Nurse Practitioner (NP)

Physician Assistant (PA)

Internal Medicine (ABIM)

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Image References

  • Cervical cancer pap smear, High Grade: https://commons.wikimedia.org/wiki/File:High-Grade_SIL.jpg
  • Cervical cancer pap smear, Low Grade: https://commons.wikimedia.org/wiki/File:Low-Grade_SIL_with_HPV_Effect.jpg
  • Healthy pap smear: https://en.wikipedia.org/wiki/Pap_test#/media/File:Normal_PAP_(Cervical)_Smear.jpg