|Written||2004-11||Roberta Vanni, Giuseppina Parodo|
|Dip. Scienze e Tecnologie Biomediche, Sezione di Biologia e Genetica, Università di Cagliari, Cittadella Universitaria, 09142 Monserrato (CA), Italy|
(Note : for Links provided by Atlas : click)
|Phylum||Female organs: Uterus::Uterus tumor|
|WHO/OMS Classification||Female organs|
|Note||Anatomically, uterine neoplasms may be localized at the corpus, isthmus (the transition between the endocervix and uterine corpus) and cervix. The fallopian tubes and uterine ligaments may also undergo tumour tranformation. This overview will focus on uterine cervix and corpus tumours, including benign, pre-malignant and malignant lesions. They may affect the endometrium, muscles or other supporting tissue. Uterine tumours may be histologically typed according to several classification systems. Those used most frequently are based on the WHO (World Health Organization) International Histological Classification of Tumours and on the ISGYP (International Society of Gynecological Pathologists). The most widely-accepted staging system is the FIGO (International Federation of Gynecology and Obstetrics) one.|
| According to WHO recommendations, the main UTERINE CERVIX categories are:
The main UTERINE CORPUS categories, once again according to WHO recommendations, are:
3. Clinics and Pathology
|Note||Female pelvic gynaecological malignancies account for almost 15% of all cancers in women. Uterine cancer is the most common, specifically endometrial cancer of the uterine corpus.|
|Disease||UTERINE CERVIX NEOPLASIA|
|Note|| In countries that have well-developed screening programs using the Papanicolaou smear test to detect premalignant lesions, the incidence of invasive cervical cancer continues to decline. Age-standardised incidence rates vary from about 10 per 100,000 in most developed countries to more than 40 (up to 100) per 100,000 in many of the developing countries. Worldwide, invasive cervical cancer is the second most common female malignancy after breast cancer, with 500,000 new cases diagnosed each year. |
Among benign lesions, endocervical polyps are the most common, while among malignant lesions,
|Etiology||Carcinomas of the uterine cervix are thought to arise from precursor lesions, and different subtypes of human papilloma virus (HPV) are major etiological factors in disease pathogenesis. Only certain types of HPV cause cervical cancer: HPV 16, 18, 33, 35, 45, 56, called high-risk types, are associated with high-grade Squamous Intraepithelial Lesions (SIL) and invasive carcinomas, whereas low- risk HPV 6, 11, 42, 44 are associated with genital condyloma and low-grade SIL. 5% of cervical cancers are HPV DNA-negative.|
|Epidemiology||Epidemiologic studies report that factors increasing the likelihood of exposure to HPV, such as young age at first intercourse, a large number of sexual partners, race, high parity and low socioeconomic status, favour cervical cancer development. Latin America, the Caribbean, southern Asia, southeast Asia, and sub-Saharan Africa are areas with the highest incidence.|
|Clinics||Early cervical cancer is usually asymptomatic. Approximately 80-90% of patients with cervical cancer experience abnormal vaginal bleeding. HPV causes a large spectrum of lesions ranging from relatively benign condyloma acuminatum to invasive squamous cell carcinomas.|
|Pathology|| Epithelial neoplasia|
Endocervical polyp is the most common benign lesion found in the uterine cervix. It appears as a focal hyperplastic protrusion of the endocervical folds, including the epithelium and the stroma. Microscopically, a variety of histologic patterns are observed, depending on the prevalence of the tissue type. In situ or invasive carcinomas do not usually arise from this lesion.
Fibroepithelial polyp, or stromal polyp, is a benign exophytic proliferation of the cervical stroma. It is composed of stellate-shaped cells growing chaotically, covered by stratified squamous epithelium, and is often seen in pregnant women.
Microglandular hyperplasia is a common cervical lesion associated with oral contraception or with pregnancy in young women.
Squamous intraepithelial lesion (SIL) is a precursor of squamous cell carcinoma and usually remains inactive for more than 20 years before it becomes invasive. SIL usually affects the transformation zone near the endocervical epithelium.
Three different diagnostic systems are used: - CIN (Cervical Intraepithelial Neoplasia, CIN I, CIN II, CIN III), - SIL (Low grade SIL -LSIL - High grade SIL - HSIL), - Mild, Moderate or Severe Dysplasia.
Mixed epithelial and mesenchymal neoplasia:
Secondary tumours are uterine cervix tumours originating outside the cervix.
|Treatment||Precancerous changes in the cervix may be treated with cryosurgery, cauterization or laser surgery. Cervical conization may eventually prove to be therapeutic in many patients. Depending on the stage of the disease, surgery (early invasive cancer), combined with radiation, thermotherapy or chemotherapy (more advanced cases), are treatments of choice.|
|Prognosis||Early-stage cervical cancer and precancerous cervical conditions are almost 100% curable. The five-year relative survival rate for earliest-stage cervical cancer is 91%. Although death rates fell by 74% between 1955 and 1992 and continue to drop by about 2% a year, invasive cervical cancer continues to register significant morbidity and is a major cause of cancer deaths in women worldwide. Very recently, a predictive score system that separates the thermoradiosensitive group from the thermoradioresistant group of advanced cervical cancer has been developed on the basis of the expression profiles of 35 genes, selected by cDNA microarray analysis.|
|Disease||UTERINE CORPUS NEOPLASIA|
|Note|| Uterine cancer is the fourth most common malignancy in women, following breast cancer, lung and colorectal cancer. However, as it is usually detected in early stages, it is not a common cause of cancer deaths. The most common corpus malignancy is the endometrial carcinoma (approximately 95%.); sarcomas represent only 4% and heterologous tumors such as rhabdomyosarcomas, osteosarcomas and chondrosarcomas the remaining 1%.|
The most common corpus benign tumor is leiomyoma, a proliferation of mesenchymal origin, occurring in approximately 77% of women of reproductive age, according to a study on serial uterine sections.
|Etiology||The main risk factors for uterine corpus malignancy are obesity, nulliparity, late menopause, diabetes, hypertension and radiation therapy. 10-25% of patients with mesenchymal malignancy report the administration of pelvic radiation 5 to 25 years earlier. Benign endometrial neoplasia, such as endometrial polyps, hyperplasia and adenocarcinoma, may be associated with tamoxifen therapy, possibly mediated through its agonistic estrogenic properties. As regards leiomyoma, evidence supports genetic susceptibility. Concerning gestational trophoblastic diseases, hydatiform moles arise from abnormal conceptions and most choriocarcinoma and placental site trophoblastic tumours develop following complete moles.|
|Epidemiology||The incidence of uterine malignancy varies widely throughout the world, with lower rates occurring in developing countries and higher rates in industrialized ones. Benign neoplasia, specifically leiomyomas, most commonly occur in women aged 35-49 years, but can be seen at any time between menarche and menopause. They are more common in black than in white women (3-9:1).|
|Clinics||Onset is frequently accompanied by metrorrhagia, menometrorrhagia, spotting and irregular bleeding, for both benign and malignant lesions, including trophoblastic diseases. Early pathological proliferation may sometimes be asymptomatic. Pain and pelvic pressure are usually manifestations of advanced disease.|
|Pathology|| Epithelial neoplasia: |
These tumours arise primarily from two distinct tissues: myometrial muscle (leiomyosarcoma) and endometrial stroma (mesodermal and stromal sarcomas).
Mixed epithelial and mesenchymal neoplasia:
Gestational trophoblastic tumors:
Gestational trophoblastic tumors are neoplastic disorders arising from placental trophoblastic tissue after abnormal fertilization.
Secondary tumours are uterine corpus tumours originating outside the uterus.
|Treatment|| The vast majority of uterine corpus malignant tumours are highly curable since they present early symptoms and may often be diagnosed precociously. Knowledge of the surgicopathologic, as well as clinical, staging is crucial in developing an appropriate management plan. Surgical therapy is usually necessary for the majority of endometrial malignancies. Other adjuvant/adjunctive therapies such as radiation therapy, chemotherapy and hormonal therapy may be considered.|
Treatment for benign uterine corpus lesions depends on the symptoms, tumor size and location and age of the patient
|Prognosis|| Prognostic significance of hormone receptors in endometrial cancer has been reported; moreover, immunohistochemistry for both estrogen and progesterone receptors has been shown to correlate with FIGO grade as well as survival. HER-2/neu overexpression has been reported to be associated with a poor prognosis. Endometrioid adenocarcinoma and adenosquamous carcinoma have the highest overall 5-year survival rates. (respectively 76% and 68%), clear cell and papillary serous carcinomas the lowest (respectively 51% and 46%).|
The evolution of sarcoma depends primarily on the extent and stage of the disease at diagnosis. Recurrences are very frequent. The overall 5-year survival rate is 15-25%.
Among benign neoplasias, endometrial polyps may undergo malignant tranformation, while leiomyomas usually do not.
|Note|| The vast majority of endometrial cancers are sporadic. However, hereditary predisposition to develop uterine carcinoma is associated with hereditary non-polyposis colorectal carcinoma (HNPCC) and Cowden syndrome.|
Germline mutations of the FH (fumarate hydratase) have been found to be involved in syndromes associated with uterine leiomyomas. Evidence supports the existence of genetic factors predisposing to non-syndromic uterine leiomyoma, although susceptibility genes have not yet been identifed.
| UTERINE CERVIX: |
Karyotypic analysis on uterine cervix lesions is limited. No specific chromosome changes have been reported, although most lesions show cytogenetic abnormalities, including polyploidy. Chromosomes 5 and 17 are those most frequently involved in changes in carcinomas. UTERINE CORPUS:
|Cytogenetics Molecular|| |
UTERINE CERVIX. A pronounced chromosomal instability in advanced cervical carcinomas has been observed by comparative genomic hybridization (CGH.). CGH profiles show 2q33-q37 deletions and 3q gains as characteristic changes. FISH analysis on squamous cell carcinoma showed an increased DNA copy number in chromosomes 3 and X in the development and progression from HSIL to cervical carcinoma.
5. Genes involved and Proteins
|Note|| Notch1 exerts specific protective effects against HPV-induced transformation through suppression of E6/E7 expression. In high-grade HPV-positive cervical lesions , down-regulation of the cell signaling molecule Notch1 allows for increased expression of E6 and E7 oncogenes, which promote malignant cervical cell transformation. |
A putative progression model for sporadic endometrioid adenocarcinoma developing through atypical endometrial hyperplasia has recently been proposed. Tumour initiation and progression are characterized by the acquisition of various molecular alterations. In this model, the most frequent, earliest events are the mutation of PTEN and K-ras, possibly followed by inactivation of e-cadherin (playing a role in progression) and later by p53 mutations, overexpressin of her/neu and inactivation of p16. An alternative pathway may lead directly to a high-grade tumour type by p53 mutation and her2/neu amplification, respectively.
Mutations in the MSH2/MSH6 complex seem to play a central role in endometrial carcinoma associated with HNPCC .
Fusion of the JAZF1 and JJAZ1 genes is found in endometrial stromal lesions, possibly restricted to the classic histologic subset.
Intragenic PTEN mutations are involved in the genesis of uterine carcinosarcomas with endometrioid-type carcinoma components.
Complete moles show overexpression of several growth factors, including c-myc, epidermal growth factor, and c-erbB2, as compared to a normal placenta. On rare occasions, complete moles may be familial, inherited as an autosomal trait: they are biparental in origin and result from misexpression of imprinted genes. A candidate region of chromosome arm 19q13.4 has been identified.
Germline mutations of the fumarate hydratase (FH) gene, located at 1q42.1, are involved in syndromic uterine leiomyomas. Very recently, loss of the FH gene has been demonstrated in a subgroup of nonsyndromic uterine leiomyoma characteried by 1q rearrangements.
Dysregulation of the HMGA2 (12q15) and HMGA1 (6p21.3) genes has been observed in uterine leiomyomas, as well as in endometrial polyps.
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|This paper should be referenced as such :|
|Vanni, R ; Parodo, G|
|Uterus tumours: an overview|
|Atlas Genet Cytogenet Oncol Haematol. 2005;9(1):44-50.|
|Free journal version : [ pdf ] [ DOI ]|
|On line version : http://atlasgeneticsoncology.usal.es/classic/Tumors/UterusTumOverviewID5157.html|
8. External links
|REVIEW articles||automatic search in PubMed|
|Last year articles||automatic search in PubMed|
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