37Cervical Cancer

CHARACTERISTICS

There are approximately 400,000 new cases of cervical cancer worldwide annually. In 2017 there were 12,820 anticipated new cases identified with approximately 4,210 deaths in the United States.

•   The most common symptom of cervical cancer is abnormal vaginal bleeding—specifically, postcoital and intermenstrual bleeding, menorrhagia, and postmenopausal bleeding. Other symptoms include pelvic fullness/pain, unilateral leg swelling, bladder irritability, and tenesmus. Cervical cancer is also commonly asymptomatic, found only following an abnormal Pap smear, colposcopic exam, or cervical biopsy.

•   Common signs of advanced cervical cancer are a fungating cervical mass, unilateral leg edema, and obstructive renal failure.

•   Cervical cancer often results from persistent infection with high-risk HPV types (most commonly 16 and 18). Risk factors associated with cervical cancer are: prior history of sexually transmitted diseases (STDs), early age of first coitus, multiple sexual partners, multiparity, nonbarrier methods of birth control, and smoking.

•   Cervical cancer primarily spreads by direct extension from the cervix to the parametria, vagina, uterine corpus, and the pelvis. Other routes of spread include lymphatic and hematogenous dissemination, as well as direct peritoneal seeding.

•   Lymph node (LN) metastasis usually occurs in a sequential fashion, traveling first to the parametrial LNs, then to pelvic (obturator, internal, and external iliac), common iliac, para-aortic, then scalene LN.

PRE-TREATMENT WORKUP

The pre-treatment workup of cervical cancer begins with a history and physical exam. Laboratory studies to assess hematologic, renal, and liver functions should be performed. Imaging studies should also be performed to include pelvic imaging and a CXR (Figure 2.1).

•   FIGO-approved imaging studies include barium enema, intravenous pyelogram, and chest x-ray. Other modalities such as CT (to assess LNs and evaluate for hydronephrosis), MRI (to assess integrity of tissue planes and extent of cervical disease), or PET/CT (to evaluate for distant metastasis) are non-FIGO-approved staging tests due to the poor availability of these imaging modalities in medically underserved countries. However, advanced imaging is important in depicting important prognostic factors and, when available, is recommended in addition to the clinical examination.

•   Cervical conization should be used to evaluate microscopic disease. Conization can differentiate between microinvasive versus invasive early-stage disease.

•   For lesions that are macroscopic, an office examination or an examination under anesthesia (EUA) with cystoscopy and proctoscopy is indicated.

•   If patients cannot tolerate an office exam, or if there is ambiguity about the staging in an office setting, an EUA should be performed. There are data to suggest that EUA can significantly change clinical staging: 23% were upstaged, most to IIA or IIB disease. Patients were down staged less often (9%) to IB2 and IIB. Proctoscopy was not found to be helpful, but cystoscopy identified 8% of patients with stage IVA disease, and a CXR was abnormal in 4% of patients (1).

•   Multiple studies have supported the use of PET scans. An analysis of 15 published (FDG)-PET studies on cervical cancer showed that the pooled sensitivity and specificity of FDG-PET for detecting pelvic LN metastasis were 79% (95% CI: 65%–90%) and 99% (95% CI: 96%–99%), compared with 72% (95% CI: 53%–87%) and 96% (95% CI: 92%–98%) for MRI, and 47% (95% CI: 21%–73%) for CT (specificity not available). The pooled sensitivity and specificity of FDG-PET for detecting PA-LNs were 84% (95% CI: 68%–94%) and 95% (95% CI: 89%–98%) (2). A study from Israel (3) revealed a sensitivity of 60%, a specificity of 94%, a PPV of 90%, and an NPV of 74%. PET–CT may not pick up lesions smaller than 1.5 cm. There are data to suggest that treatment modification can occur in 25% of patients based on PET–CT results.

39HISTOLOGY

There are several different histologic types of cervical cancer, the most common being squamous (85%). Other types include adenocarcinoma (15%–20%), verrucous carcinoma, adenosquamous carcinoma, clear cell carcinoma, neuroendocrine carcinomas, and undifferentiated types.

•   Adenocarcinoma: about 15% have no visible lesion because the lesion arises from the endocervical canal, forming a “barrel-shaped” lesion. Cells frequently stain CEA+. Variants are the more common mucinous endocervical, mucinous intestinal type, signet ring type, and colloid variants. Adenoma Malignum/Minimal Deviation Variant has an infiltrative pattern distinct from those listed elsewhere with cytologically benign appearing cells on low power but moderate nuclear atypia seen on higher power and are seen in patients with Peutz–Jeghers syndrome. There is a three-tiered system developed to classify risk of LN metastasis developed by Silva et al. (4).

        Pattern A: well-demarcated glands frequently forming clusters or groups with lobular architecture and lacking destructive stromal invasion or LVI. LN metastasis risk: 0%.

        Pattern B: localized destructive invasion with small clusters or individual tumor cells within desmoplastic stroma often arising from pattern A glands. Often well to moderately differentiated. LVI ±. LN metastasis risk: 4.4%.

        Pattern C: diffusely infiltrative glands and associated desmoplastic response. Confluent growth filling a 4× field (5 mm) or mucin lakes present, solid poorly differentiated component with LVI. LN metastasis risk: 23.8% (5).

•   Verrucous carcinoma: this is a well-differentiated squamous cell carcinoma. It is known to recur locally, but does not metastasize. Historically, these tumors should not be treated with radiation therapy (XRT) because radiation can cause anaplastic transformation; however, recent evidence does not support this. It is associated with HPV6.

•   Adenosquamous carcinoma: this is a mixed glandular and squamous carcinoma. It behaves similar to adenocarcinoma.

•   Glassy cell carcinoma: this is a poorly differentiated type of adenosquamous carcinoma.

•   Clear cell carcinoma: this is a poorly differentiated carcinoma. It is nodular and reddish in gross appearance. It has a hobnail cell shape microscopically. It can be associated with intrauterine DES exposure.

•   Neuroendocrine carcinoma: this includes the small cell, large cell, and carcinoid (typical and atypical) carcinomas. Small cell is the most common neuroendocrine tumor in the cervix. It contains adenoid basal cells with scarce myoepithelial differentiation.

•   Papillary squamous cell: this is a variant of squamous cell carcinoma. It appears as transitional or cuboidal cells on microscopy.

•   Mesonephric adenocarcinoma: remnants of the mesonephric ducts are occasionally seen in the lateral aspects of the cervix, are PAS+, and do not contain intracytoplasmic mucin (Tables 2.1A–D and 2.2).

40STAGING

TREATMENT

The treatment of cervical cancer may involve the use of surgery, chemotherapy, radiation therapy (XRT) or a combination of therapies. About 70% of newly diagnosed patients with invasive carcinoma of the cervix have disease limited to the uterine cervix and are, therefore, potential operative candidates. 54 to 84% of these patients will need adjuvant therapies for intermediate or high-risk factors; so thorough investigation of the full extent of disease should be performed. NCI statements support treatment with the fewest number of interventions; thus, if high-risk factors are found on conization, which predict a high probability for the need of adjuvant therapies, it may be prudent to not perform surgery.

•   Treatment options by stage:

        Stage IA1:

             No LVSI: a simple (type I/extrafascial) hysterectomy or cold knife cone with 3 mm negative margins (if fertility-sparing treatment is desired) are adequate therapies. Intracavitary XRT can be used alone if the patient is not a surgical candidate. If margins on the CKC are positive, repeat CKC should be performed. Consideration of simple trachelectomy if fertility is desired is another option. If margins continue to be positive for carcinoma, a type II radical hysterectomy with pelvic LND can be considered.

             LVSI: a type II (modified) radical hysterectomy with pelvic LND (P-LND) with/without para-aortic LND should be considered. Whole pelvic (WP) external beam XRT (EBXRT) with brachytherapy can also be considered. If fertility is desired, a cone biopsy with negative 3 mm margins with a pelvic LND, and consideration of para-aortic LND (PA-LND) should be performed. A radical trachelectomy with pelvic LND can also be considered.

        Stage IA2:

             A type II or type III radical hysterectomy with P-LND with/without PA-LND can be offered. Similar outcomes have been seen with both types of radical hysterectomy (6) or

             Pelvic EBXRT with brachytherapy

43         Stages IB1 and IIA1:

             A type III radical hysterectomy and pelvic LND with/without PA-LND can be offered with consideration of SLN mapping. Surgical candidates are those with lesions that are not bulky or barrel shaped.

             Definitive treatment can also be primary external beam radiation therapy (EBXRT) and brachytherapy with concurrent cisplatin chemotherapy. Total dosing for XRT should be 80–85 Gy. Similar cure rates are seen with either radical surgery or XRT (7).

        Stages IB2 and IIA2:

             A combination of EBXRT and brachytherapy with chemotherapy is the standard of care. Patients with large cervical lesions staged IB2 have a high rate of needing adjuvant therapies after surgical approach and primum non nocere states the least injurious approach be the standard of care. Total dosing with XRT should be ≥85 Gy.

             A type III radical hysterectomy with P-LND with/without PA-LND can be considered.

             Surgical LN staging can be considered via extraperitoneal or transperitoneal laparoscopic LND. If negative, tailored field EBXRT and brachytherapy with concurrent cisplatin chemotherapy can be administered. If positive, then the need arises for EBXRT to cover the para-aortic and involved LN basins.

             Surgery can be considered as adjuvant therapy in certain situations; for example, if there is residual tumor after definitive chemotherapy–XRT or uterine anatomy precludes adequate brachytherapy. Total dose with this approach is 75–80 Gy.

        Stage IB2, IIA2, IIB, IIIA, IIIB, IVA: CT of chest, abdomen, and pelvis should be obtained:

             If imaging shows adenopathy:

                  Positive pelvic adenopathy but negative PA adenopathy: consider laparoscopic LND of pelvic and PA basins or fine needle aspiration (FNA) of suspicious LN:

                   –   If positive PALN: WP EBXRT and brachytherapy with extended field XRT concurrent with cisplatin chemotherapy.

                   –   If negative PALN: then WP EBXRT with brachytherapy concurrent with cisplatin chemotherapy (tailored fields).

                  If no surgical LN evaluation is performed: WP EBXRT with brachytherapy concurrent with cisplatin chemotherapy with/without extended field para-aortic (PA-XRT) can also be considered.

                  Positive pelvic and PA adenopathy on imaging: consider laparoscopic LND followed by WP and PA EBXRT to affected LN basins with brachytherapy, concurrent with cisplatin chemotherapy.

                  If distant metastases are seen: systemic chemotherapy with individualized palliative XRT.

        Stage IVB: chemotherapy should be used for disseminated disease and XRT can be considered for pelvic tumor control or palliation of symptoms including bleeding.

        If cancer is incidentally found on a postoperative hysterectomy specimen:

             Stage IA1 with LVSI or >stage IA2: imaging should be obtained with pathologic review:

                  Negative margins and negative imaging:

                   –   WP EBXRT and brachytherapy with concurrent cisplatin chemotherapy should be offered or

                   –   A parametrectomy with upper vaginectomy and P-LND with/without PA-LND can be performed

                  Positive margins or gross residual disease:

                   –   If imaging is negative for adenopathy: WP EBXRT with concurrent cisplatin chemotherapy with/without brachytherapy based on vaginal margins

                   –   If imaging is positive for adenopathy: consider debulking of grossly enlarged LN followed by WP and PA EBXRT with concurrent cisplatin chemotherapy with/without brachytherapy based on vaginal margins

•   Most randomized trials included 5% to 8% of patients with adenocarcinoma, so they are applicable to cite in treating adenocarcinoma of the cervix.

•   Margin status is important in conization. In one study evaluating adenocarcinoma in situ (8), 33% of patients with negative margins had residual disease at the time of hysterectomy and 14% had invasive cancer; 53% of those with positive margins had residual disease and 26% were found to have invasive cancers. In another study, which reviewed patients with invasive squamous cell cancer on conization (9), 24% of patients had residual disease if they had negative margins and 60% were found to have residual disease if they had positive margins.

•   The incidence of positive LNs with squamous cell and adenocarcinomas is 5% for stage IA2, 15% for stage IB1, 30% for stage IB2, 45% for stage IIB, and 60% for stage IIIB.

•   The incidence of adnexal metastasis with adenocarcinoma is 1.7% compared to 0.5% for squamous cell lesions. According to GOG 49 (10), this is a nonsignificant difference, and all patients with ovarian metastasis had evidence of other extra-cervical disease.

•   The rate of an aborted radical hysterectomy for grossly positive LNs is approximately 7% to 8% (11). Per GOG 49, the rate of abandoned radical hysterectomy was 8.3%.

•   If a positive LN is found at the time of radical hysterectomy, there are two management options: completion of, or abortion of, radical hysterectomy.

        Some proceed and complete the radical hysterectomy. The rationale is that removal of bulky LNs leaves less residual tumor for XRT to sterilize.

        Another study showed that the local recurrence and distant recurrence rates were not significantly different for LN positive aborted versus completed radical hysterectomy patients. The progression-free survival (PFS) was 74.9 months versus 46.8 months (p = 0.106) and the overall survival (OS) was 91.8 months versus 69.4 months (p = 0.886) (12). Potter (13) found similar outcomes and the trend favored definitive XRT. Leaving the uterus in situ can help with treatment planning and can move the small bowel out of the treatment field. Debulking of LN greater than 2 cm prior to abortion of hysterectomy may be beneficial additionally.

         The number of positive LN affects OS. The 5-year survival (YS) decreases for each additional positive LN: 1 node (79%), 2 to 3 nodes (63%), 4+ nodes (40%) (14).

•   Surgical staging in locally advanced cervical cancer may be beneficial. In one study, surgical staging of women with locally advanced cervical cancer was suggested to improve overall clinical outcome, as those with positive LNs had a modification in standard XRT fields in up to 43% of patients (15).

•   LN debulking can potentially improve the 5 YS in patients with locally advanced cervical cancer (16). One study showed that if grossly metastatic LNs were resected, the survival of women in that group approached the level of those women who had microscopic LN involvement only (50%, 5 YS), which was significantly higher than the women with unresectable LNs (0%) (16). There was a 10.5% incidence of severe XRT-related morbidity and a 1% incidence of treatment-related deaths due to combined therapies.

•   A cut through hysterectomy refers to a cancer either found incidentally on final pathology or resected without radical surgery. Treatment of a “cut through” can include adjuvant XRT or a radical parametrectomy. There are data to suggest that the 5 YS is better with adjuvant XRT versus radical parametrectomy with a 68.7% versus a 49% 5 YS. This is stage and margin dependent. The 5 YS for women staged IA2 and IIA was 96% (17), but was much lower for women stage IIB or higher who had a 5 YS of 28%.

•   Hydronephrosis found on imaging predicts a worse OS and PFS. Relief of ureteral obstruction has been associated with improved survival. Management with stenting via cystoscopy from below, or antegrade from above, is beneficial for preservation of renal function and enabling full dosing of radiosensitizing chemotherapy (18).

SURGICAL TREATMENT

•   Hysterectomy types: Piver classification I–V is based on the degree of resection of vagina, parametria, cardinal ligaments, and uterosacral ligaments (19).

        Class I radical hysterectomy is the same as a simple hysterectomy. It is indicated for stage IA1 cervical cancers without lymphovascular space involvement.

        Class II radical hysterectomy is a modified radical hysterectomy. It involves resection of the medial half of the cardinal and uterosacral ligaments. The uterine artery is taken at its junction with the ureter. The upper one fourth (or 1–2 cm) of the vagina is also removed. This results in a wider local treatment margin than a simple hysterectomy.

        Class III radical hysterectomy is also called a Wertheim/Meigs–Okabayashi hysterectomy. Originally, Wertheim did not include lymphadenectomy, whereas Meigs and Okabayashi did. In this procedure, the cardinal and uterosacral ligaments are completely transected and one third to one half of the vagina is removed. The uterine artery is taken at its origin. The autonomic nerves for bladder and rectal function are also resected, which can result in a high incidence of prolonged or permanent bladder dysfunction (Figure 2.2).

        Class IV radical hysterectomy is reserved for larger bulky lesions. This procedure involves completely transecting the cardinal and uterosacral ligaments at their origin. One half of the vagina is removed; therefore, sexual dysfunction occurs from the shortened vagina. The superior vesical artery is sacrificed and all periureteral tissue is removed.

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