Cervical cancer Flashcards
General findings
Cervical cancer is the third most common type of cancer amongst US women. In the United States, its incidence and mortality is well below that of breast, lung, endometrial, colon, and ovarian cancer. The mortality and incidence of cervical cancer have significantly declined after the introduction of routine Papanicolaou (Pap) smear screening. Cervical cancers are most often squamous cell carcinomas that arise from infection with a high-risk human papillomavirus (HPV) serotype. Consequently, the risk factors for cervical cancer are the same as those for HPV (e.g., early onset of sexual activity, multiple sexual partners, history of STDs, and immunosuppression). Growth of cervical carcinoma is preceded by cervical intraepithelial neoplasia (CIN), which can be detected via Pap smear. In the US, Pap smears are recommended for women between the ages of 21 and 64 and are subsidized for uninsured patients. Another method of prevention is vaccination against HPV. Currently, the HPV vaccine is recommended for individuals aged 9–45. Primary (i.e., vaccination) and secondary (i.e., screening) prevention are particularly important given that most patients are asymptomatic during early stages. Advanced cervical cancer typically presents with vaginal bleeding, pelvic pain, and/or lower back pain. Colposcopy, which allows for a cervical biopsy to be obtained, is a valuable diagnostic procedure. Lesions consisting of a high-grade CIN may be excised using conization. The treatment of invasive cervical cancer includes a combination of surgery, radiation therapy, and/or chemotherapy, depending on the stage of disease.
Epidemiology
Incidence of gynecological malignancies :
- Endometrial
- Ovarian
- Cervical (Most common gynecological cancer worldwide because of poor screening and prevention.)
Mortality rate due to gynecological malignancies in the United States 1.Ovarian 2.Cervical 3.Endometrial Mean age at diagnosis: 48 years
Risk factors
1.Early onset of sexual activity; multiple sexual partners (strongest risk factors)
2.Nulliparità o prima gravidanza tardiva
3.Immunosuppression (e.g., HIV infection)
4.History of sexually transmitted infections (e.g., herpes simplex, chlamydia)
5.Cigarette smoking and/or exposure to second-hand smoke (for squamous cell cancer types only)
6.Oral contraceptives 🧨, terapia ormonale sostitutiva! NB
7.Low socioeconomic status
In-utero exposure to diethylstilbestrol (DES) has also been linked to cervical cancer, independently of HPV infection
Infection with high-risk HPV types: 16 , 18
E6 → inhibiton of p53 protein → inhibition of intrinsic apoptotic pathway and inhibition of p21
E7 → Inhibiton of retinoblastoma protein → increased activity of E2F-family of transcription factors
Inhibits p21 and p27 (CDK inhibitors) → increased activity of cyclin-dependent kinase
Clinical features
Patients are usually asymptomatic in early stages. Symptoms commonly first appear in advanced disease!👓
- Abnormal vaginal bleeding: menometrorrhagia, postcoital spotting, irregular vaginal bleeding
- Abnormal vaginal discharge: blood-stained or purulent malodorous discharge (not necessarily accompanied by pruritus)
- Cervical ulceration
- Late symptoms: Tumor spread in this condition commonly occurs per continuitatem to the vagina, bladder, rectum and parametria.
- Hydronephrosis: obstructive nephropathy caused by compression of the ureters
- Compression of veins or lymphatic vessels in the pelvic area, leading to swelling of the lower extremities
Features of disseminated disease: lymphadenopathy or, rarely, abdominal, bone, or chest abnormalities (e.g., pain)
🧨Always consider cervical cancer as a cause of postcoital bleeding!
Pap smear
Attenzione, i COILOCITI sono visibili all’esame istologico non a quello citologico! (A dysplastic squamous cell characterized by a well-defined, clear, balloon-like, perinuclear halo and hyperchromasia. Pathognomonic of HPV infection.)
The proper technique is essential for obtaining highly specific test results.
The specimen is collected using a spatula or brush:
-Scraping of ectocervix
-Scraping of endocervix
A thin layer is uniformly applied to a glass slide.
Immediate fixation using 95% ethyl alcohol (or spray fixative). Avoid air-drying!
Stain with Papanicolaou dye
Interpretation of cytologic smear according to the Bethesda system!
Bethesda system:
1.Specimen unsatisfactory for evaluation
< 30 years: Repeat after 2–4 months if HPV status is unknown
≥ 30 years: Repeat after 2–4 months or perform colposcopy if HPV positive
2.Negative for intraepithelial lesion or malignancy but positive for high-risk HPV type
-Repeat cervical smear and HPV testing after 12
months
3.Atypical squamous cells of undetermined significance (ASC-US)
-21–24 years,Repeat cytology at 12 months
-> 24 years:
Perform HPV test
Positive → colposcopy
Negative → repeat smear and HPV test in three years
4.ASC-H: colposcopy! ( If cytology does not show any obvious cancer, colposcopy (examination of the vagina and cervix with a magnifying lens) can be used to identify areas that require biopsy. Colposcopy-directed biopsy with endocervical curettage is usually diagnostic. If not, cone biopsy (conization) is required; a cone of tissue is removed using a loop electrical excision procedure (LEEP), laser, or cold knife.)
5.LSIL:
-21–24 years, repeat cytology at 12 months
-25–29 years: colposcopy
-≥ 30 years
HPV status negative → repeat smear and HPV test in 12 months
If negative → repeat smear and HPV test in 3 years
If positive → colposcopy
- HSIL:
-21–24 years: colposcopy, then:
If CIN II or CIN III absent
Colposcopy and cytology every 6 months for 2 years
If positive: biopsy
If negative twice: routine screening
If CIN II or CIN III present: See “Treatment” below.
-> 24 years: colposcopy or loop electrosurgical excision
Colposcopia: acido acetico al 3%, test di Shiller (assorbimento di Lugol)
HPV testing (elevato potere predittivo negativo)
Serve per identificare il genotipo HPV (16, 18)
Indications: women > 30 years of age! (nei soggetti immunocompromessi, prima dei 30 anni)
Procedures
PCR: detection of HPV DNA
Histology: presence of koilocytes
Prolonged screening interval: screening every 5 years with HPV co-test (Pap smear + HPV test) instead of every 3 years with Pap smear alone
Pap smear testing and HPV testing (co-testing) are routine once patients reach the age of 30
Cervical carcinoma
Most commonly arises from metaplastic squamous cell epithelium in the transformation zone.
1.Squamous cell carcinoma (∼ 80% of cases) 💥
2.Adenocarcinoma (∼ 20% of cases; increasing incidence)
Subtypes include mucinous, endometrioid, clear cell, and serous adenocarcinoma. The most common is the endocervical mucinous subtype.
-Direct complications of cervical carcinoma
Infiltration of ureter leading to urinary obstruction → hydronephrosis → kidney failure
Fistula formation in locally advanced disease, e.g., rectovaginal, vesicovaginal, urethrovaginal
Compression of veins or lymphatic vessels in the lesser pelvis, leading to congestion in the lower extremities
Cancer anorexia-cachexia syndrome (CACS)
-Complications of radiation therapy
Vaginal stenosis
Radiogenic cystitis/proctitis
Fistula formation
Invasive disease
- For microinvasive carcinoma
- Cone biopsy and follow-up
- OR hysterectomy - For advanced disease: First-line treatment is chemotherapy, radiation therapy, or a combination of both in patients with advanced disease, lymph node metastases, or who are poor surgical candidates.
Staging
NB Il fattore prognostico più importante è lo stadio clinico (da 1 a 4 secondo la stadiazione FIGO)
Cervical cancers are clinically staged based on biopsy, physical examination (clinica) , and chest x-ray results. (see table Bethesda Classification of Cervical Cytology). In the International Federation of Gynecology and Obstetrics (FIGO) staging system, stage does not include information about lymph node status. Although not included as staging, lymph node status is one of the most important prognostic factors in early-stage cervical cancer (stages IA1 to IB1); it is required for treatment planning and affects the radiation therapy field.
If the stage is > IA2, CT or MRI of the abdomen and pelvis is typically done to identify metastases, although results are not used for staging. PET with CT (PET/CT) is being used more commonly to check for spread beyond the cervix. If PET/CT, MRI, or CT is not available, cystoscopy, sigmoidoscopy, and IV urography, when clinically indicated, may be used for staging.
Treatment
Il trattamento chirurgico prevede o la conizzazione (solo IAI) o la isterectomia radicale. Il trattamento chirurgico viene considerato per lesioni al di sotto dei 4 cm. Questo significa: 1A1, 1A2, 1B1, 2A1
Da 1B2 in poi, > 4 cm, radio-chemioterapia
✔Stadio I: tumore confinato all’utero
Carcinoma microscopico
IA1, invasione stromale minore di 5 mm
IA2, in vasione stromale tra 3 e 5 mm
Carcinoma clinicamente visibile IB1, lesione minore di 4 cm IB2, lesione maggiore di 4 cm
✔Stadio II: tumore che supera il collo uterino , ma senza arrivare alla parete pelvica o al terzo inferiore della vagina
IIA1, lesione sotto i 4 cm, no parametrio IIA2, invasione parametrio
💥Nello stadio IAI, se non c’è evidenza di coinvolgimento linfonodale non si fa linfadenectomia. La linfadenectomia sempre invece da stadio IA2 in poi.
- Excision or curative radiation therapy if there is no spread to parametria or beyond
- Radiation therapy and chemotherapy if there is spread to parametria or beyond
- Chemotherapy for metastatic and recurrent cancer
Treatment of cervical cancer may include surgery, radiation therapy, and chemotherapy. If hysterectomy is indicated but patients cannot tolerate it, radiation therapy plus chemotherapy is used.
(CIN1: escissione, mentre CIN2 e CIN 3 conizzazione)
✔Cervical intraepithelial neoplasia (CIN) and squamous cell carcinoma stage IA1:
👓Conization or simple hysterectomy!
Microinvasive cervical cancer, defined as FIGO stage IA1 with no lymphovascular space invasion (LVSI), has a < 1% risk of lymph node metastases and may be managed conservatively with conization using LEEP, laser, or cold knife. Conization is indicated for patients who are interested in preserving fertility. Simple hysterectomy should be done if patients are not interested in preserving fertility or if margins are positive after conization.
In cases of stage IA1 with lymphovascular space invasion, conization (with negative margins) and laparoscopic pelvic sentinel lymph node (SLN) mapping plus lymphadenectomy (lymph node dissection) is a reasonable strategy.
✔For stage IA2 or IB1 cervical cancer, the standard recommendation is:
👓Radical hysterectomy with bilateral pelvic lymphadenectomy
✔For stage IB2 to IIA cervical cancer
👓Combined chemotherapy and pelvic radiation
✔Stages IIB to IVA
👓Radiation therapy plus chemotherapy (eg, cisplatin)
✔Stage IVB and recurrent cancer
👓Chemotherapy is the primary treatment, but only 15 to 25% of patients respond to it. (paclixatel, cisplatino)
HPV vaccine (prevenzione primaria)
- Administration of 2 doses of nine-valent HPV vaccine (Gardasil 9) to all individuals between 11–12 years of age
- The 2nd dose should be administered 6–12 months after the 1st dose.
- Immunization can be started as early as 9 years of age. - Administration of 3 doses of nine-valent HPV vaccine to all unvaccinated individuals between 15–26 years of age.
- The 2nd dose should be given 1–2 months after the 1st dose and the 3rd dose 6 months after the first dose.
- Also preferred regimen for vaccination of immunocompromised individuals (e.g., HIV)
!FDA-approved vaccines
- Bivalent vaccine (Cervarix®): protection against high-risk HPV types 16 and 18
- Tetravalent vaccine (Gardasil®): protection against high-risk HPV types 16 and 18, as well as against low-risk types 6 and 11 (most common cause of genital warts)
- Nine-valent vaccine (Gardasil®9): protection against high-risk HPV types 16, 18, 31, 33, 45, 52, and 58, as well as against low-risk types 6 and 11
Barrier protection (condoms) during sexual intercourse
Secondary prevention
< 21 years: no screening required
21–29 years: Pap smear every 3 years
30–65 years: Pap smear every 3 years OR co-testing (Pap smear with HPV test) every 5 years
> 65 years: no more testing required if the previous testing was negative
Immunocompromised women (e.g., HIV) and women with DES exposure but average life-expectancy should continue screening
Screening for women with HIV: Pap smear twice in the first year after HIV diagnosis and annually thereafter
Pregnancy
Cervical cytology should be obtained from women during pregnancy!🧨
1–3% of women suffering from cervical cancer are diagnosed during or shortly after their pregnancy.
Management should take the patient’s wishes into consideration and depends on the stage of pregnancy and disease.
1.Early pregnancy
FIGO IA: Diagnostic conization; vaginal or cesarian delivery possible
If margins are not clear → cesarian delivery and repeat conization postpartum
No microscopic tumor: simple trachelectomy or neoadjuvant chemotherapy depending on tumor size
2.Late pregnancy
FIGO IA-IB1: Treatment may be postponed until after delivery.
Advanced cancer: neoadjuvant chemotherapy or termination of pregnancy
