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name the 3 types of squamous cell neoplasia [cervix]: Cervical Intraepithelial Neoplasia (CIN)
Microinvasive Squamous Cell Carcinoma
Invasive Squamous Cell Carcinoma
Define: Cervical Intraepithelial Neoplasia (CIN): Spectrum of intraepithelial changes that begins with minimal atypia and progress through stages of more marked intraepithelial abnormalities to invasive squamous cell carcinoma.
Pathology of cervical intraepithelial neoplasia (CIN): 1. Considered a precancerous lesion.
2. Precancerous changes represent a continuum of morphologic changes with relatively indistinct boundaries.
3. Lesions may spontaneously regress.
4. Associated with human papillomavirus (HPV) infection.

Abnormal cells migrate toward the surface of the epithelium and are sloughed. They exhibit koilocytotic atypia (a viral cytopathic effect caused by HPV infection: cells present a perinuclear halo and a wrinkled nucleus.) Indeed, epithelial cells containing HPV particles are known as koilocytes.
What are the grades used for cervical intraepithelial neoplasia?: ⬢ CIN-1
⬢ CIN-2
⬢ CIN-3
CIN grades describe how deeply the abnormal cells have gone into the surface layer of the cervix.

Half of the CIN-1 regress, 10% progress to CIN-3 and less than 2% progress to invasive cancer.
At least 20% of the cases of CIN-3 progress to invasive carcinoma.
CIN-1: Mild dysplasia: changes are seen in the basal one-third of the epithelium
CIN-2: Moderate dysplasia: cellular abnormalities are in the lower and middle one-third of the epithelium (2/3 affected).
CIN-3: Includes both
Severe dysplasia: abnormal cells involve more than two-thirds of the epithelium

and

Carcinoma in situ: abnormal cells involve all layers of the squamous epithelium, but the underlying stroma has not been invaded.
Define and describe Microinvasive Squamous Cell Carcinoma: DEFINITION: Early stage in the spectrum of cervical cancer (stage IA), characterized by minimal invasion of the stroma by neoplastic cells. Lesions have the following characteristics:

- invasion of the stroma to a depth of less than 3 mm below the basement membrane.
- lack of vascular invasion.
- no lymph node metastases
- cure by simple hysterectomy
Define Invasive Squamous Cell Carcinoma [cervix]: Malignant cervical cancer that generally evolves from precursor CIN lesions
Pathology of Invasive Squamous Cell Carcinoma [cervix]: 1. The tumor generally evolves from precursor CIN (25 years after the peak of CIN-1 and CIN-2 and then 10-15 years after CIN-3).

2. 95% of squamous carcinomas are composed of relatively large cells, with either keratinizing (well-differentiated) or nonkeratinizing (moderately differentiated) patterns. Only 5% are poorly differentiated or undifferentiated squamous cell carcinomas.

3. Spreads by direct extension, through lymphatic vessels. Local extension into surrounding tissues (peritoneum, urinary bladder, ureters, rectum and vagina) results in ureteral compression (complications). Metastases affect local and distant lymph nodes. Distant metastases occurs to the liver, lungs, bone marrow and others.
Types of Invasive Squamous Cell Carcinoma [cervix]: Manifests in three distinctive patterns:
1. Fungating (or exophytic),
2. Ulcerating
3. Infiltrative.
Most common is the fungating tumor, that produces an obviously neoplastic mass that projects above the surrounding mucosa.
Clinical features of Invasive Squamous Cell Carcinoma: 1. Evolve slowly over the course of many years.
2. During this interval, the only sign of disease may be the shedding of abnormal cells from the cervix.
3. Prognosis and survival depend largely on the stage at which cancer is discovered: 5-year survival rate of 80-90% with stage I, 75% with stage II, 35% with stage III and 10-15% with stage IV.
Definition and pathology of cervical adenocarcinoma.: DEFINITION: Cervical carcinoma that presumably arise in the endocervical glands.

PATHOLOGY:
1. Accounts for 10-25% of malignant cervical tumors.
2. Shares causative factors with cervical squamous cell carcinoma and behaves and spreads in a similar fashion.
3. Tend to have a less favorable prognosis compared to the squamous cell carcinoma of similar stage.
Etiology of cervical neoplasia: ïƒ˜ The most important etiological factor in cervical oncogenesis is infection with Human Papillomavirus (HPV).

- HPV DNA is detected in 85% of cervical cancers. *Around 25% of oral cancers may also contain HPV DNA.
- HPV types have the capability to transform cells in culture.
- Introduction of HPV E6 or E7 genes into cultured keratinocytes produces morphologic changes nearly identical to precancerous changes.
Major risk factors of cervical neoplasia: 1. Early age at first intercourse
2. Multiple sexual partners
3. A male partner with multiple previous sexual partners.

Clinical, pathologic, molecular and epidemiologic data implicated a sexually transmitted agent, HPV, on the basis of the risk factors for cervical cancer.

Other potential secondary risk factors are: Smoking, oral contraceptives, high parity, altered immune status or host gene alterations. They are subordinate to the 3 mentioned above, primarily multiple sexual partners.
The human papillomavirus life cycle: The papillomavirus life cycle differs from all other virus families: infection requires the availability of epidermal or mucosal epithelial cells that are still able to proliferate (basal layer cells). This infection usually occurs in microlesions of skin or mucosa.

1. In the cells of the basal layer, viral gene expression is largely suppressed. However, the limited expression of specific 'early' viral genes (such as E5, E6 and E7) results in enhanced proliferation of the infected cells and their lateral expansion.

2. Some of the progeny migrate into the suprabasal differentiating cell layers. â€˜Late' viral gene expression is initiated; the circular (episomal) viral genome is then replicated and structural proteins form.

3. In the upper layers of the epidermis or mucosa, complete viral particles are assembled and released at the surface. They may then infect additional tissue.
HPV genes in cancer: - The human papillomavirus (HPV) genome contains eight genes â€” E6, E7, E1, E2, E4, E5, and L2 and L1 â€” coding for 'early' (E) or 'late' (L) proteins.

- A key role for malignant transformation can be assigned to the E6 and E7 genes. They are consistently expressed in malignant tissue. Several functions have been described for E6 and E7. The most relevant functions are:

E6 inhibits p53 --> resistance to apoptosis and chromosomal instability
E7 inhibits Rb --> blocks binding to transcription factors --> activates cell cycle
High-risk HPV infections: â€˜High-risk' HPVs (16, 18, 31, 33, 35): HPV types found preferentially in cervical cancers. The most common are HPV16 and HPV18.

ïƒ¼ High-risk HPV types, particularly HPV16, are widespread within all human populations. Infection is commonly transmitted by sexual contact.
Low-risk HPV infections: â€˜Low-risk' HPVs (6, 11, 42-44). HPV types found in genital warts and non-malignant lesions.

The most common are HPV6 and HPV11.
DIFFERENCES BETWEEN HIGH-RISK AND LOW RISK HPVs:: 1. Only the E6 gene of high-risk types is able to bind to p53.
2. High-risk HPVs (HPV16 and 18) integrate into the human genome.

High risk HPV --> Integration --> Invasive carcinoma

Low risk HPV --> Episomal --> Condyloma; Low grade lesions
Define endometrial polyps: Benign, localized masses of variable size that project from the endometrial surface into the endometrial cavity.
Pathology of endometrial polyps: 1. single (80%) or multiple (20%), between 0.5 and 3.0 cm in diameter.
2. Most arise in the fundus. Microscopically, the core of a polyp is composed of (1) endometrial glands, (2) a fibromatous endometrial stroma and (3) thick-walled, coiled, and dilated blood vessels, all covered by a mantle of endometrial epithelium.

3. Two histological types made up of:
(1) functional glandular endometrium, paralleling the adjacent cycling endometrium
(2) hyperplastic endometrium, mostly of the cystic variety. Most common.

4. Cytogenetic studies: stromal cells in endometrial polyps are clonal with choromosome (6p21) rearrangements, indicating that genetic alterations may play a role in their development.
Clinical features of endometrial polyps: 1. They are generally not preneoplastic.

2. observed in association with the administration of tamoxifen (therapy for breast cancer).

3. may be asymptomatic or may cause abnormal bleeding if they ulcerate or undergo necrosis.
Endometrial Hyperplasia and Adenocarcinoma: Endometrial Hyperplasia and Adenocarcinoma represent a broad spectrum of proliferative disease that constitutes a morphologic and a biologic continuum, similar to multistep carcinogenesis in other tissues. Progression may take 10 years.
Define endometrial hyperplasia: refers to a morphologic continuum that ranges from simple glandular crowding to a conspicuous proliferation of atypical glands. The risk of developing carcinoma increases with progressively higher degrees of endometrial hyperplasia.
Conditions leading to endometrial hyperplasia: ïƒ˜ End. hyperplasia is related to an abnormally high, prolonged level of estrogenic stimulation with diminution or absence of progestational activity. Occurs most commonly around menopause or in association with persistent anovulation in younger women. May cause abnormal bleeding.

1. anovulatory cycles
2. polycystic ovary syndrome
3. an estrogen-producing tumor
4. obesity
5. intake of estrogenic drugs.
Classification of endometrial hyperplasia: 1. Simple Hyperplasia: Minimal glandular complexity and crowding but not cytologic atypia. One cell layer for the epithelial lining. Stroma between the glands is abundant. 1% progress to adenocarcinoma.

2. Complex Hyperplasia: Severe glandular complexity and crowding but no cytologic atypia. Stroma between glands is scanty. 3% progress to adenocarcioma.

3. Atypical Hyperplasia: Displays cytologic atypia and marked glandular crowding, frequently as back-to-back glands. The glands may have a complex architecture. 1/3 progress to adenocarcinoma.
Define endometrial adenocarcinoma: Carcinoma presumably linked to prolonged estrogenic stimulation of the endometrium. Most frequent cancer of the female genital tract in American women (7% of all cancers in women).
Pathology of endometrial adenocarcinoma: 1. Linked to same conditions as endometrial hyperplasia. Other risk factors are: obesity, diabetes, hypertension, nulliparity, and late menopause.

2. Regardless of its site of origin, the tumor often involves multiple areas. Large tumors are often hemorrhagic and necrotic.

3. It may spread directly to the para-aortic lymph nodes, skipping the pelvic nodes. Advanced cancers may also develop pulmonary metastases.
Clinical features of endometrial adenocarcinoma: Typically occurs in perimenopausal or postmenopausal women. It causes abnormal bleeding that permits early detection and cure at an early stage.
Classification of endometrial adenocarcinoma: 1. Pure (or Endometrioid) Adenocarcinoma of the Endometrium: composed entirely of glandular cells. Most common histologic variant (60%). The morphology varies from highly differentiated (grade1) to poorly differentiated (grade 3)

2. (Endometrioid) Adenocarcinoma with Squamous Differentiation: containing squamous cells in addition to the glandular cells.

- well-differentiated adenocarcinoma with squamous differentiation (adenoacanthoma): exhibits minimal atypia.

- poorly-differentiated adenocarcinoma with squamous differentiation (adenosquamous carcinoma): appears to be malignant.
Define leiomyomas: Benign tumor of smooth muscle origin. Most common tumor of the female genital tract. If minute tumors are included, they occur in 75% of women older than 30 years of age. (Fibroids).
Pathology of leiomyomas: 1. Grossly, they are firm, pale-gray, whorled, and without encapsulation, ranging from 1mm to more than 30 cm in diameter. Most occur within the myometrium (intramural), but some are submucosal (just beneath the endometrium), or subserosal (beneath the serosa), or pedunculated.

2. They are composed of interlacing fascicles of uniform spindle cells, with elongated nuclei. Mitotic figures are scarce. Lacking nuclear atypia, with little or no malignant potential.

3. Usually asymptomatic. May increase during pregnancy. Most regress after menopause.

4. Their cause is unknown, although choromosome aberrations may play a role.
define leiomyosarcomas: Malignancy of smooth muscle origin, identified by a high mitotic count and nuclear atypia. Rare
pathology of leiomyosarcomas: 1. The pathogenesis is uncertain. Some appear to arise from within leiomyomas, although is controversial.

2. Suspected if a leiomyoma is soft, shows areas of necrosis, has irregular borders, or does not bulge above the surface when cut.

3. Usually fatal, when large and advanced stage. Tendency to recur after removal, and more than half the cases eventually metastasize to lungs, bone and brain. Dissemination throughout the abdominal cavity is also encountered.

4. Two distintive patterns:

- bulky, fleshy masses that invade the uterine wall, or
- polypoid masses that project into the uterine lumen.
General info about ovarian cancer: Ovarian cancer is the second most frequent gynecologic malignancy after endometrial cancer. However, it carries a higher mortality rate than that from all other genital cancers combined (extragonadal spread of tumor to the pelvis or abdomen at the time of diagnosis).
Define epithelial tumors of the ovary (most common): Tumors that arise from the surface epithelium or serosa of the ovary. Account for more than 90% of ovarian cancers.
Pathogenesis of epithelial tumors of the ovary: ïƒ˜ Epithelial neoplasms of the ovary are associated with the repeated disruption of the epithelial surface that results from cyclic ovulation.

1. They afflict women who are nulliparous, least often afflict women in whom ovulation has been suppressed (pregnancy or oral contraceptives).

2. Mutations in BRCA-1 gene has been incriminated in the pathogenesis of familial ovarian cancers.
Morphologically, epithelial tumors of the ovary are classified as:: 1. Serous tumors: resemble the epithelium of the fallopian tube.
2. Mucinous tumors: mimic the mucosa of the endocervix.
3. Endometrioid tumors: similar to the glands of the endometrium.
4. Clear cell tumors: glycogen-rich cells that resemble endometrial glands in pregnancy.
5. Transitional cell tumors
Benign tumors of the ovary: Frequently large, often growing to between 15 - 30 cm in diameter. Affect women between 20 and 60 years. Typically cystic (also called CYSTADENOMA).

Most common:
⬢ Serous cystadenomas: tend to be bilateral, and unilocular.
⬢ Mucinous cystadenomas: composed of hundreds of small cysts.
Transitional cell tumor (brenner tumor) of the ovary: - Benign neoplasm composed of solid nests of transitional-like (urothelium-like) cells encased in a dense, fibrous stroma.
- The size varies from microscopic focus to masses as large as 8 cm or more.
Borderline tumors (ovary): - Group of ovarian tumors with excellent prognosis. Surgical cure is almost always possible if the tumor is confined to the ovaries. 5-year survival is around 80%.

Most common:
⬢ Serous tumors: tend to be bilateral.
⬢ Mucinous tumors: may achieve gigantic size
Malignant tumors (ovary): - Time of diagnosis, usually metastasized (35% 5-year survival rate)
- Non functional: they do not secrete hormones.
Serous Cystadenocarcinoma: - most common malignant ovarian tumor (1/3 all cancers of the ovary).
- In half of the patients, tumors are bilateral.
- vary from well-differentiated to poorly differentiated.
Mucinous cystadenocarcinoma: - 10% of all ovarian cancers.
- among the largest tumors, tipically cystic and multilocular
- vary from well-differentiated to poorly differentiated.
Endometrioid Adenocarcinoma: - identical histologically to carcinoma of the endometrium
- 20% of all ovarian cancers
Clear Cell Adenocarcinoma: - often found in association with endometriosis.
- 5-10% of all ovarian cancers
Germ cell tumors of the ovary: - Derived from germ cells of the ovary.
- Benign in adult women, malignant in children and young adults.
Dysgerminoma: - ovarian counterpart of testicular seminoma and is composed of primordial germ cells.
- 10% of ovarian cancers in patients younger than 20 years of age.
- 5-year survival is 80-100%.
Teratoma: - tumor of germ cell origin that shows differentiation toward somatic structures

2.2.1. Mature Teratoma (mature cystic teratoma or dermoid cyst): benign neoplasm although around 1% undergo malignant transformation. Half of the tumors exhibit smooth muscle, cartilage, bone, teeth, and respiratory tract epithelium.

2.2.2. Immature teratoma: is composed of elements derived from the 3 germ layers. It contains embryonal tissues (immature bone and cartilage).
Endoderminal sinus tumor (yolk sac carcinoma): - highly malignant tumor of women younger than 30 years of age that, histologically, resembles the mesenchyme of the primitive yolk sac.

-it secretes alpha-fetoprotein.
choriocarcinoma: - rare tumor that mimics the epithelial covering of placental villi.
- it secretes hCG.
Sex cord/stromal tumors of the ovary: - Derived from either the primitive sex cords or the mesenchymal stroma of the developing gonad.
- Account for most of the clinically functional ovarian tumors.
- Frequently differentiate toward female or male structures.
ovarian fibroma: - most common ovarian stromal tumor
- virtually always benign.
thecomas: - benign, functional ovarian tumors that arise in postmenopausal women.
- they produce signs of estrogen production.
granulosa cell tumor: - prototypical functional neoplasm associated with estrogen secretion. Endometrial hyperplasia is a common presenting sign.
- malignant (potential for local spread and distal metastases).
sertoli-leydig cell tumors: - rare mesenchymal neoplasm with low malignant potential. It resembles the embryonic testis and often secretes androgens.
Tumors metastatic to the ovary: - 3% of ovarian cancers arise outside the ovary (breast, large intestine, stomach, and other genital tract organs).

**Krukenberg tumors: ovarian metastases in which the tumor appears as nests of mucin-filled, â€œsignet-ringâ€ cells within a cellular stroma derived from the ovary.

The STOMACH is the primary site in 75% of the cases. Others are in the colon.
Define fibrocystic change (breast): DEFINITION: Refers to a constellation of morphologic features characterized by:
(1) cystic dilatation of terminal ducts
(2) increase in fibrous stroma
(3) variable proliferation of terminal duct epithelial elements

Cause is unknown. Occurs in 60-80% of adult women in the US.
Types of fibrocystic change (breast): - 1. Nonproliferative Fibrocystic Change: Increase in stroma and some degree of cystic dilatation of the terminal ducts.
- 2. Proliferative Fibrocystic Change: Increased number of cells lining the dilated terminal ducts (ductal hyperplasia).
- 3. Sclerosing Adenosis: Proliferation of small ducts and myoepithelial cells in the region of the terminal duct lobular unit (adenosis)
prognostic significance of fibrocystic change.: PROGNOSTIC SIGNIFICANCE: Relationship between FC and breast cancer.

Association between FC and cancer is proportional to the degree of epithelial hyperplasia and atypia seen. A minority of biopsies of FC reveal proliferative lesions.

- 1. Nonproliferative FC does not indicate an increased risk.
- 2. Proliferative FC is associated with 1.5-2.0-fold increased risk.
- 3. â€œAtypicalâ€ proliferative lesions are associated with 4.0-5.0-fold increased risk.
Fibroadenoma (breast): DEFINITION: BENIGN Tumor composed of epithelial and stromal elements that originates from the terminal duct lobular unit. Most common benign neoplasm of the breast.

PATHOLOGY:
They commonly enlarge more rapidly during pregnancy and cease to grow after menopause. Usually 2-4 cm in diameter. They double the risk of developing breast cancer. Treatment is surgical excision.
Malignant tumors: carcinoma of the breast: DEFINITION: Adenocarcinomas derived from the glandular epithelium of the terminal duct lobular units. Spreads through lymphatics.

Breast cancer is the most common malignancy of women in the United States. The mortality rate is second in women (after lung cancer).
Risk factors for malignant tumors of the breast: 1. Genetic Factors (family history of breast cancer in first-degree relatives).
Mutations in: BRCA1
BRCA2
p53 (Li-Fraumeni cancer syndrome)
2. Hormonal Status
Early menarche, late menopause, older age at first-term pregnancy, nulliparity
3. Environmental Influences
Dietary factors (fat content)
4. Fibrocystic Change
Only in the presence of specific proliferative lesions
5. Previous Cancer
Previous primary breast carcinoma
Define carcinoma in situ: pre-invasive form of breast cancer.
Intraductal Carcinoma in situ: Tumor that arises in the terminal duct lobular unit, greatly distending and distorting the ducts by its growth. Histologic variants:

1.1. Comedocarcinoma: Composed of large, pleomorphic cells with irregular nuclei. Grows in a solid pattern and often becomes centrally necrotic.

1.2. Intraductal Papillary Carcinoma: Form papillary structures and small, regular fenestrations rather than a solid growth.
Lobular Carcinoma in situ: Arising also in the terminal duct lobular unit, the malignant cells appear as solid clusters that pack and distend the terminal ducts, but not to the extent of in situ ductal carcinoma.

Cancer cells tend to be smaller and more monotonous than those of the ductal type.

No necrosis.
Ductal carcinoma: [invasive carcinoma of breast]

⬢ Most common form of breast cancer
⬢ Presents as a hard, fixed mass, often referred to as scirrhous carcinoma. Grossly, tumor is typically firm and shows irregular margins.
⬢ Microscopically, it grows as irregular nests and cords of epithelial cells, usually within a dense fibrous stroma.
lobular carcinoma: ⬢ Second most common form of invasive breast cancer.
⬢ Clinical presentation varies from a discrete, firm mass to a diffuse, indurated area.
⬢ Microscopically, single strands of malignant cells infiltrating between stromal fibers.
medullary carcinoma: ⬢ Presents as a circumscribed mass, which lacks calcifications on mammography.
⬢ Microscopically, sheets of cells that are highly pleomorphic and have a high mitotic index (however, it has better prognosis)
Define cervicitis: Acute or chronic infection of the cervix with many micro-organisms, particularly Streptococcus, Staphylococcus and Enterococcus.
Define salpingitis: Acute or chronic infection of the fallopian tubes, usually by N. gonorrhoeae, E. coli, Chlamydia and Mycoplasma.
define endometriosis: Is the presence of benign endometrial glands and stroma outside the uterus. Frequently involves ovaries.
define pelvic inflammatory disease: Describes an infection of the pelvic organs that follows extension of a variety of micro-organisms beyond the uterine corpus.

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