The Detergents And Disinfectants For Instruments And Surfaces (Hexanios - Surfanios)

CERVICAL INTRAEPITHELIAL NEOPLASIA

• Histopathologically, CIN (used synonymously with dysplasia) is the term for all epithelial abnormalities of the cervix and is a precancerous lesion. Almost all CINs originate from the transformation zone. Progression of CINs to invasive cancer 12-18. It can take months to decades.

Risk Factors for Cervix Pemalignant and Malignant Diseases

• High-risk HPV infections (especially HPV 16 and 18)

• Advanced age

• First coitus at an early age (< 16 years)

• Low socioeconomic level and low education level

• Multiple sexual partners or polygamous women

• High parity number (multiparity)

• Exogenous hormone exposure;

► use of combined oral contraceptives; Increases HPV persistence and oncogene expression.

► Intrauterine DES exposure; The risk of high-grade cervical disease is doubled.

• Smoking

• Obesity

• other sexually transmitted diseases such as HSV type 2 and Chlamydia; are cofactors for HPV

• Chronic immunosuppression; AIDS, transplant patients, immunosuppressive users

• Nutritional disorders; Vitamin A, C, E, beta carotene and folic acid deficiencies

• Race: Black race, Latin American countries

• Inadequate cervical screening

HPV Infection and Tumorogenesis

• More than 99% of squamous cervical cancers contain HPV DNA.

- Low Risk (condyloma): 6, 11,26,42,43,44,54,55,70,73 

- High Risk (HSIL / Cervical cancer):  16, 18, 31, 33, 35, 39, 45, 51, 52, 56,58,59,66,68, 73

• Oncogenic HPV serotypes cause the production of oncoproteins by integrating into the host DNA. Oncoproteins encoded by the genetic part of the oncogenic HPV subtypes E6 and E7 form complexes with the host's anti-oncogenes, p53 and pRB (retinoblastoma protein), respectively, and inactivate them.

• Only persistent HPV infections trigger neoplastic processes. Many HPV infections disappears spontaneously in a 9-15 months, but persistence occurs more in smokers, contraceptive users, malnourished people, and those with new STDs.

• HPV-6 and HPV-11 are weak oncogenes and are frequently observed in condylomas. The most frequently detected HPV types in cervical cancers are 16, 18 and 45, respectively. Among them, HPV-18 has the highest specificity.

Prophylactic HPV Vaccines

• HPV vaccines are created against capsid proteins (especially L1) and virus-like particle technology is used. These particles are empty capsids that do not contain viral DNA and do not contain oncogenic antigens or infectious material. HPV vaccine triggers humoral immunity. Aluminum is used as an adjuvant in HPV vaccines.

• There are three vaccines available; bivalent vaccine, quadrivalent vaccine and nonvalent vaccine. While there are virus-like particles belonging to HPV16 and 18 in bivalent vaccines; Quadrivalent vaccines contain virus-like particles of HPV 6 and 11 in addition to HPV 16 and 18. Nonvalent vaccine contains virus-like particles of HPV 6, 11, 16, 18, 31, 33, 45, 52 and 58.

• Quadrivalent and nonvalent vaccines also reduce the incidence of vulvar condyloma and HPV-related VIN/VAIN. Quadrivalent and nonvalent vaccines also have protection against genital warts in men.

• Vaccines are recommended for routine use in women aged 9-45 years.

• It can be applied during lactation but should not be used in pregnant women. It can also be used in patients with immunodeficiency. Previous sexual activity, history of HPV-related disease and HPV test positivity are not contraindications for vaccination.

• HPV vaccines prevent most HPV-related cancers, but since they do not prevent all, cervical cancer screening should be continued following vaccination.

Screening and Diagnosis

• With cervical cytology (smear) every 3 years in women aged 21-30; Between the ages of 30-65, it is recommended to be screened every 5 years with a co-test, in which HPV DNA and cervical cytology are examined together. Since the smear is a screening test and does not make the diagnosis, the diagnosis is made by cervical biopsy taken with colposcopic examination in patients with abnormal cervicovaginal (PAP) smear results.

Classification

• Smears are evaluated cytologically according to the Bethesda system.

Management in Abnormal Cervical Cytology

Management in Abnormal Cervical Cytology
ASC-US	a. between the ages of 21-24; Repeat smear after 1 year
	If the control smear result is abnormal, colposcopy is performed.
	b. ≥ 25 years; HPV DNA test (reflex test) should be done;
	→ If HPV DNA is negative; Co-test (HPV+ smear) after 3 years
	→ If HPV DNA is positive; colposcopy
	→ HPV DNA test is not available or unknown; Smear follow-up after 1 year
ASC-H	In all patients; colposcopy
L-SIL	a. between the ages of 21-24; Repeat smear after 1 year
	b. ≥ 25 years; The approach is determined according to the result of the HPV DNA test (co-test).
	→ If negative; After 1 year, co-test (HPV + smear) is preferred or colposcopy can be performed.
	→ If positive; colposcopy
	→ HPV DNA test is not performed (co-tested) or unknown; colposcopy
H-SIL	a.21-24 years old; Colposcopy (with endocervical evaluation)
	b. ≥25 years;
	→ Colposcopy (with endocervical evaluation) is preferred
	LEEP (see and treat) is acceptable.
AGC	Colposcopy + endocervical canal curettage and Endometrial biopsy
	→ In patients aged 35 years and over, or
	→ Patients under 35 years of age at risk for endometrial cancer (abnormal uterine bleeding, chronic anovulation)

The co-test should be repeated one year later in patients aged 30 years or older with cytology negative but HPV positive.

Cytology should be repeated after 2-4 months in women with an unsatisfactory cytology result.

In high-risk HPV infections, an increase in p16 level is observed due to the production of E7 oncoprotein. Therefore, immunostaining with p16 can be used as a differential marker in transformed HPV infections. If the immunostaining with p16 is negative in patients with histological diagnosis of CIN II, the risk of progression to CIN III is very low.

TREATMENT

Ablative Treatments

• Among these treatment modalities, cryotherapy, electrocoagulation diathermy

and CO2 laser.

General indications of ablative treatment modalities

1. The lesion should be on the ectocervix and be fully visible.

2. The active (new) squamocolumnar junction should be fully observed.

3. Invasive cancer should not have colposcopic warning signs

4. No cytological or histological evidence of invasive cancer

5. Compatibility of cytology and histology findings

6. No evidence of high-grade disease in endocervical curettage

7. No cytological or histological suspicion of high-grade glandular neoplasia

Excisional Treatments

• These treatment modalities include LEEP, excisional conization, CO2 laser excision and hysterectomy.

General indications of excisional treatment methods

1. Inconsistent (negative or low grade) biopsy results or insufficient colposcopy in patients with high-grade cytology results

2. Having a cytology result in favor of AGC-neoplasia (Atypical glandular cells)or adenocarcinoma in situ

3. Presence of adenocarcinoma in situ histology

4. Presence of high-grade or ungraded CIN or glandular neoplasia in endocervical canal curettage

5. Recurrence following high-grade CIN therapy

Except for adolescents, in H-SIL, if there is no endocervical canal involvement, the treatment method that should be preferred first is LEEP.

Conization indications

1. H-SIL

2. AGC and Adenomacarcinoma in situ

3. Inability to see lesion borders with colposcopy

4. Failure to see the squamo-columnar junction in colposcopy

5. Histologically positive (CIN II-III) endocervical canal curettage (ECC)

6. Significant discrepancies between cytology, colposcopy, and biopsy

7. Suspicion of microinvasive cancer in cytology, colposcopy and biopsy

8. Failure to exclude invasive cancer with colposcopy

Situations where hysterectomy is necessary

1. Concomitant pathology that may require hysterectomy (dysfunctional uterine bleeding, fibroid, prolapse, endometriosis, pelvic inflammatory disease, patient's request for sterilization); It is the most common indication.

2. Having microinvasive cancer

3. Detection of CIN III at the surgical margin of the conization material (in selected patients)

4. His patient's inability to cooperate with treatment demands

5. Recurrent high-grade CIN cases who have completed their fertility, or patients for whom recurrent cervical excision is absolutely indicated but technically impossible

6. Adenocarcinoma in situ without desire for fertility; It is the preferred treatment method and there is an absolute hysterectomy indication.

CIN and AGC Management
CIN I	If the previous smear result is ASCUS or LSIL; FOLLOW-UP between the ages of 21-24; smear after a year 25 years and over; one year later If the previous smear result is ASC-H or HLSIL; EXCISIONAL PROCEDURE
CIN II-III	It must be treated with excisional or ablative procedures.
AGC and adenocarcinoma in situ AIS	Colposcopy-guided cervical biopsy + Endocervical canal curettage (ECC) + If invasive cancer is not detected as a result of endometrial biopsy, conization should be performed. If AIS is detected histologically in conization, hysterectomy should be preferred.

management during pregnancy

► Colposcopy can be performed if necessary to rule out invasive cancer in pregnant women. Colposcopy and ectocervical biopsy are safe during pregnancy, but endocervical canal curettage and endometrial biopsy should not be performed.

► All pregnant women over the age of 21 should be evaluated like the general population in the presence of abnormal smears. However, it is an acceptable approach to postpone the evaluation of ASCUS and LSIL cytology until at least 6 weeks postpartum. Prenatal colposcopy-guided biopsy is recommended for pregnant women with HSIL detected in cervical cytology.

► Regardless of the stage of cervical intraepithelial lesions, treatment can be delayed until the end of pregnancy after excluding invasive cancer. Pregnant women with histological diagnosis of CIN 1 should be followed without treatment. Treatment of CIN2 or CIN3 by ablation or excision is contraindicated during pregnancy. Preinvasive lesions detected during pregnancy are not treated during pregnancy, but should be re-evaluated 6 weeks after pregnancy. Spontaneous regression may occur after birth.

Cervical cancer

• It is the most common gynecological cancer.

• It is the malignancy with the highest chance of early diagnosis and treatment. In addition, HPV vaccines contributed to the decrease in the incidence. It has a long preinvasive period. The mean age of onset is 48, with two peaks (35-39 years and 60-64 years).

Risk factors

risk factors for premalignant and malignant diseases of the cervix

High-risk HPV infections (especially HPV 16 and 18)

Advanced age

First coitus at an early age (< 16 years)

Low socioeconomic level and low education level

Multiple sexual partners or polygamous women

High parity number (multiparity)

Exogenous hormone exposure;

► use of combined oral contraceptives; Increases HPV persistence and oncogene expression.

► Intrauterine DES exposure; The risk of high-grade cervical disease is doubled.

Smoking

Obesity

Other sexually transmitted diseases such as HSV type 2 and Chlamydia; are cofactors for HPV

Chronic immunosuppression; AIDS, transplant patients, immunosuppressive users

Nutritional disorders; Vitamin A, C, E, beta carotene and folic acid deficiencies

Race: Black race, Latin American countries

Inadequate cervical screening

Clinic

• Cervical cancer often remains asymptomatic until advanced disease occurs. The most common symptom of cervical cancer is abnormal vaginal bleeding. These bleedings can be postcoital (most common), intermenstrual or postmenopausal bleeding. Large tumors are often infected before they bleed and can sometimes cause a foul-smelling vaginal discharge.

• In advanced-stage tumors, symptoms such as pelvic pain, symptoms of pressure on the bowel or bladder, or stool or urine coming from the vagina may be seen.

Spread

direct invasion

► Cervical cancers can spread to the cervical stroma, corpus uteri, vagina and parametrium by direct invasion.

lymphatic metastasis

► Lymphatic drainage of the cervix mainly drains into paracervical and parametrial lymph nodes. Lymphatic drainage from paracervical and parametrial lymph nodes is drained to obturator lymph nodes, internal, external, common iliac lymph nodes and finally to paraaortic lymph nodes. Inguinal lymph nodes are not primarily involved.

Lymphatic drainage of the cervix uterine

a) Primary lymph group

1. Paracervical and parametrial nodes (first lymph node involved)

2. Obturator nodes

3. Internal iliac (hypogastric) nodes

4. External iliac nodes

5. Sacral nodes

b) Secondary lymphatic group

1. Major iliac nodes

2. Paraaortic nodes

hematogenous metastasis

► However, it can be seen in the future. By this route, the liver is most frequently followed, followed by the lung.

and bone (especially vertebra) metastases.

Intraperitoneal implantation

Histopathological Classification of Cervical Cancer

I. Epithelial tumors:

A) squamous Cell carcinoma: The most common is invasive cervix  cancer

1. Large cell non-keratinized carcinoma

2. Large cell keratinized carcinoma

3. Small cell carcinoma

a. Poorly differentiated squamous cell carcinoma

b. small cell anaplastic carcinoma

4. Verrucous carcinoma; It is associated with HPV 6 and is associated with condyloma.

5. Papillary (transitional) carcinoma

B) Adenocarcinoma: There is a significant increase in young women and shows endophytic development.

1. Mucinous adenocarcinomas;

a. endocervical

b. intestinal,

c. Minimally deviating adenocarcinoma (Adenoma malignum);

May be associated with Peutz-Jeughers Syndrome

D. Villoglandular papillary adenoacrcinoma; It is frequently observed in pregnant and COC users.

2. Endometrioid adencarcinoma

3. Clear cell adenocarcinoma

4. Serous carcinoma

5. Mesonephric adenocarcinoma

C) Mixed cervical carcinoma:

1. Adenosquamous carcinoma

a. Glassy cell (glassy cell) carcinoma

b. Adenoid basal carcinoma

c. Adenoid cystic carcinoma (cylindroma)

D) Neuroendocrine carcinoma

1. Small cell neuroendocrine carcinoma

2. Large cell neuroendocrine carcinoma

3. Atypical carcinoid

4. Classical carcinoid; Has a good prognosis

II- Mesenchymal tumors (sarcomas)

1. Carcinosarcoma; It is the most common sarcoma of the cervix.

2. Embryonal rhabdomyosarcoma (botryoid sarcoma)

3. Adenosarcoma

4. Leiomyosarcoma

5. Mixed mesodermal sarcoma

III- Other tumors

1. Metastatic tumors;

a. It is frequently involved in endometrial and vaginal cancer, but vaginal cancer is very rare.

b. Tumors in the peritoneal cavity (Over, bladder, colon); It metastasizes over the cul de sac.

c. Breast

D. Stomach

to. Kidney

2. Lymphoma; It is most commonly seen in the cervix in the genital area.

3. Leukemia

4. Malignant melanoma

While HPV 18 is detected in 50% of adenocancers, HPV 18 is detected in 15% of squamous cancers.

Staging

• Staging of cervical cancers is done clinically.

FIGO staging (2018)
Stage 1	Limited carcinoma of the entire cervix
1A	Invasive carcinomas (microinvasive cancer) that can only be diagnosed microscopically and have a depth of invasion <5 mm
1a1	Depth of invasion< 3 mm
1a2	Depth of invasion ≥3 mm <5 mm
1B	Invasive carcinomas of the cervix with a limited depth of invasion (greater than stage IA) of 25 mm
1b1	Depth of invasion ≥5 mm and size of lesion <2 cm
1b2	Lesion size ≥ 2 cm < 4 cm
1b3	Lesion size ≥4 cm
Stage 2	Carcinoma that has invaded the female uterus but has not reached the pelvic wall or lower 1/3 of the vagina
2A	There is no parametrial invasion, but there is involvement in the upper 2/3 of the vagina
2a1	Lesion size < 4 cm
2a2	Lesion size ≥ 4 cm
2B	Tumors with parametrial invasion but no pelvic wall involvement
Stage 3	Has spread to the lower 1/3 of the vagina and/or has spread to the pelvic wall and/or
3A	Carcinoma that has caused hydronephrosis or a dysfunctional kidney and/or has spread to the pelvic and or paraaortic lymph nodes
3B	There is no extension to the pelvic wall, but there is spread to the lower 1/3 of the vagina
3C	Extension to the pelvic wall and/or hydronephrosis or dysfunctional kidney Pelvic and/or paraaortic lymph node involvement, regardless of tumor size and spread (Note: It should be indicated with the symbol 'r' if it is radiologically detected, and 'p' if it is pathologically detected)
3c1	Pelvic lymph node metastasis only
3c2	Paraaortic lymph node metastasis
Stage 4	Carcinomas that have spread to the out of the true pelvis or have biopsy demonstrated invasion of the rectum or bladder mucosa
4A	Spread to neighboring pelvic organs; Invasion of the bladder and/or rectal mucosa (must be shown on biopsy)
4B	Distant organ metastases

Detection of bullous edema in the bladder does not make the stage IVA, mucosal involvement should be demonstrated on biopsy.

Lymphovascular space involvement and endometrial spread do not change the staging of cervical cancer. The amount of horizontal spread of the lesion laterally to the cervix is also no longer used in staging.

Treatment

• Surgery, radiotherapy, chemotherapy and chemoradiotherapy can be applied in the treatment of cervical cancers.

• Since the depth of invasion is important in determining the type of surgical intervention, conization must be applied before the operation is planned in cancers with microinvasion.

• The risk of metastasis to the ovary is 0.9% in early stage cervical cancers younger than 40 years of age and the ovaries can be preserved.

Treatment approach in cervical cancer
stage 1A 1
<3 mm invasion, no lymphovascular area involvement, fertility expectation	conization
<3 mm invasion, no lymphovascular space involvement, no expectation of fertility	Type 1 (extrafacial) Hysterectomy
< 3 mm invasion, lymphovascular area involvement, fertility expectation	Modified radical trachelectomy + Pelvic LND or sentinel LN biopsy
<3 mm invasion, lymphovascular area involvement, no expectation of fertility	Type2 (modified radical) Hysterectomy + Pelvic LND or sentinel LN biopsy
Stage IA 2
>= 3 mm - <5 mm invasion, fertility expected	Modified radical trachelectomy + Pelvic LND or sentinel LN biopsy
>= 3 mm - <5 mm invasion, no expectation of fertility	Type il (modified radical) Hysterectomy + Pelvic LND or sentinel LN biopsy
Stage 1B
>=5 mm invasion - tumor< 2 cm, fertility expected	Modified radical/radical trachelectomy + Pelvic LND or sentinel LN biopsy
>= 5 mm invasion - tumor < 2 cm, no expectation of fertility	Type 2 (modified radical)/Type 111 (radical) Hysterectomy + Pelvic LND or sentinel LN biopsy
Stage 1B2 (>= 2 cm - <4 cm)	Type 3 (radical) Hysterectomy + Pelvic LND
Stage 1B3 (>= 4 cm)	Primary chemoradiation (pelvic area)
Stage IIA1	Type 3 (radical) Hysterectomy + Pelvic LND or Primary chemoradiation (pelvic area RT)
Stage IIA2, 11B, IIIA	Primary chemoradiation (pelvic area RT)
Stage 3B, IIIC 1	Primary chemoradiation (pelvic ±wide field RT)
Stage IIIC2	Primary chemoradiation (pelvic + wide field RT + systemic chemotherapy)
Stage IVA	Primary chemoradiation (pelvic + wide area RT ) or Pelvic exenteration
Stage IVB	Systemic chemotherapy ± radiotherapy (pelvic or modified area)

Radical Trachelectomy

0 It is the removal of only the cervix and also the removal of a part of the parametrium and vagina in cases with cervical cancer with the expectation of fertility. In general, pelvic lymphadenectomy is added to this operation.

Most Frequent indications of radical trachelectomy

• Having a desire to preserve fertility

• Phase;

► Stage IAl cervical cancer with widespread lymphovascular invasion

► Stage IA2 cervical cancer

► Stage IBl cervical cancer with tumor size i2cm and upper endocervical involvement not observed in MRI or frozen examination

• Histological type; Having squamous cell, adenocarcinoma, or adenosquamous carcinoma

• Absence of lymph node metastasis

Prognosis

Prognostic Factors

1. The stage of the disease; The most important prognostic factor

2. Involvement of lymph nodes; It is the best independent indicator of survival.

3. The size of the primary tumor (<2 cm good, 4 cm bad); It is an independent risk factor

4. Depth of invasion (<1 cm good, > 1 cm bad); It is the most important determinant for pelvic lymph node metastasis and recurrence.

5. Parametrial spread

6. Lymphovascular space involvement; May be predictive for lymph node metastasis

7. The condition of the surgical margin in patients undergoing surgery

8. Patient's age

• Adenocarcinomas of the cervix have a much worse prognosis than squamous ones, because these tumors metastasize to near and distant in the early period without symptoms. In addition, adenocancers have a higher risk of metastasis to the ovaries.

Causes of Death in Cervical Cancer Cases

1. Uremia (50-60%)

2. Infection

3. Bleeding

Recurrence

Risk Factors for Recurrence in Cervical Cancers

1. Moderate risk factors

a. Large tumor size

b. Cervical stromal invasion depth in the middle or deep 1/3rd part

c. Presence of lymphovascular space invasion

2. High degree of risk factors

a. positive or adjacent surgical margin

b. positive lymph nodes

c. Microscopic parametrial involvement

• Adjuvant radiotherapy is recommended after surgery in patients with moderate and high risk factors.

Pregnancy and Cervix cancer

• Among genital cancers, the most common malignancy with pregnancy is cervical cancer.

• A smear test should be applied to all pregnant women over the age of 21 at their first visit, and in addition, a direct biopsy should be taken from suspicious lesions during the examination. In case of suspicion of HSIL, adenocarcinoma in situ or malignancy as a result of the smear, a biopsy should be taken with colposcopy.

• If microinvasive carcinoma is reported as a result of biopsy, conization should be performed to clearly identify or rule out invasive disease. Since conization will cause complications for both mother and fetus. It should be done in the third trimester (14-20 weeks).

• Conization is therapeutic in patients with a depth of invasion < 3mm (Stage IA1), no lymphovascular space involvement, and negative surgical margin as a result of conization. Vaginal delivery at term can be accepted in these patients with negative surgical margins.

• In pregnancies with stage IA2 cervical cancer and positive lymphovascular space invasion, stage IA1 cervical cancer pregnancies should be followed by term or lung maturation followed by cesarean section with classical incision followed by Type il hysterectomy (modified radical hysterectomy) + pelvic lymph node dissection.

• In cases with invasive cancer, because pregnancy may adversely affect the prognosis, the necessary treatment for the stage is applied immediately without considering the fetus before the 24th gestational week. In cases with invasive cancer with a gestational week above 24, until lung maturation occurs. (34th week) followed by cesarean section and the necessary treatment for the stage is applied after delivery.

Since vaginal delivery in invasive cancers increases the risk of recurrence, the planned delivery method should be cesarean section.