Learning Objectives:After participating in this continuing professional development activity, the provider should be better able to:
1. Compare and contrast cervical adenocarcinoma and squamous cell carcinoma.
2. Select appropriate diagnostic testing for patients with adenocarcinoma in situ.
3. Identify the primary treatment strategies for patients with adenocarcinoma in situ and invasive cervical adenocarcinoma.
Although the rate of cervical cancer is declining, the global burden remains high with over 600,000 new diagnoses every year, including nearly 14,000 in the United States.1 The overall decline in cervical cancer is related primarily to the decreasing incidence of squamous cell carcinoma (SCC), the most common subtype. However, the incidence of cervical adenocarcinoma, the second most common subtype, continues to rise, accounting for 20% to 25% of all cases.2 As with SCC, this disease disproportionately impacts young patients.
Risk factors for cervical adenocarcinoma and SCC are similar, including a greater number of sexual partners, obesity, human papillomavirus (HPV) infection, and oral contraceptive use. In contrast to SCC, smoking does not seem to increase the risk of adenocarcinoma.3
Invasive cervical adenocarcinoma and its preinvasive precursor adenocarcinoma in situ (AIS) arise from the glandular endocervix. This differs from SCC, which originates from the transformation zone in proximity to the ectocervix. Despite these distinct origins, cervical adenocarcinoma and SCC have historically been grouped together in the cervical cancer literature. However, there is increasing recognition of important differences between these 2 disease entities (Table 1). In this review, we focus on the diagnosis, histopathologic classification, and management of cervical adenocarcinoma.
Clinical Presentation and Diagnosis
The most common presenting symptom of cervical adenocarcinoma is vaginal bleeding, often postcoital. In rare cases a cervical mass or lesion will be detectable on physical examination, and a diagnostic biopsy should be obtained. However, most patients are asymptomatic and diagnosed after routine screening.
Both AIS and invasive cervical adenocarcinomas are more readily detected by HPV testing (either alone or cotesting) than pap cytology alone.4-6 In one retrospective cohort study of 87 patients, 52% of those with AIS and 24% of those with invasive adenocarcinoma had a negative or low-risk pap cytology preceding diagnosis, but all tested positive for high-risk HPV.6 This is explained in part by the fact that cervical adenocarcinoma arises from the endocervix, which may not be as accessible by traditional cytology collection techniques.
Of those who do have a preceding high-risk pap cytology, atypical glandular cells (AGC or AGUS) is the most common.6 In a large study of AGUS pap smears, 2.9% were diagnosed with AIS and 5.2% with invasive cancer, of which 57.6% were endometrial adenocarcinoma and 23.6% were cervical adenocarcinoma.7 After an abnormal screening test, the diagnosis of AIS or invasive adenocarcinoma is then confirmed with colposcopy, cervical biopsy, and/or endocervical curettage (ECC).
Histopathologic Classification
Over the past decade, there have been significant changes to the histopathologic classification of cervical adenocarcinoma. In 2018, the International Endocervical Adenocarcinoma Criteria and Classification was revised to include 2 major subtypes: HPV-associated (HPVA) and non-HPV-associated or HPV-independent (HPVI) (Table 2).8 This classification system was adopted by the World Health Organization in 2020.
HPV-Associated Cervical Adenocarcinoma
HPVA tumors are more common, comprising 80% to 90% of all cervical adenocarcinomas. HPVA tumors are further stratified by histopathologic characteristics, with "usual type" accounting for nearly 75% of all cervical adenocarcinomas.8 Other HPVA variants include mucinous, invasive stratified mucin-producing carcinoma, micropapillary, and villoglandular. Villoglandular tumors generally have a good prognosis compared with other variants.9
Similar to SCC, HPV16 is the most common genotype associated with AIS and invasive cervical adenocarcinoma; however, there is a higher proportion of HPV18 infection detected in cervical adenocarcinomas compared with SCC.4,10,11 HPV association also serves as an important prognostic indicator, as patients with HPVA cervical adenocarcinomas have improved survival and reduced risk of recurrence when compared with HPVI cervical adenocarcinomas.12
HPV-Independent Cervical Adenocarcinoma
Of the HPVI cancers, gastric-type is the most common, representing 10% of all cervical adenocarcinomas. Gastric-type cancers are characterized by tumor cells with prominent eosinophilic, mucinous cytoplasm and an infiltrative pattern of invasion.13 Because they are HPV negative, these tumors tend to be diagnosed at an advanced stage. In addition, they behave more aggressively than the HPVA types and have a worse prognosis.14
Other HPVI subtypes include mesonephric, clear cell, and endometrioid. Mesonephric adenocarcinomas represent less than 1% of all cervical adenocarcinomas and arise from hyperplasia of the mesonephric remnants along the posterolateral wall of the cervix.15 Clear cell cervical adenocarcinomas account for approximately 3% of all cervical adenocarcinomas and are historically associated with in utero diethylstilbestrol exposure.16 Endometrioid tumors of the endocervix are very rare, representing less than 1% of cervical adenocarcinomas.13 Given the glandular origin, all types of endocervical tumors may be difficult to distinguish from primary endometrial tumors arising from the lower uterine segment. However, cervical adenocarcinomas typically lack hormone receptors and are more readily associated with carcinoembryonic antigen and p16 expression.17
Adenocarcinoma in Situ
AIS is the preinvasive counterpart of invasive adenocarcinoma. If untreated, the average time for progression of AIS to invasive adenocarcinoma ranges from 5 to 13 years.4,18 As described previously, the diagnosis of AIS is made with colposcopy, cervical biopsy, and/or ECC. The median age at diagnosis is 35, and the incidence continues to rise, particularly among patients aged 30 to 39 years.19,20
After initial diagnosis, an excisional procedure is recommended to exclude invasive adenocarcinoma. Cold knife cone (CKC) is the preferred excisional method and the specimen should be removed intact with a recommended length of at least 10 mm, and up to 20 mm if childbearing is complete. Loop electrode excision (LEEP) is acceptable if CKC is not able to be performed. However, this can result in a higher rate of positive margins requiring additional excisional procedures. Performance of a "top hat" to achieve adequate depth is unacceptable as the entire specimen should be removed intact. ECC should be performed after the excisional procedure.21
In AIS, achieving negative margins on an excisional procedure reduces but does not eliminate the risk of residual or recurrent disease.20 In a large meta-analysis of outcomes based on margin status after excisional treatment of AIS, the risk of recurrent disease in patients with negative margins was 2.6% compared with 19.4% of those with positive margins. The rates of residual disease were 20.3% and 52.8%, respectively.20 This may be explained in part by the tendency for AIS to have skip lesions within the endocervix and/or uterine corpus rather than spreading contiguously from a focal origin. Because of this risk of residual disease, completion hysterectomy is recommended after excision of AIS with negative margins. Patients should then be surveilled with cotesting annually for 3 years, followed by 3-year interval cotesting for at least 25 years.22
Patients may also opt for fertility-sparing management, provided they have an excision with negative margins, can adhere to surveillance recommendations, and have received adequate counseling regarding the risks of residual or recurrent AIS. Surveillance includes cotesting (pap cytology and HPV) and ECC every 6 months for 3 years then annually.23 Once childbearing is complete, hysterectomy is recommended. Based on limited data, continued surveillance can be considered if HPV testing remains negative.23,24
If the excisional specimen has positive margins, options include a repeat excisional procedure (preferred if feasible) or either simple or modified radical hysterectomy.23 These patients should be referred to gynecologic oncology for definitive surgery.
Invasive Adenocarcinoma
Diagnosis and Staging
Invasive cervical adenocarcinoma is typically diagnosed from a colposcopic or excisional biopsy. As with SCC, stage at diagnosis is the most important prognostic indicator for cervical adenocarcinoma. Staging is performed in accordance with the 2018 FIGO classification system (Table 3). The use of imaging and clinical staging as adjuncts to definitive surgical staging is important to help identify which patients are appropriate surgical candidates. All imaging modalities are permitted for staging, and positron emission tomography (PET)-CT is considered the most accurate imaging modality for detection of lymph node metastases.25 Some patients with negative PET-CT will benefit from laparoscopic para-aortic lymphadenectomy, which is more sensitive in detecting metastatic disease to the lymph nodes than PET-CT before treatment planning. Cystoscopy and proctoscopy can also aide in the clinical evaluation if extension into the bladder or rectum is suspected.
Management
The National Cancer Center Network clinical practice guidelines provide recommendations for the management of cervical cancer.26 At present, the guidelines are similar for both SCC and cervical adenocarcinoma. The method of treatment depends on disease stage, desire for fertility, performance status, and the patient's goals of care. In general, primary treatment options include surgery (conservative or radical depending on stage and risk factors), concurrent platinum-based chemoradiation (CCRT), systemic chemotherapy, and/or immunotherapy.
Early-Stage Disease
Most patients will present with early-stage disease. In a retrospective study of over 18,000 patients with cervical adenocarcinoma from 2004 to 2017, 57.1% were diagnosed with early-stage cancers (IA1-IB2).27 Microinvasive cervical adenocarcinoma, defined as stage IA without lymphovascular space invasion (LVSI), has a favorable prognosis and conservative, fertility-sparing management strategies can be considered.28 Similar to AIS, the initial management is a CKC. If negative margins are achieved and fertility-sparing management is desired, the patient can be followed with close surveillance. If childbearing is complete, simple hysterectomy is recommended.
For patients with stage IA1 with LVSI or IA2 disease, modified radical hysterectomy with pelvic lymph node sampling is recommended. Patients with IA2 disease and no LVSI may be candidates for more conservative surgery with simple hysterectomy with pelvic lymph node sampling. For those who desire fertility, options include CKC or radical trachelectomy with pelvic lymph node sampling.29
For patients with higher-risk early-stage cervical adenocarcinoma (stages IB1 and IB2), primary radical surgery is preferred, but CCRT can also be considered. As with SCC, a key consideration in the management of patients with high-risk early-stage cervical adenocarcinoma is determining who should receive adjuvant radiation after primary radical surgery. This decision must balance the risk of recurrent disease with the increased morbidity when surgery and radiation are combined.
Adjuvant radiation after radical surgery is recommended for patients with a high recurrence risk. The findings of positive lymph nodes, positive surgical margins, and/or positive parametria substantially increase recurrence risk after surgery and thus chemoradiation is recommended for these patients. Additionally, the Sedlis criteria (LVSI, depth of invasion, and tumor size) have historically defined a cohort of patients with a high risk of recurrence after surgery who benefitted from radiation.30 However, this criterion was developed primarily for patients with SCC, and more recent data suggest that only tumor size remains associated with an increased risk of recurrence for patients with cervical adenocarcinoma.31 In addition, recurrence rates for patients with cervical adenocarcinoma seem to be higher than those with SCC in the absence of adjuvant radiation. Because of these differences, a histology-specific nomogram has been proposed that would better predict the need for adjuvant radiation among patients with cervical adenocarcinoma.31 Further prospective studies are needed.
Locally Advanced, Metastatic, and Recurrent Disease
Approximately 31% of patients will be diagnosed with locally advanced disease (stages IB3, II, III, and IVA).27 CCRT is the primary treatment strategy, and data suggest similar survival benefit from CCRT for patients with both cervical adenocarcinoma and SCC.32 For those with metastatic (stage IVB) and recurrent cervical adenocarcinoma, systemic platinum-based chemotherapy is the mainstay of treatment33 and response to chemotherapy is similar between SCC and cervical adenocarcinoma.34 Additionally, there is a growing role for immunotherapy in the treatment of advanced cervical cancer.
For a centralized, isolated local recurrence, pelvic exenteration may be considered for well-selected candidates. Regardless of treatment strategy, recurrent, advanced cervical adenocarcinoma has a poor prognosis, and goals of care should be addressed for all patients.35
Ovaries: Clinical Significance and Management
Ovarian metastases are more common in cervical adenocarcinoma than in SCC, occurring in about 5% of cases overall and 2% of those with early-stage disease.36,37 As with other gynecologic malignancies, the route by which cervical adenocarcinoma spreads to the ovaries is not completely understood and may vary for different tumors.
The increased frequency of ovarian involvement in cervical adenocarcinoma compared with SCC had historically led to the recommendation for bilateral salpingoophorectomy as part of the surgical management of these patients. However, this disease often impacts young patients for whom ovarian preservation would otherwise be desired. More recently, an analysis of nearly 4000 patients with early-stage cervical cancer demonstrated improved overall survival for patients with stage IA cervical cancer who underwent ovarian conservation, including those with cervical adenocarcinoma.38 Further research has supported these findings, and thus ovarian preservation is considered safe in patients with early-stage disease for whom primary surgical management is appropriate.
Disparities
As with other gynecologic malignancies, there are significant disparities in outcomes for patients with cervical adenocarcinoma. Recent data suggest that Black patients and those with public insurance are less likely to be diagnosed at an early stage.27 In addition, although the incidence of cervical adenocarcinoma is highest among Hispanic and White patients, Black patients experience the greatest associated mortality.39 These disparities in diagnosis and mortality are complex but likely arise in part due to barriers to care and limited access to screening and guideline-concordant treatments. Developing interventions to address these disparities is of critical importance.
Conclusion
AIS and invasive cervical adenocarcinoma have been increasingly recognized as different from their squamous cell counterparts. Glandular disease can be more difficult to detect by routine screening methods and once detected, management differs in several important ways given the distinct risk factors for recurrence and pattern of disease spread. Fertility-sparing surgery is often an option for patients with noninvasive or early disease who desire future childbearing. However, patients with additional risk factors or more advanced disease require more radical surgery and/or different treatment modalities including radiation, chemotherapy, and immune therapy. HPV vaccination and screening in accordance with ASCCP guidelines remain the most important tools we have for reducing cervical cancer morbidity and mortality.
Practice Pearls
* Cervical adenocarcinoma currently accounts for nearly 20% to 25% of cervical cancers.
* Cervical adenocarcinomas are classified as either HPV-associated or HPV-independent; HPV-associated tumors account for up to 75% of cervical adenocarcinomas and have a more favorable prognosis.
* AIS should initially be managed with an excisional procedure (with goal of negative margins) before completion hysterectomy or surveillance.
* Patients with AIS and early-stage invasive cervical adenocarcinoma can be offered fertility-sparing treatment options.
* Patients with AIS should be offered definitive hysterectomy at the completion of childbearing.
* Cervical adenocarcinoma and SCC have similar response rates to CCRT and systemic chemotherapy.
* Ovarian metastases are more common in cervical adenocarcinoma, but ovarian preservation is considered safe for early-stage disease.
* Black patients experience greater mortality from cervical adenocarcinoma.
References