Invasive cervical adenocarcinoma

INTRODUCTION — Cervical cancer encompasses several histologic types, of which squamous cell carcinoma (SCC) is the most common (70 percent) (table 1). The incidence of invasive cervical adenocarcinoma and its variants has increased dramatically over the past few decades; this cell type now accounts for approximately 25 percent of all invasive cervical cancers diagnosed in the United States [1,2]. Neuroendocrine (predominantly small cell poorly differentiated) carcinomas and other rare cell types together comprise 3 to 5 percent of all cases. (See "Small cell neuroendocrine carcinoma of the cervix".)

Most of our knowledge on the treatment of cervical cancer comes from studies in which the majority of the patients had SCC; adenocarcinoma has comprised, on average, 10 percent of the cases. Very few of these studies report separate outcomes for adenocarcinoma, and no prospective study has focused on the treatment of adenocarcinoma as the sole histology. As a result, our understanding of the natural history and optimal management of adenocarcinoma of the cervix is limited. However, as there are many similarities between adenocarcinoma and SCC of the cervix, they are treated the same at most institutions.

This topic will focus on unique issues pertaining to invasive cervical adenocarcinoma. Clinical features, staging, and management issues that are common to SCC and adenocarcinoma, as well as adenocarcinoma in situ, are discussed in depth separately. (See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis" and "Invasive cervical cancer: Staging and evaluation of lymph nodes" and "Management of early-stage cervical cancer" and "Management of locally advanced cervical cancer" and "Cervical adenocarcinoma in situ".)

EPIDEMIOLOGY AND RISK FACTORS — There are both similarities and differences in the epidemiology of adenocarcinoma of the cervix compared with squamous cell carcinoma (SCC):

●Estrogen – The incidence of invasive cervical adenocarcinoma and its variants has increased dramatically over the past few decades, particularly in younger patients [3,4]. One possible causative factor that has been proposed to explain this trend is an increased exposure to estrogen.

•A pooled analysis of data from eight case-control studies suggests that endogenous estrogen (eg, obesity) has a stronger association with adenocarcinoma as compared with SCC [5].

•Exposure to exogenous estrogens (eg, hormonal contraception, postmenopausal estrogen therapy) is a risk factor for adenocarcinoma [6-9]. However, a systematic review concluded that use of oral contraceptives was a risk factor for both adenocarcinoma and SCC [10].

●Human papillomavirus (HPV) – Cervical adenocarcinoma shares some of the same risk factors with SCC, the most important of which is prolonged infection with high-risk subtypes of HPV, particularly subtypes 16 and 18 [5,11,12]. However, adenocarcinoma and SCC have slightly different associations with HPV genotypes [12,13]. The available data suggest that HPV 18 accounts for approximately 50 percent of adenocarcinomas compared with 15 percent of SCCs and that the proportion of adenocarcinomas associated with HPV 16 and 18 infections is higher in adenocarcinomas relative to that of SCC, which is associated with a greater diversity of HPV types [13]. (See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis", section on 'Epidemiology'.)

●Smoking – In contrast to its squamous counterpart, cigarette smoking does not appear to be a risk factor for adenocarcinoma [14].

●Parity – The pooled analysis of case-control studies above also suggested that parity has a weaker association with adenocarcinoma as compared with SCC [5].

HISTOPATHOLOGY — The World Health Organization (WHO) and International Endocervical Adenocarcinoma Criteria and Classification (IECC) system distinguishes cervical adenocarcinomas into those that are HPV associated or HPV independent (table 1) [15,16].

HPV-associated adenocarcinomas include:

●Usual type – Cervical adenocarcinomas of the usual endocervical type account for at least 80 percent of cervical adenocarcinomas. They are characterized by an irregular haphazard arrangement of glands lined by cells resembling those that line normal endocervical glands.

Morphologic variations have been described and include:  

•Villoglandular

•Mucinous type – Mucinous types include intestinal, signet ring, or not otherwise specified

•Invasive stratified mucin producing intraepithelial lesion

•Adenosquamous

•Mucoepidermoid

•Adenoid basal cell

HPV-independent adenocarcinomas include:

●Gastric type

●Clear cell type

●Mesonephric type

●Endometrioid type – Endometrioid-type adenocarcinomas with the characteristic histology of tubular glands are infrequently diagnosed, but they have a better prognosis than adenocarcinomas of the usual endocervical type [17]. These tumors display histologic features that are identical to endometrial carcinomas, and the possibility of a primary endometrial adenocarcinoma with endocervical extension or drop metastasis must be excluded before the diagnosis of a primary endocervical endometrioid adenocarcinoma is established. Despite the better prognosis, management for endometrioid histology is generally the same as for other cervical adenocarcinomas. (See 'Specific management issues' below.)

The precursor lesion of most invasive cervical adenocarcinomas is believed to be adenocarcinoma in situ (AIS) (see "Cervical adenocarcinoma in situ"). By contrast, adenosquamous carcinoma is a tumor composed of admixed malignant glandular and squamous elements. It does not appear to originate from AIS and demonstrates more aggressive features than other cervical adenocarcinomas, such as higher tumor grade and lymphovascular invasion [18].

CLINICAL MANIFESTATIONS — Clinical manifestations of cervical adenocarcinoma are the same as for squamous cell carcinoma. Many patients are asymptomatic, and, where cervical cancer screening is routinely performed, cervical adenocarcinoma is most commonly detected through cervical cytology, especially when the endocervical canal is adequately sampled. When symptoms occur, patients are most likely to present with postcoital bleeding. In some patients, a cervical mass is discovered upon pelvic examination that is performed for other indications. (See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis", section on 'Clinical manifestations' and "Screening for cervical cancer in resource-rich settings".)

DIAGNOSIS AND STAGING — As with squamous cell carcinoma (SCC), cervical adenocarcinoma is diagnosed with a cervical biopsy. The depth of invasion, which correlates with the incidence of metastatic disease, is measured from the luminal surface of the tumor or overlying benign epithelium to the deepest invasive tumor nest [19].

The vast majority of adenocarcinomas have an obvious invasive component. The exception to this is microinvasive disease. Microinvasive cervical adenocarcinoma (also termed early invasive adenocarcinoma, International Federation of Gynecology and Obstetrics [FIGO]/American Joint Committee on Cancer [AJCC] stage IA1 or 1A2 disease (table 2)) is most commonly detected postoperatively on a conization performed for presumed adenocarcinoma in situ (AIS). (See 'Staging system' below.)

A diagnostic excisional procedure (eg, cold knife conization, loop electrosurgical excision procedure) with a negative margin is required to define the microinvasive lesion, and an endocervical curettage (ECC) is recommended to confirm the absence of additional disease. This is particularly important for cervical adenocarcinoma since, in contrast to cervical SCC, noncontiguous lesions ("skip lesions") are often found. In general, we do not recommend additional biopsies in the setting of a negative conization margin and negative ECC.

If the excisional margin or ECC is positive for invasive tumor, a second conization is mandatory. If there is no residual disease on the second procedure, then a diagnosis of microinvasive (stage IA1 or IA2) disease can safely be made. If the second conization demonstrates additional invasive disease, then it should be classified as invasive disease and staged accordingly.

Staging system — The staging schema for cervical adenocarcinoma and its variants is the same as for SCC. The FIGO staging system and the AJCC tumor, node, and metastasis (TNM) staging system are presented in the tables (table 3 and table 2) [20,21]. (See "Invasive cervical cancer: Staging and evaluation of lymph nodes".)

Staging workup — As with SCC, the 2018 FIGO guidelines allow the provider to use imaging (ie, ultrasound, computed tomography [CT], magnetic resonance imaging [MRI], positron emission tomography) to provide information on tumor size, nodal status, and local or systemic spread. However, it is recognized that there will be limitations in imaging (eg, in lower middle-income countries, access to these extensive imaging services is often sparse or not available).

Additionally, image-guided fine needle aspiration or biopsy or surgical excision of suspicious sites is allowed to supplement clinical findings and provide a more accurate assignment of disease stage.

FIGO no longer mandates any investigative procedures; however, in patients with frank invasive carcinoma, a conventional chest radiograph and assessment of hydronephrosis (with renal ultrasound, intravenous pyelography, CT, or MRI) should be performed. The bladder and rectum are evaluated by cystoscopy and sigmoidoscopy if the patient is clinically symptomatic. Cystoscopy is also recommended in cases of a barrel-shaped endocervical growth and in cases where the growth has extended to the anterior vaginal wall. Suspected bladder or rectal involvement should be confirmed by biopsy. (See 'Role and extent of lymphadenectomy' below and 'Locoregionally advanced (IIB to IVA) disease' below and "Invasive cervical cancer: Staging and evaluation of lymph nodes", section on 'Staging procedure'.)

PROGNOSTIC FACTORS AND DIFFERENCES IN OUTCOME COMPARED WITH SCC — The major prognostic factors for cervical adenocarcinoma are the same as for squamous cell carcinoma (SCC), including stage, nodal status, tumor volume, depth of cervical stromal invasion, lymphovascular space invasion, grade, and human papillomavirus (HPV) status [15,22-24]. (See "Management of early-stage cervical cancer", section on 'Prognosis'.)

Some potential differences in prognostic factors and outcomes between adenocarcinoma and SCC are discussed here.

●Histologic type – As with SCC, HPV status appears to affect prognosis, with HPV-related compared with HPV-independent cancers conferring a better prognosis [15,25]. However, there is controversy as to whether histologic type itself is an independent prognostic factor in cervical cancer [26-38]. While older studies suggest that adenocarcinoma compared with SCC is associated with worse outcomes, a 2020 study showed that, when adjusted for stage, prognosis is similar [38]. In this retrospective study of 4131 patients with either adenocarcinoma or SCC of the cervix from the Surveillance, Epidemiology, and End Results (SEER) database, five-year overall survival was similar between groups.

●Patterns of dissemination – Ovarian metastases are more common with adenocarcinoma than with SCC (5.0 versus 0.8 percent in one series [39]). As a result, we usually recommend bilateral oophorectomy at the time of hysterectomy for those with adenocarcinoma (but not SCC).

●Treatment response – While treatment for adenocarcinoma generally follows the same principles established for SCC, patients with adenocarcinoma may respond differently to specific components of therapy. For patients with adenocarcinoma compared with SCC:

•Adjuvant external beam radiation therapy (EBRT) may be more effective – In one randomized trial of 277 patients (59 with non-SCC histology) with surgically treated stage IB cervical cancer, negative nodes, and at least two adverse prognostic factors, the addition of EBRT compared with observation reduced the risk of recurrence for non-SCC tumors more than for SCC tumors (recurrence rate with EBRT versus observation was 9 versus 44 percent; the corresponding values for SCC were 20 versus 28 percent) [40].

•RT alone may be less effective – In another randomized trial of 243 patients (50 adenocarcinomas) with resected stage IA2, IB, or IIA cervical cancer with high-risk features treated with chemoradiotherapy versus RT alone, patients with adenocarcinoma had a worse prognosis than SCC when treated with RT alone; this difference disappeared in patients who received chemotherapy in addition to RT [41].

Surgery, compared with RT alone, may be more effective for patients with adenocarcinoma. In another randomized trial including 343 patients (46 adenocarcinomas) with stage IB or IIA cervical cancer who were assigned to surgery or radical RT, five-year disease-free and overall survival were not different between the surgery and RT arms; however, among those with adenocarcinoma, there appeared to be a significant advantage for surgery compared with RT alone (five-year overall survival 70 versus 59 percent, disease-free survival 66 versus 47 percent) [42].

However, these results are from unplanned subset analyses of small groups of patients, and they should be considered hypothesis-generating at best.

SPECIFIC MANAGEMENT ISSUES — General principles of management, particularly where they vary from those for squamous cell carcinoma (SCC), are presented here.

Microinvasive (IA1 and IA2) disease — Management of microinvasive cervical adenocarcinoma depends upon patient age and desire to maintain fertility. The prognosis of microinvasive adenocarcinoma is generally excellent, and conservative, nonradical surgery is appropriate for some patients [43,44]. As an example, an overall relapse rate of 3 percent was found in a national United States cancer database (Surveillance, Epidemiology, and End Results [SEER]) study of 1170 patients with surgically treated microinvasive cervical adenocarcinoma [45].

●Stage IA1 – For patients wishing to preserve fertility, cold knife conization with widely negative margins is acceptable. For patients who have completed childbearing or for postmenopausal patients, simple hysterectomy is a reasonable option since surveillance of the endocervical canal is challenging over time. Pelvic lymphadenectomy is not necessary. (See 'Fertility preservation' below.)

●Stage IA2 – We tend to perform a modified radical hysterectomy for stage IA2 lesions; the added surgical morbidity of this approach compared with simple hysterectomy is minimal when performed by experienced gynecologic oncologists. In a modified radical hysterectomy, the uterine artery is ligated where it crosses over the ureter; the uterosacral and cardinal ligaments are divided midway toward their attachment to the sacrum and the pelvic side wall, respectively, so that the parametrium medial to the ureter is removed; and the upper one-third of the vagina is resected. The Piver-Rutledge-Smith classification of hysterectomy is shown in the table (table 4); other classification systems have been published (eg, Querleu and Morrow (table 5)) [46,47]. We also include sentinel lymph node biopsy or a pelvic lymph node dissection for stage IA2 disease. (See 'Role and extent of lymphadenectomy' below and "Management of early-stage cervical cancer" and "Radical hysterectomy", section on 'Types of radical hysterectomy'.)

Invasive early stage (IB and IIA) disease — Stage IB and IIA cervical cancer can be cured by either surgery (usually radical hysterectomy, bilateral salpingo-oophorectomy, and sentinel node biopsy or pelvic lymph node dissection) or radiation therapy (RT), which is typically administered with concurrent chemotherapy (ie, chemoradiotherapy). (See "Management of early-stage cervical cancer", section on 'Surgery preferred over radiation'.)

In general, the management of early-stage invasive cervical adenocarcinoma and its variants is similar, stage for stage, to that of SCC, with some minor modifications [19,48]. As an example, due to the higher risk of ovarian metastases, patients with nonmicroscopic cervical adenocarcinoma who are appropriate for surgical treatment should be counseled about oophorectomy at the time of hysterectomy. (See 'Prognostic factors and differences in outcome compared with SCC' above.)

The general principles that guide therapy are to offer patients single-modality treatment if at all possible and to avoid radical surgery followed by chemoradiotherapy. Surgery is generally preferred over initial chemoradiotherapy if the patient is an appropriate candidate for surgery, given the lower rate of long-term treatment-related adverse effects [48,49]. However, if risk factors are identified pretreatment (eg, evidence of lymph node involvement on pretreatment imaging, tumor size >4 cm, deep stromal invasion to the middle or deep one-third, or lymphovascular space invasion as seen in the initial biopsy) that indicate the need for adjuvant therapy after surgery, then we prefer upfront chemoradiotherapy. (See "Management of early-stage cervical cancer", section on 'High-risk disease'.)

The preference for surgery is based on data from a prospective trial in which 343 patients with stage IB and IIA cervical carcinoma (14 percent adenocarcinoma) were randomly assigned to primary surgery or RT (but without concurrent chemotherapy) [42,50]. At a median follow-up of 87 months, the five-year overall and disease-free survival rates were the same for both treatment groups (83 and 74 percent, respectively). However, multivariate analysis demonstrated a survival advantage for patients with adenocarcinoma who underwent primary surgery. It remains to be determined whether this result was due to an increased effectiveness of surgery or the absence of a benefit from RT (possibly due to the lack of concurrent chemotherapy) in patients with adenocarcinoma.

As noted above, some data raise the possibility that adenocarcinomas have a poorer outcome with RT alone than do SCCs, but that relative radioresistance might be overcome through the use of concurrent chemotherapy. As a result, when RT is administered for adenocarcinoma, we usually give concurrent cisplatin-based chemotherapy. (See 'Prognostic factors and differences in outcome compared with SCC' above and "Management of early-stage cervical cancer".)

Posttreatment extrafascial hysterectomy — Extrafascial hysterectomy is not routinely performed following chemoradiotherapy because chemoradiotherapy alone yields low local recurrence rates. The benefit of postradiotherapy surgery was addressed in a GOG trial in which 256 patients with cervical cancer >4 cm were randomly assigned to RT alone or RT followed by surgery [51]. While the surgery group had lower rates of local relapse at five years (14 versus 27 percent), survival was not improved.

A simple extrafascial hysterectomy could be considered for patients at high risk for a poor outcome with chemoradiotherapy alone, although there is no consensus as to which patients fit this category. We consider this approach for patients with early-stage cervical cancer and no evidence of nodal involvement who have an initially large cervical lesion (>7 cm), lower uterine segment involvement, or a high residual tumor volume after chemoradiotherapy [52]. Although such an approach has the potential to enhance local control, patients will be exposed to the combined morbidity of radical surgery and RT. (See "Management of locally advanced cervical cancer", section on 'Role of hysterectomy after chemoradiation'.)

Role and extent of lymphadenectomy — Nodal metastases are the most important prognostic variable for cervical cancer. Lymph node metastases portend a poor outcome, particularly among those with adenocarcinoma [29]. Detecting their presence is crucial to guide treatment planning.

Pelvic lymph node assessment with either sentinel node mapping or lymphadenectomy is a mandatory component of initial surgery for early-stage, operable cervical adenocarcinoma (stage IA2, IB1, and IIA disease) as it is with SCC. However, unless there is gross evidence of nodal or adnexal disease at the time of visual inspection during surgery, extension of the node dissection to include the paraaortic lymph nodes is not mandatory [53]. We consider that patients who have suspicious lymph nodes on pretreatment imaging are more appropriate for initial chemoradiotherapy than surgery. The role of therapeutic debulking lymphadenectomy in such patients is controversial and discussed below. (See 'Role of therapeutic lymphadenectomy' below.)

Indications for adjuvant therapy after hysterectomy — As with cervical SCC, patients with one or more of the following findings are considered to be at high risk for recurrent disease and should receive adjuvant chemoradiotherapy following hysterectomy:

●Positive or close resection margins

●Positive lymph nodes

●Microscopic parametrial involvement

(See "Management of early-stage cervical cancer", section on 'High-risk disease'.)

Adjuvant therapy is also recommended for patients at intermediate risk of recurrence (large tumor size, deep cervical stromal invasion to the middle or deep one-third, or lymphovascular space invasion), but at least for SCC, there is less consensus on the optimal form of adjuvant therapy (RT versus chemoradiotherapy). In view of the above data suggesting that adenocarcinomas have a poorer outcome with RT alone than do SCCs, but that relative radioresistance might be overcome through the use of concurrent chemotherapy, we administer concurrent cisplatin-based chemotherapy. (See 'Prognostic factors and differences in outcome compared with SCC' above and "Management of early-stage cervical cancer", section on 'Intermediate-risk disease'.)

Locoregionally advanced (IIB to IVA) disease — For patients with locoregionally advanced cervical SCC, primary RT has been the treatment of choice at most institutions, although practice varies. Guidelines from the National Comprehensive Cancer Network (NCCN) suggest either radical hysterectomy or initial chemoradiotherapy in this setting [54].

However, in our view, these patients should be approached initially with chemoradiotherapy. One of the main arguments against a primary surgical approach in this setting is the high potential for multimodality therapy, given that the majority of patients will have high-risk or intermediate-risk disease for which postoperative chemoradiotherapy is recommended. (See "Management of locally advanced cervical cancer", section on 'Definition of locally advanced-stage cervical cancer' and "Management of locally advanced cervical cancer".)

Multiple randomized phase III trials, which enrolled predominantly SCC, as well as a meta-analysis have confirmed the survival benefit of adding cisplatin-based concurrent chemotherapy to RT for primary treatment of locally advanced cervical cancer. (See "Management of locally advanced cervical cancer", section on 'Primary chemoradiation'.)

It is reasonable to apply these results to adenocarcinoma and its variants for the following reasons:

●These trials included patients with adenocarcinoma histology.

●There is evidence that early-stage cervical adenocarcinomas are sensitive to cisplatin-based chemoradiation [41].

●Adenocarcinoma-specific phase III trials cannot feasibly be conducted due to the low incidence of glandular disease.

However, the dismal prognosis of all histologic types of advanced disease, especially stage III and IV, emphasizes the need for novel approaches [52,55].

Role of therapeutic lymphadenectomy — The role of therapeutic lymphadenectomy in patients undergoing primary chemoradiotherapy for locoregionally advanced cervical cancer is controversial. Surgical staging is the most accurate method of determining lymph node involvement, which is one of the most important prognostic factors. In addition, there is a potential therapeutic survival benefit of resecting lymph nodes, particularly bulky nodes, prior to chemoradiotherapy, but this has not been proven.

For both cervical SCC and adenocarcinoma, some clinicians use the results of radiographic staging studies to select patients for a therapeutic lymphadenectomy. Pre-irradiation staging lymphadenectomy (which can be accomplished laparoscopically or robotically) may be offered to medically fit patients if they have evidence of bulky nodes on computed tomography (CT) scan or if a pretreatment fluorodeoxyglucose (FDG)-positron emission tomography (PET) or PET/CT shows FDG uptake in the region of the infrarenal paraaortic or pelvic lymph nodes. If both are negative, routine staging lymphadenectomy is not performed. Guidelines from the NCCN suggest consideration of an extraperitoneal lymph node in this situation [54]. (See "Management of locally advanced cervical cancer", section on 'Pretreatment evaluation' and "Management of locally advanced cervical cancer", section on 'Treatment of para-aortic nodes'.)

Given the controversy as to whether debulking of nodes is associated with a real survival advantage, we generally do not perform a therapeutic lymphadenectomy in patients undergoing primary chemoradiotherapy who have bulky adenopathy identified on pretreatment imaging. However, this is a controversial area, and some clinicians would recommend removal of suspicious nodes in good surgical candidates.

Neoadjuvant chemotherapy — SCC of the cervix is a chemosensitive neoplasm particularly when cisplatin-based regimens are used, and neoadjuvant chemotherapy is an accepted approach for patients with locally advanced disease. (See "Management of locally advanced cervical cancer", section on 'Neoadjuvant chemotherapy'.)

Adenocarcinomas are similarly chemotherapy sensitive, at least in the setting of advanced disease [26,56]. The use of neoadjuvant chemotherapy may be beneficial in selected patients [57,58], but whether this strategy provides superior outcomes over chemoradiotherapy is unknown.

In our view, this approach should be considered experimental for adenocarcinomas and not pursued outside of the context of a clinical trial.

Stage IVB, persistent and recurrent disease

Surgery and/or RT for localized recurrence — Following radical hysterectomy or definitive chemoradiotherapy for early-stage cervical SCC, the predominant site of disease recurrence is local (vaginal apex) or regional (pelvic sidewall). The same holds true for adenocarcinoma. Exenterative surgery is an option only for those few patients with centrally relapsed disease. (See "Management of recurrent or metastatic cervical cancer", section on 'Candidates for surgical resection'.)

Chemotherapy — Patients with more extensive primary or locoregionally relapsed disease or distant metastatic disease are usually treated with chemotherapy. Small prospective studies have evaluated the response of adenocarcinoma to chemotherapy [26,56,59-61], but in general, it is managed similarly to SCC. (See "Management of recurrent or metastatic cervical cancer", section on 'Metastatic disease'.)

In addition, the GOG no longer conducts clinical trials in non-SCC cervical carcinoma because it was deemed not to be feasible, and the available data suggest similar outcomes when nonsquamous and squamous cervical cancers are treated with platinum-based combination chemotherapy [26].

We prefer that eligible patients enroll in clinical trials testing new strategies. However, if a clinical trial is not available or feasible, we treat these patients similar to those with SCC. Our preferred chemotherapy regimen consists of a platinum-based combination (eg, paclitaxel with cisplatin or carboplatin). On the basis of the results of GOG 240, we also incorporate the angiogenesis inhibitor bevacizumab in the first-line treatment setting. This study showed a significant improvement in median overall survival (OS) associated with the incorporation of bevacizumab (17 months) when compared with use of chemotherapy alone (13.3 months, hazard ratio 0.71, 98% CI 0.54-0.95) [62]. The results of GOG 240 are discussed separately. (See "Management of recurrent or metastatic cervical cancer", section on 'Initial treatment' and "Management of recurrent or metastatic cervical cancer", section on 'Metastatic disease'.)

For patients with a poor performance status and those who progress following first-line therapy, acceptable options include single-agent chemotherapy, best supportive care, and/or palliative RT. (See "Management of recurrent or metastatic cervical cancer", section on 'Second-line therapy'.)

Surgery for metastatic disease — Surgical resection may be useful in carefully selected patients with cervical adenocarcinomas who have isolated pulmonary metastases. (See "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques" and "Surgical resection of pulmonary metastases: Outcomes by histology".)

Fertility preservation — The management dilemma in patients with cervical adenocarcinoma who wish to preserve fertility is complicated by the inherent risks of residual disease and the relatively poor predictive value of conization margins. This is of somewhat greater concern than with squamous disease, since adenocarcinoma tends to be multifocal. Fertility preservation in patients with cervical cancer is discussed in detail separately. (See "Fertility-sparing surgery for cervical cancer".)

POSTTREATMENT SURVEILLANCE — The optimal surveillance strategy has not been established, and clinical practice is variable. Posttreatment surveillance for invasive cervical cancer is addressed in detail elsewhere. (See "Invasive cervical cancer: Patterns of recurrence and post-treatment surveillance".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Treatment of cervical cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Cervical cancer (The Basics)")

●Beyond the Basics topics (see "Patient education: Cervical cancer treatment; early-stage cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Epidemiology and risk factors – Cervical adenocarcinoma comprises 25 percent of invasive cervical cancers; squamous cell carcinoma (SCC) account for 70 percent. Some risk factors for cervical adenocarcinoma are shared with squamous disease, particularly infection with high-risk subtypes of human papillomavirus (HPV). By contrast, cigarette smoking does not appear to be a risk factor for adenocarcinoma. (See 'Introduction' above and 'Epidemiology and risk factors' above.)

●Clinical manifestations – Many patients with cervical adenocarcinoma are asymptomatic. When symptoms occur, patients are most likely to present with postcoital bleeding. (See 'Clinical manifestations' above.)

●Diagnosis and staging – Cervical adenocarcinoma is diagnosed with a cervical biopsy. Conization is required to define a microinvasive lesion, and a negative margin is required to confirm the diagnosis. (See 'Diagnosis and staging' above.)

The staging system used for cervical adenocarcinoma is the same as for SCC (table 3). We usually perform both a positron emission tomography/computed tomography and magnetic resonance imaging in nonmicroscopic invasive and more advanced cervical adenocarcinoma to help guide treatment. (See 'Diagnosis and staging' above.)

●Management of microinvasive disease – Management of microinvasive (stage IA1 to IA2) cervical adenocarcinoma depends on patient age and desire to maintain fertility. The prognosis of microinvasive disease is excellent, and conservative, nonradical surgery is appropriate for some patients. (See 'Microinvasive (IA1 and IA2) disease' above.)

•Stage IA1 – For most patients with stage IA1 cervical adenocarcinoma, we suggest simple hysterectomy rather than radical hysterectomy (Grade 2C). Pelvic lymphadenectomy is not necessary. Conization is a reasonable option in patients who wish to preserve fertility and who do not have lymphovascular space invasion. (See 'Microinvasive (IA1 and IA2) disease' above.)

•Stage IA2 – For patients with stage IA2 cervical adenocarcinoma, we suggest modified radical hysterectomy rather than simple hysterectomy (Grade 2C). We also perform pelvic lymphadenectomy in these patients. Radical trachelectomy is a reasonable option in patients who wish to preserve fertility and who do not have lymph node metastases and/or widespread evidence of lymphovascular space invasion. (See 'Microinvasive (IA1 and IA2) disease' above.)

●Management of invasive disease

•Most patients with stage IB or IIA1 – For most patients with stage IB or IIA1 cervical adenocarcinoma who are appropriate surgical candidates, we suggest initial surgery (radical hysterectomy, bilateral salpingo-oophorectomy, plus sentinel node biopsy or pelvic lymph node dissection) rather than primary chemoradiotherapy (Grade 2C). (See 'Invasive early stage (IB and IIA) disease' above and 'Role and extent of lymphadenectomy' above.)

The presence of positive or close resection margins, positive lymph nodes, or microscopic parametrial involvement indicates a high risk for recurrence. As with SCC, we recommend postoperative cisplatin-based concomitant chemoradiotherapy rather than adjuvant radiation therapy (RT) alone for these patients (Grade 1B). Although the optimal regimen has not been established, we suggest weekly cisplatin (40 mg/m² to a cumulative dose of at least 200 mg/m²) during RT (Grade 2C). (See 'Indications for adjuvant therapy after hysterectomy' above and "Management of early-stage cervical cancer", section on 'Surgery preferred over radiation'.)

As with SCC, we recommend adjuvant RT after hysterectomy for patients who are at intermediate risk of recurrence (large tumor size, deep cervical stromal invasion to the middle or deep one-third, or lymphovascular space invasion) (Grade 1B). We suggest adding concomitant chemotherapy to adjuvant RT for patients with intermediate-risk disease (Grade 2C). (See 'Indications for adjuvant therapy after hysterectomy' above and "Management of early-stage cervical cancer", section on 'Surgery preferred over radiation'.)

•Selected candidates for initial chemoradiation – For certain subsets of patients with invasive cervical adenocarcinoma, we suggest initial chemoradiation rather than surgery (Grade 2B). These include patients with the following (see "Management of locally advanced cervical cancer", section on 'Primary chemoradiation' and 'Invasive early stage (IB and IIA) disease' above):

-Locoregionally advanced stage IIB to IVA disease (table 3)

-Bulky early-stage disease (ie, stage IB2, IIA2)

-Evidence of lymph node involvement by imaging or clinical examination

•Patients with locoregionally advanced disease – For patients with locoregionally advanced disease, we suggest not pursuing neoadjuvant chemotherapy followed by hysterectomy outside of the context of a clinical trial (Grade 2C). (See 'Neoadjuvant chemotherapy' above.)

●Prognosis

•Patients with small tumors – In general, for patients with small tumors <2 cm in size without lymphovascular space invasion, the survival difference between adenocarcinoma and SCC is negligible. Surgical management results in low recurrence rates and high overall survival rates with no differences in outcome related to histologic type. (See 'Prognostic factors and differences in outcome compared with SCC' above.)

•Other patients – Other patients (eg, lymphovascular space invasion, tumor size >4 cm, deep stromal invasion to the middle or deep one-third) have worse prognosis and distant failure is more common when chemotherapy is omitted. (See 'Invasive early stage (IB and IIA) disease' above.)

●Disseminated, recurrent, or persistent disease

•Exenterative surgery is an option only for those few patients with centrally relapsed disease. (See 'Surgery and/or RT for localized recurrence' above.)

•For patients with a good performance status who wish to receive chemotherapy, and who are able to tolerate it, we suggest a platinum-based combination regimen plus bevacizumab in the first-line setting rather than chemotherapy alone (Grade 2B). Patients who are not candidates for bevacizumab should receive combination chemotherapy. (See 'Chemotherapy' above and "Management of recurrent or metastatic cervical cancer", section on 'Initial treatment' and "Management of recurrent or metastatic cervical cancer", section on 'Metastatic disease'.)

The choice of the specific regimen should be based upon prior toxicity, preexisting morbidity, scheduling considerations, and patient preference. A standard regimen is paclitaxel with cisplatin or carboplatin. (See 'Chemotherapy' above and "Management of recurrent or metastatic cervical cancer", section on 'Metastatic disease'.)

•Surgical resection is an alternative to chemotherapy for highly selected patients with isolated, potentially resectable pulmonary metastases. (See "Surgical resection of pulmonary metastases: Outcomes by histology", section on 'Gynecologic cancers' and "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques".)

•For patients with a poor performance status and those who progress following first-line therapy, acceptable options include single-agent chemotherapy, best supportive care, and/or palliative RT. (See "Management of recurrent or metastatic cervical cancer", section on 'Second-line therapy' and "Management of recurrent or metastatic cervical cancer", section on 'Management of acutely symptomatic patients'.)