ABNORMAL SMEAR TEST AND MANAGEMENT OF ORAL CANCER PRECIOUS LESIONS
Cervical cancer is the second most common gynecological cancer in developed countries and the leading cause of cancer death in developing countries. Although the incidence and mortality rates have decreased significantly in the last 50 years; continues to be an important health problem worldwide. Effective screening programs and effective treatment of pre-cancer (pre-invasive) diseases are held responsible for the decrease in the incidence and mortality rates.
When we look at abnormal pap-test (smear) results in general, approximately 4.5% of the screened population has ASC (ASC-US and ASC-H), 1.5% LSIL, 0.5% HSIL, 0.3% AGC/AIS, and 0.3% Cancer is detected in 0.02 of them. (According to the Breast & Cervical Cancer Early Detection Program report, the frequency of abnormal smears is approximately 6%).
Patient Management in Cytological Abnormalities
ASC-US (aka Borderline smear) is the most frequently reported cytological (cellular) abnormality (mean 4%) in pap-smears. Human Papilloma Virus (HPV) is positive in 86% of ASC-US cases. When biopsy is performed, Cervical Intraepithelial Neoplasia (CIN) is detected in approximately 10% of cases and cervical (cervical) cancer is detected in 0.1-0.2% of cases.
According to the guidelines of ASCCP (American Society of Colposcopy and Cervical Pathology), initial management of women with ASC-US can be in 3 ways: direct colposcopy, HPV-DNA test or repeat cytology (smear) (at 6 and 12 months). . The recommended initial approach in women of childbearing age is HPV-DNA testing and colposcopy if HPV is positive. If a CIN lesion is detected in colposcopy, an approach is taken as recommended by the ASCCP guide. If CIN is not detected, HPV positive cases are followed up with cytology (at 6 and 12 months) or HPV-DNA test (at 12 months). If ≥ ASC-US or HPV (+) in the follow-up, colposcopy is repeated, if the tests are negative, routine screening is started (See recommendations of the American Cancer Society and ACOG for routine screening).
In post-menopausal (post-menopausal) cases with ASC-US, the most appropriate initial approach is repeat smear after intra-vaginal (applied to the vagina) estrogen therapy (1 week after the treatment is completed), although immediate colposcopy or HPV-DNA testing may also be acceptable. are approaches.
Due to the high self-healing (clearance) rates; For adolescents (≤20 years), repeat smear after 12 months is the recommended approach (the same approach is also used in Adolescent LSIL). If ≥ HSIL is detected in this smear, colposcopy is performed. If ASC-US or LSIL is reported, repeat cytology after 12 months. If ≥ ASC-US is reported this time, colposcopy is performed; If there is a negative smear, routine screening is started.
ASC-H should evoke a more negative situation than ASC-US. CIN 2/3 is found in 24-94% (mean 50%) when biopsy is performed on women with this cytological abnormality. On the other hand, HPV positivity rate in these cases is lower than ASC-US (60-85%). For these reasons, HPV-DNA testing has no role in the initial management and the recommended initial approach is immediate colposcopy. If CIN 2/3 is not detected after colposcopy, follow-up is continued with cytology or HPV-DNA test as in ASC-US.
LSIL is the second most common (1.5%) reported cytological abnormality. In the biopsy, CIN 1 is detected in approximately 50% of the cases, CIN 2/3 in 20% and cancer in 0.1%. 85% of cases are HPV positive. Colposcopy (and guided biopsy) is the recommended initial approach. If CIN 2/3 is not detected after colposcopy, it is followed by cytology or HPV DNA test as in ASC-US and ASC-H.
Colposcopy in pregnant women with LSIL can be delayed until after delivery. If colposcopy is performed and CIN 2/3 is not detected, post-partum monitoring is discontinued. Postmenopausal cases are managed like ASC-US. In adolescents, the preferred approach is cytological follow-up; Colposcopy is performed only if the abnormality persists at follow-up, HSIL is detected, and cancer is suspected.
The mean frequency of HSIL is 0.5%, with CIN 2/3 in 70-75% and cancer in 1-2% of women with this cytological abnormality reported. The initial approach recommended in HSIL is immediate colposcopy+ECC (endocervical curettage). “See & treat” approach can also be applied by performing LEEP. If colposcopy is sufficient and CIN 2/3 is not detected, observation (observation with colposcopy and cytology at 6-month intervals for 1 year) or LEEP method can be selected (Or as a third alternative, cytology, biopsy and colposcopy results are reviewed). If the observation method is chosen, if negative cytology is obtained in both visits, routine screening is started. If HSIL is detected in any of the visits, LEEP is performed. If colposcopy is not sufficient, LEEP should be performed.
Only colposcopic biopsy is recommended for CIN 2/3 and suspected cancer in pregnant women (ECC is contraindicated, not performed). Colposcopy is not required in pregnant women (even if CIN 2/3 is detected) until delivery.
Treatment is not recommended unless biopsy-confirmed CIN 2/3 is detected in adolescents. Unlike adult HSIL, the “see and treat” approach is not an appropriate approach in adolescent HSIL.
Glandular Cell Abnormalities (AGC, AIS, Adenocarcinoma)
AGC is the cytological abnormality reported in an average of 0.3% of pap-smears. However, it should be kept in mind that the sensitivity of pap-test in showing glandular (gland cell) abnormalities is lower (50-72%). In the biopsies of women with AGC reported in Pap-smear, 8.5% CIN 1, 11% CIN 2/3, 3% AIS, 1.5% endometrial hyperplasia (abnormal cellular increase in the uterus) and 5.2% cancer were detected (AGC-NOS smears have CIN 2/3, AIS or cancer is detected in an average of 20%) (this rate varies between 25-95% in the AGC-favor neoplasia group). Although AIS is reported less frequently in Pap-smears, this cytological abnormality means endocervical AIS in 60% and invasive cervical adenocancer in 40%. In addition, 50% of AIS cases also have accompanying squamous lesions.
When AGC cytology is reported; if it is specified as “Atypical Endometrial Cells”, it starts with endometrial and endocervical biopsy. If endometrial pathology is not detected, colposcopy is performed. In all other categories, it starts with colposcopy + HPV DNA test + ECC +/- endometrial biopsy (endometrial biopsy is absolutely necessary in those with >35 Y, bleeding and reported AIS).
If glandular lesion or CIN is detected in biopsy in those reported with AGC-NOS, appropriate treatment is approached. If no lesion (glandular or squamous) is detected in the biopsy, action is taken according to the HPV status (the ones whose HPV status is unknown are followed up with a total of 4 cytology repeats at 6-month intervals, HPV negative ones are followed up with cytology repeat and HPV test at 12 months, HPV positive ones are 6. They are followed up with repeat cytology and HPV test in 1 month. If ASC or more severe abnormality is reported in the tests or if HPV is positive, colposcopy is performed, if both tests are negative, routine screening is started). If the initial cytological diagnosis is AGC-favor neoplasia or AIS and no invasive disease is detected in the biopsy, the diagnostic excisional procedure is performed.
Cold conization (CKC) is recommended instead of LEEP as a diagnostic excisional procedure, especially in AIS cases. LEEP was associated with a high rate of positive margin (surgical margin) status (if the margin is positive in a case with AIS, this means 25% residual AIS and 2% residual cancer). In margin-positive cases, CKC is recommended again to rule out invasive cancer before performing a hysterectomy. While AIS cases without fertility desire are treated with hysterectomy; Those who desire fertility can be followed-up by performing a biopsy every 6 months.
Treatment Methods in Abnormal Smear and Precancerous Lesions
Treatment approaches of pre-invasive cervical lesions can be grouped under 4 main headings, not counting the option of follow-up without treatment. These are: local (local) ablative treatments (Cryotherapy, Laser ablation, Electrocoagulation), local excisional (tissue removal) treatments (LEEP, laser conization, cold conization), hysterectomy, and medical (with medication) treatments. In appropriately selected cases, the cure rates of ablative and excisional treatments are similar and are around 90-98%. Excisional treatments have the advantage of obtaining specimens for histological examination and margin evaluation. Ablative treatments are not appropriate in ECC positive cases, glandular lesions and high grade squamous (CIN 3) lesions. After excisional treatments, the rate of residual disease is generally 45%.
If we look at the morbidity (negative effects) of local treatments; In general, morbidity seems to be slightly higher in excisional methods. The risk of early hemorrhage (bleeding) is given as 4-5% in CKC, 1.3% in LEEP, and 1.7% and 0% in laser ablation and cryotherapy, respectively. In terms of long-term adverse effects, the risks of pregnancy-related morbidity (preterm delivery, PROM, cervical insufficiency, LBW) and cervical stenosis (cervical canal stenosis) increase approximately 2 times in all excisional procedures. According to the findings obtained from studies with weak evidence level, ablative methods do not increase pregnancy-related morbidity.
The tissue healing process is 6-10 weeks after treatment; therefore, cytology is not recommended especially in the first 6 weeks (inflammatory reaction: cytological diagnosis difficulty!). Patients should be followed up regularly to exclude residual disease and detect possible recurrence. Since it is difficult to diagnose residual disease with a single pap-test, serial follow-up is required. In the follow-up, the first pap-test is done at 6 weeks (and repeated at 3-month intervals in the first year, with 6-month periods in the second year). In addition, annual HPV-DNA testing is performed because recurrence is more common in cases with persistence of HPV.
Cryotherapy is a simple, portable, inexpensive, safe and well tolerated method that is highly effective in ablating (melting) small lesions located in the ectocervix (outer surface of the cervix). The cryotherapy probe cools the tissue down to -85 ºC and at a depth of 4-6 mm. With the effect of cold, dehydration, crystallization, denaturation of membrane (cell membrane) proteins, thermal shock and vascular stasis occur in cells. In this method, the “double freeze” technique is generally used. The total processing time is 15-20 minutes and it is relatively time consuming. In order of frequency; cramp-like pain, prolonged (2-4 weeks) vaginal discharge, spotting-like bleeding, necrotic plaque syndrome.
laser ablation; It is an ablative method that is expensive, difficult to maintain, requires training, and has no superiority over cryotherapy. Electrocoagulation is not used much nowadays.
LEEP (Loop Electrosurgical Excision Procedure) / LLETZ
LEEP is the most commonly used and most popular method. In this method, the Transformation Zone-TZ (active cellular change zone) is excised (removed) in the form of a ring. It is a method that is easy to apply, does not take time (approximately 1 minute after the patient is prepared), and has a high efficiency (91-98%). Following the application of local anesthetic (preferably containing vasoconstrictive-vascular astringent-agent), an excision is performed at a depth of approximately 1 cm, with the loop direction at 9→3 o’clock or 12→6 o’clock position. If more endocervix (cervical canal tissue) needs to be removed, a second loop (loop) is taken. The loop is removed intact (without deforming) as a single piece and marked at 12 o’clock and sent to Pathology (to guide the pathologist for examination and margin evaluation). Lugol application (Schiller test) during the procedure can be a guide in selecting dysplastic (containing abnormal cells) areas. The use of a metal speculum should be avoided during LEEP in order to prevent thermal damage to surrounding organs. It is also recommended to use an aspirator to prevent inhalation (breathing) of HPV particles by the practitioner. When the procedure is completed, bleeding areas (if any) are controlled with Monsel solution (ferric subsulfate), silver nitrate, buffer or electrocautery (Ball type probe) methods.
The “see & treat” approach is not recommended for visible lesions (suspected non-CIN lesion!) and LSIL (overtreatment!). This approach may be an appropriate approach with an acceptable (mean 10%) negative histological result (overtreatment) in adult HSIL.
Cold conization is preferred especially in lesions exceeding LEEP capacity (endocervical localized lesion, ECC positivity or ectocervix lesion with endocervical extension more than 1.5 cm), in cases where there is suspicion of microinvasion and in glandular pathologies. Here, the cervical tissue in the form of a cone with the base down and the top up is removed with a scalpel. Because of the possibility of bleeding (~5%) after the procedure, “pre-conization cerclage” application is recommended. The incision is made 3-4 mm outside the TZ. As mentioned before, especially in wide excisions (>15 mm conization), subsequent fertility and pregnancy-related morbidity increase.
Medical (Drug) Treatment Methods
These; Photodynamic therapy can be listed as 5-FU, Imiquimod, Retinoids (Isotrenytoin) and INF (α and γ) therapy. It is reported that the best results regarding medical treatments are obtained with topical INF application. However, medical methods in the treatment of cervical pre-invasive lesions remain mostly as research subjects (experimental) today.
In the treatment of pre-invasive lesions, hysterectomy is applied in very special cases. >40 years of age (alone is not sufficient), those with no desire for fertility (alone not sufficient), patients who cannot come to follow-up, the presence of other concomitant pathology requiring hysterectomy, residual lesion after excisional procedures, when AIS is reported, and finally Hysterectomy is indicated when microinvasion is detected.
In the management of microinvasive disease (FIGO IA1 and IA2), the patient’s fertility status, the degree of vertical and horizontal spread of the lesion (IA1 or IA2), margin status (negative or positive), and LVSI status (with LSVI or without LVSI) are determinants of the treatment modality. For example; In IA1, LVSI (-) and marginal (-) cases, conization alone (without lymphadenectomy) was sufficient both as a standard approach and as a fertility-preserving option; An IA1 and LVSI (+) case is treated with “Type 1 Hysterectomy + lymphadenectomy” or “Radical Trachelectomy (Dargent operation) + lymphadenectomy” according to her fertility status and desire.
As a result; The management of cervical cytological abnormalities and pre-invasive lesions should be done in accordance with the ASCCP guidelines and to meet the individual needs of the patient. Colposcopy (and directed biopsy) is the most important tool in management (colposcopy is the recommended initial approach for all cytological abnormalities in adults except ASC-US). The treatment method to be chosen (ablative, excisional, other) should also be specific to the patient and the pathology detected. More conservative approaches are almost always preferred in adolescents and pregnant women. It is important for the Gynecologist and Pathologist to cooperate for effective management and treatment. The gynecologist should deliver the appropriate and sufficient material for the diagnosis to the Pathologist under appropriate conditions and should know how to act in line with the cytological or histological diagnosis reported by the Pathologist. The pathologist should also report the lesion (or cytological abnormality) using current/standard definition systems (Bethesda 2001), provide information about margin status and multifocality/multicentricity in pre-invasive disease, the degree of vertical/horizontal spread of the lesion if microinvasion is present, and whether there is LVSI. should specify.
From the point of view of patients; The patient with an abnormal smear test or cervical biopsy result should consult a specialist who is concerned with the treatment of cervical cytological (cellular) and histological (textual) abnormalities, namely a Gynecological Oncologist, accept in advance that the treatment and follow-ups will sometimes take many years, and take care to comply with the screening and follow-up program recommended by the physician. should show good health, try to keep the immune system and body resistance in good condition and eliminate risk factors to prevent relapses, and finally, still discuss the possibility of HPV vaccination with his physician.
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