3.5 Female repro pathology Flashcards
[neoplasia of the cervix]
Most tumors of the cervix are of epithelial origin and are caused by oncogenic strains of HPV. During development, the ____________ epithelium of the endocervix is joined to the ______________ of the exocervix at the cervical os.
With the onset of puberty, the squamocolumnar junction undergoes _____________, causing the columnar epithelium to become visible on the exocervix. The exposed columnar cells, however, eventually undergo squamous metaplasia, forming a region called the transformation zone, where tumors most commonly arise
columnar mucus-secreting;
squamous epithelial covering;
eversion
[neoplasia of the cervix- pathogenesis]
HPV, the causative agent of cervical neoplasia, has a tropism for the________________. Most HPV infections are transient and are eliminated within months by the host immune response. A subset of infections persists, however, and some cause squamous intraepithelial lesions (SILs), which are precursors from which most invasive cervical carcinomas develop.
HPV is detectable by molecular methods in nearly all cases of cervical intraepithelial neoplasia (CIN) and cervical carcinoma. Important risk factors for the development of CIN and invasive carcinoma thus are directly related to HPV exposure and include:
- _____________
- _____________
- _____________
- _____________
immature squamous cells of the transformation zone;
- Early age at first intercourse
- Multiple sexual partners
- Male partner with multiple previous sexual partners
- Persistent infection by high-risk strains of papillomavirus
[neoplasia of the cervix- pathogenesis]
[neoplasia of the cervix- pathogenesis]
Like most other DNA viruses, HPV uses host cell DNA polymerases to replicate its genome and produce virions. Virions must be shed from the surface of the squamous mucosa, yet under normal circumstances squamous cell maturation is accompanied by a cessation of DNA replication, which would prevent virus production. HPV “solves” this problem through the action of two viral oncoproteins, E6 and E7.
The E6 and E7 proteins of “high risk” HPV variants inhibit _____________, respectively , two potent tumor suppressors that act to suppress the division of squamous cells as they mature. E6 and E7 thus have a central role in the life cycle of HPV and largely explain the carcinogenic activity of HPV in the cervix and other sites that are prone to HPV infection (e.g., vulva, penis, oropharynx).
p53 and RB
[neoplasia of the cervix- pathogenesis]
HPV variants are classified as high-risk or low-risk types based on their propensity to induce carcinogenesis. High-risk HPV infection is the most important risk factor for the development of SIL that can progress to carcinoma. Two high-risk HPV viruses, _____________ account for approximately 70% of cases of SIL and cervical carcinoma. In general, infections with high-risk HPV types are more likely to persist, which is a risk factor for progression to carcinoma. These HPV types also show a propensity to integrate into the host cell genome, an event that is linked to progression.
Low-risk HPV variants (e.g., types __________) associated with the development of condylomas of the lower genital tract , by contrast, express E6 and E7 variants with different or weaker activities and do not integrate into the host genome, remaining instead as free episomal viral DNA.
Despite the strong association of HPV infection with cancer of the cervix, HPV is not sufficient to drive the neoplastic process. As mentioned later, HPV-infected high-grade precursor lesions do not invariably progress to invasive cancer. Diverse other factors such as immune and hormonal status and coinfection with other sexually transmitted agents are suspected to play a role. Collectively these factors favor the acquisition of somatically acquired mutations that involve both oncogenes and tumor suppressor genes.
Viral integration appear to contribute to transformation in two ways: 1) integration always disrupts an HPV gene that negatively regulates E6 and E7, which leads to their increased expression; and 2) sometimes HPV integrates near a ____________ , leading to its overexpression as well.
types 16 and 18,
6 and 11;
host cell oncogene such as MYC
[Squamous Intraepithelial Lesion (SIL, Cervical Intraepithelial Lesion)]
HPV-related carcinogenesis begins with the precancerous epithelial change termed SIL, which usually precedes the development of an overt cancer by many years, sometimes decades. In support of this idea, SIL peaks in incidence at about 30 years of age, whereas invasive carcinoma peaks at about 45 years of age.
The classification of cervical precursor lesions has evolved with time. The current terminology is a two-tiered system that not only reflects the biology of the disease but also patient management, replacing a three-tiered system.
- SIL is divided into low-grade squamous intraepithelial lesion (LSIL), still often referred to as __________________, and high-grade squamous intraepithelial lesion (HSIL), encompassing ___________________ of the previous three-tiered system.
- LSIL is associated with productive HPV infection and does not progress directly to invasive carcinoma. Actually, most LSILs regress and only a small percentage progress to HSIL.
- HSIL demonstrates increased proliferation, arrested epithelial maturation, and lower levels of viral replication. LSIL is not treated as a premalignant lesion, whereas HSIL is considered at high risk for progression to carcinoma.
Importantly, LSIL is 10 times more common than HSIL and while HSILs are precancerous, the majority of them fail to progress to cancer and may even regress. Patient management rests on the histopathologic diagnosis as discussed later.
cervical intraepithelial neoplasia I (CIN I);
cervical intraepithelial neoplasia II and III (CIN II and III)
[Squamous Intraepithelial Lesion (SIL, Cervical Intraepithelial Lesion)- morphology]
What is LSIL characterized by?
LSIL is characterized by dysplastic changes in the lower third of the squamous epithelium and koilocytotic change in the superficial layers of the epithelium.
[Squamous Intraepithelial Lesion (SIL, Cervical Intraepithelial Lesion)- morphology]
What is HSIL characterized by?
- In HSIL (CIN II), dysplasia extends to the middle third of the epithelium in the form of variation in cell and nuclear size, heterogeneity of nuclear chromatin, and the presence of mitoses, some atypical, above the basal layer extending into the middle third of the epithelium. The superficial layer of cells in CIN II still shows differentiation and occasional koilocytotic changes HSIL.
- (CIN III) is marked by almost complete loss of differentiation, even greater variation in cell and nuclear size, chromatin heterogeneity, disorderly orientation of the cells, and abnormal mitoses, changes that affect virtually all layers of the epithelium. Koilocytotic change usually is absent.
[Invasive Carcinoma of the Cervix]
The most common cervical carcinomas are ______________, followed by ____________and mixed adenosquamous carcinomas (20%) and small cell neuroendocrine carcinomas (<5%). All of these types of carcinomas are associated with HPV. Of interest, the relative proportion of adenocarcinomas has been increasing in recent decades owing to the decreasing incidence of invasive squamous carcinoma and suboptimal detection of glandular lesions by Pap smear.
Squamous cell carcinoma has a peak incidence at the age of about 45 years, some 10 to 15 years after detection of precursor SIL. As already discussed, progression of SIL to invasive carcinoma is variable and unpredictable and requires HPV infection as well as mutations in tumor suppressor genes and oncogenes. Risk factors for progression include cigarette smoking and human immunodeficiency virus (HIV) infection, the latter finding suggesting that immune surveillance plays a role in preventing progression. Although risk factors may help identify patients who are likely to progress from SIL to carcinoma, the only reliable way to monitor the disease course is with ________________.
squamous cell carcinomas (75%);
adenocarcinomas ;
frequent physical examinations coupled with Pap smears and biopsy of suspicious lesions.
[Invasive Carcinoma of the Cervix- morphology]
Invasive carcinomas of the cervix develop in the transformation zone and range from microscopic foci of stromal invasion to grossly conspicuous exophytic tumors.
Microscopically, the invasive tumors often consist of ______________ that produce a desmoplastic stromal response. Grading is based on the ________________, which ranges from minimal to well-differentiated tumors that elaborate keratin pearls.
Rare tumors with neuroendocrine differentiation resemble ______________ morphologically.
Tumors encircling the cervix and penetrating into the underlying stroma produce a ____________, which can be identified by direct palpation.
Extension into the parametrial soft tissues can affix the uterus to the surrounding pelvic structures. The likelihood of spread to pelvic lymph nodes correlates with the depth of tumor invasion and the presence of tumor cells in vascular spaces. The risk of metastasis increases from less than 1% for tumors less than 3 mm in depth to more than 10% after invasion exceeds 3 mm.
tongues and nests of squamous cells;
degree of squamous differentiation;
small cell carcinomas of the lung;
barrel cervix
what is the presentation for someone with invasive carcinoma of the cervix?
Invasive cervical cancer most often is seen in women who have never had a Pap smear or who have not been screened for many years. In such cases, cervical cancer often is symptomatic, with patients coming to medical attention for unexpected vaginal bleeding, leukorrhea, painful coitus (dyspareunia), or dysuria
what is the primary treatment for someone with invasive carcinoma of the cervix?
The primary treatment is hysterectomy and lymph node dissection; small microinvasive carcinomas may be treated with cone biopsy. Radiation and chemotherapy are also of benefit in instances where surgery alone is not curative. Mortality is most strongly predicted by tumor stage and, in the case of neuroendocrine carcinomas (which pursue an aggressive course) to cell type.
[Endometrial Hyperplasia]
An _____________, if sufficiently prolonged or marked, can induce exaggerated endometrial proliferation (hyperplasia), which is an important precursor of endometrial carcinoma. A common cause of estrogen excess is obesity, as adipose tissue converts steroid precursors into estrogens. Other potential causes of estrogen excess include _______, _____________, ______________________.
Endometrial hyperplasia is placed in two categories based on the presence of cytologic atypia: hyperplasia without atypia and hyperplasia with atypia . The importance of this classification is that the presence of cytologic atypia correlates with the ______________.
Hyperplasia without cellular atypia carries a low risk (between 1% and 3%) for progression to endometrial carcinoma, whereas hyperplasia with atypia, also called _______________, is associated with a much higher risk (20%–50%). When hyperplasia with atypia is discovered, it must be carefully evaluated for the presence of cancer and usually warrants a ______________ in patients no longer desiring fertility. In younger patients, treatment with_____________ may be used in an attempt to preserve the uterus.
Unopposed estrogen is also a risk factor for the most common type of endometrial carcinoma (see later), and inactivation of the PTEN tumor suppressor gene has been identified at a substantial frequency in hyperplasia with atypia (approximately 50%) and endometrioid carcinoma (>70%). Along with clinicopathologic and epidemiologic studies, these findings indicate that hyperplasia with atypia is a precursor lesion for endometrioid endometrial carcinoma.
excess of estrogen relative to progestin;
failure of ovulation (such as in perimenopause), prolonged administration of estrogenic steroids without counterbalancing progestin, and estrogen-producing ovarian lesions (such as polycystic ovary syndrome and granulosa-theca cell tumors of the ovary).
development or concurrent finding of endometrial carcinoma;
endometrial intraepithelial neoplasia (EIN);
hysterectomy;
high-dose progestins
what is the most common type of endometrial cancers?
Endometrial carcinoma can be broadly divided into two histologically and pathogenically distinct categories: endometrioid and serous carcinoma. There are other less common types of endometrial carcinoma, such as clear cell carcinoma and mixed Mullerian tumor (carcinosarcoma). The endometrioid type accounts for 80% of cases of endometrial carcinomas. These tumors are designated as endometrioid because of their histologic similarity to normal endometrial glands.
In what setting does endometriod cancers arise?
estrogen excess in the setting of endometrial hyperplasia in perimenopausal women
In what setting does serous endometrial cancers arise?
endometrial atrophy in older postmenopausal women
