adenocarcinoma of the cervix

Current Obstetrics & G.waecology (1999) 9. I241 29 0 1999 Harcourt Publishers Ltd .

Mini-Symposium: Diagnosis and management of cervical neoplasia

Adenocarcinoma of the cervix

J. L. Burton, J. M. Lopes and M. Wells

Cervical cancer is the second commonest cancer in women. Adenocarcinoma of the cervix (ACC) is an uncommon neoplasm with a poor prognosis. The disease accounts for 8-34%) of primary carcinomas of the cervix, and the incidence is increasing in young women. In this article, we review the epidemiology and molecular pathology of these tumours, before discussing the clinical, histological and cytological features of the various sub-types of these neoplasms. A discussion of the prognostic factors of these tumours is also included. 0 1999 Harcourt Publishers Ltd

EPIDEMIOLOGY

In developed countries, adenocarcinoma accounts for 8-34% of primary carcinomas of the cervix. In young women (under 35 years of age), the relative incidence of these tumours doubled between 1970 and 1980. This apparent increase may reflect a genuine increase in disease incidence, but is probably due - at least in part - to the declining incidence of squamous carcinomas of the cervix brought about by mass cervical cytology screening programmes.‘~? Cervical screening has a much lower sensitivity for adenocarcinoma in situ than for squamous carcinoma in situ. In addition, a history of negative smears offers no protection from the development of adenocarcinom.a.j With improved sampling of the endocervix and transfor- mation zone with devices such as the cytobrush, the frequency of diagnosis by cytology is increasing.?

The risk factors for the development of ACC include an inadequate smear history, the number of sexual partners, and the age at first intercourse. ACC is associated with cervical intraepithelial neoplasia (CIN) or squamous cell carcinoma in 60% of cases,

Julian L. Burton and Michael Wells, Department of Pathology, Division of Oncology and Cellular Pathology, University of Sheffield Medical School, Beech Hill Road, Sheflield SIO ZRX, UK. JosC M. Lopes Institutio de Patologia e Imunologia Molecular de Universidade de Porto, 4200 Porto, Portugal

Correspondence to: J.L.B.

and with adenocarcinoma in situ in up to 50% of cases.’ The association with CIN supports the theory that the epithelium of the lower female genital tract acts as a single tissue field to certain carcinogenic stimuli. It is suggested that a sexually transmitted agent - probably human papillomaviruses (HPV) - may play a role in the disease pathogenesis.’ Controversy exists regarding the association with the use of combined oral contraceptive pills with a high progesterone content. Obesity and nulliparity are barely significant risk factors.

AETIOLOGY AND PATHOGENESIS

HPVs

The molecular alterations involved in the pathogenesis of ACC are complex and remain poorly understood. The HPVs are epitheliotropic double- stranded DNA viruses that can immortalize cells and have been widely implicated in the pathogenesis of cervical neoplasia. Of the 100 types of HPV identi- fied to date, HPV 16 and 18 are commonest in these tumours. HPV infection is commonest in squamous cell carcinomas, where HPV 16 is the predominant agent. Using polymerase chain reaction analysis, HPV DNA can be detected in up to 85% of ACC. In these tumours, infection with HPV 18 is most frequent, although HPV 16 and HPV 33 infection

124

Adenocarcinoma of the cervix 125

ig. 1 High-grade cervical glandular intracpithelial ncoplasia tdenocarcinoma-in-situ) associated with squamous cervical Itraepithelial ncoplasia grade III.

lay also be demonstrated. Mixed infections occur in p to 27% of cases.Sm7

Patients with tumours containing HPV DNA are gnificantly younger than those whose tumours do ot (mean age. 5 1.6 vs 62.9 years respectively). HPV ,NA is found more often in mutinous than in non- ‘ucinous tumours (95.8 vs 60.5%) and may be associ- :ed with low grade and stage disease. In addition, the resence of HPV DNA is associated with a better rognosis.“.”

HPV is thought to target the reserve cells of the ldocervix, consistent with the observation that HPV ‘NA is found more frequently in reserve cell-derived luamous metaplasia than in ectocervical squamous lithelium. The mechanism by which HPV induces jenocarcinoma of the cervix is uncertain. HPV pro- uces two viral proteins - E6 and E7. These bind to Id inactivate the tumour suppressor protein pro- uced by wild type tp53. The loss of functional ~53 suits in deregulated cellular proliferation and ansformation. The accumulation of- abnormally abilized ~53 protein can be detected immuno- stochemically in up to 38’%1 of cases. It has been lggested that HPV infection is an early event in the stogenesis of these neoplasms.“.“’ Up to 25% of ACC do not contain HPV DNA.

lthough controversy exists, it would appear that ost tp53 mutations do not occur in tumours COII-

ining HPV DNA. tp53 mutation occurs in up to !.5’!4 of ACC and is associated with advanced stage sease and a poor prognosis. tp53 mutation is not lated to the age of the patient. The majority of tp53 utations occur in the absence of HPV and may be a te event in disease progression in ACC.“.” ‘I’

ther aspects of molecular pathology

he IX/S gene encodes a 21 kDa protein (~21) with TPase activity that is involved in normal cell- ceptor signal-transduction pathways. Parker et al.“’ Lve detected k-r.c/.s mutations in 9% of ACCs, all :curring in cases of stage 1 disease. They were unable

Fig. 2 Low-grade cervical glandular intraepithelial neoplasia. Note the increased nuclear stratification and mitotic activity of the endocervical mutinous epithelium.

to detect a correlation between k-rus mutation, HPV infection, or tp53 mutation, but the number of cases studied was small.

Oestrogen (ER) and progesterone (PgR) receptors are present in normal endocervical columnar epithelium. and the quality of endocervical mucus fluctu- ates in response to the hormonal changes of the menstrual cycle. Fujiwara et al.” detected nuclear ER and PgR positivity in 20 and 27?4, respectively, of primary ACCs. Mutinous endocervical and endometrioid adenocarcinomas are most frequently associated with ER and PgR positivity. Although controversy exists, steroid receptor positivity does not appear to correlate with disease stage, overall survival or disease-free survival (discussed in reference Fujiwara et al.).”

It has been suggested that ACC may also share some of the complex molecular alterations observed in endometrial adenocarcinoma.’ These have been described in detail elsewhere.”

Cervical glandular intraepithelial neoplasia

There is now widespread international acceptance that precursor lesions of cervical adenocarcinoma exist, which are referred to as cervical glandular intraepithelial neoplasia (CGIN). This term encom- passes high-grade lesions including adenocarcinoma- in-situ (Fig. 1) and low-grade (or mildly dysplastic) lesions (Fig. 2). The latter have been the subject of controversy because knowledge of their natural history has been so elusive. Circumstantial evidence exists for their malignant potential; the mean age of women with low-grade, high-grade glandular intraepithelial neoplasia and microinvasive adenocarcinoma progressively increasing with a span of approximately 10 years. I3 However, by analogy with their squamous counterparts it seems inherently unlikely that all intraepithelial lesions will inevitably progress to invasion.

126 Current Obstetrics & Gynaecology

Fig. 3 Well-differentiated primary villoglandular adenocarcinoma of the endocervix.

Fig. 4 Minimal deviation adenocarcinoma of the cervix. Despite the bland appearance of the endoccrvical epithelium it extended deeply into the cervical stroma and was ultimately responsible for the death of the patient.

CLINICAL FEATURES

The majority of these tumours occur in postmenopausal women and the mean age at diagnosis is between 47 and 53 years. Up to 50% of patients are asymptomatic and diagnosed as a result of cervical cytological screening. In the remainder, the commonest symptoms include abnormal uterine bleeding, vaginal discharge, pelvic pain and dyspareunia.

Macroscopically, ACC appears as an exophytic, polypoid lesion which may be papillary, nodular, sessile or ulcerated. In the lS-30% of patients whose tumours arise high in the endocervical canal, or who have small and infiltrative tumours, the cervix may appear normal. The majority of these neoplasms (85%) are found to be confined to the cervix or invad- ing the parametrium or upper vagina at the time of diagnosis.’

HISTOLOGICAL FEATURES

On light microscopy, ACC is seen to consist of several cell types, morphological patterns and degrees of dif- ferentiation. The predominant cell type determines the taxonomy of ACC. Tumours containing more than 10% of a second cell type are designated as mixed tumours.

Endocervical type

This is the commonest variant of ACC, and accounts for up to 90% of cases. The tumours usually have a moderately differentiated glandular pattern with a desmoplastic stroma and are composed of cells similar to those lining normal endocervical crypts. Not infrequently, these tumours contain foci with a papillary growth pattern. Cervical intraepithelial neoplasia is frequently present in the overlying squamous epithelium.

The differential diagnosis of endocervical ACC includes microglandular hyperplasia, hyperplasia of mesonephric remnants, the Arias-Stella reaction and so-called tunnel clusters. These benign lesions should be excluded before the diagnosis of ACC is made.

Endocervical glandular dysplasia. adenocarcinoma in situ (AIS) and early invasive (microinvasive) adenocarcinoma are putative precursor lesions occurring in younger patients. These may be very difficult to differentiate from ACC. particularly in cytological or small cervical biopsy specimens.‘“‘”

Villoglandular papillary type

These tumours account for approximately 5% of primary adenocarcinomas of the cervix. First described in 1989, this tumour occurs at a younger age (mean, 33 years) and has a better prognosis than the usual endocervical type. The lesions are composed of vari- ably sized papillary and villous tibrovascular fronds with tibromatous stroma. These are lined by a strati- tied non-mutinous columnar epithelium. the cells of which have eosinophilic cytoplasm, mild-to-moderate nuclear atypia and a low mitotic index (Fig. 3). The majority of these tumours are well circumscribed and cervical stromal invasion is usually focal. Vascular invasion is rare. Adenocarcinoma in situ is present in the adjacent endocervix in approximately 50% of cases. I6

The differential diagnosis includes typical endocer- vital adenocarcinoma with a minor villoglandular papillary component, minimal deviation adenocarcinoma and adenosarcoma. The presence of nuclear and cellular atypia is helpful in determining the correct diagnosis.

Minimum deviation adenocarcinoma (‘adenoma malignum’)

This rare variant of endocervical-type carcinoma accounts for approximately 1% of all cervical adenocarcinomas and shares a common symptomatology with other cervical neoplasms. However, some cases are associated with Peutz-Jeghers syndrome and others co-exist with mutinous or sex-cord tumours of the ovary. Prospective diagnosis based on cervical cytology is difficult but the presence of enlarged cells


anged in honeycomb-like sheets, with moderate ounts of vacuolated or lacy cytoplasm, large :lei and a normal nuclear:cytoplasmic ratio are racteristic.” Histologically, these tumours are extremely well ‘erentiated and are composed of glands lined by a nolayer of mucin-secreting epithelial cells with lima1 cytological atypia (Fig. 4). Foci of less-well- erentiated tumour, clear cell or endometrioid ‘erentiation may be present. The malignant glands architecturally abnormal, with elongated, angu-

:d and branching crypts which invade beyond the .mal gland-bearing stroma of the cervix. Deeply asive glands may be associated with a desmoplastic )ma. In some cases, the presence of perineural or cular invasion may be the only evidence of malig- 1cy.“J8 Minimum deviation adenocarcinoma (MDA) may misdiagnosed as normal endocervical glands, but era1 histochemical and immunohistochemical hniques can be applied to distinguish the two. like normal endocervical glands, which produce phomucins and sialomucins, it has been reported t MDA produces sialomucins only. Furthermore, se tumours do not show immunoreactivity for trogen or progesterone receptors, or for CA125. :a1 carcinoembryonic antigen (CEA) immuno- ctivity may also be present.18J9 Although this tumour has a bland morphological jearance, and despite its name, MDA should be arded as an aggressive tumour requiring radical ltment, which has a poor prognosis.

dometrioid type

is rare type of ACC is morphologically similar to lometrioid endometrial adenocarcinomas of the rine corpus. They may have a mixed papillary and ndular pattern, and focal squamous metaplasia is : uncommon. It may be difficult to differentiate this on from poorly differentiated endocervical type C with little mucin production. The exclusion of a mary endometrioid endometrial adenocarcinoma h extension into the cervix is a prerequisite of diag- ;is.’ Extremely well-differentiated variants (mini- 1 deviation endometrioid adenocarcinoma) have :n reported, comprised of well-differentiated nds closely resembling proliferating endometrium hout a stromal reaction. As with minimal deviation mocarcinoma, there is minimal cellular atypia. The on may be associated with cervical intraepithelial )plasia.‘”

:ar cell type

with clear-cell adenocarcinomas of the vagina, 2r-cell adenocarcinoma of the cervix has a bimodal : distribution. The first peak occurs in women aged 17 years (mean age, 23.6 years) and approximately

two-thirds of patients have been exposed to diethylstilbestrol in utero. The second peak occurs in postmenopausal women (mean age, 71 years) in the absence of diethylstilbestrol exposure.2’ Histo- logically, these tumours contain tubulocystic papillary and solid patterns composed of clear cells with glyco- gen-rich cytoplasm and ‘hob-nail’ cells. Cytoplasmic mucin is not present and mitoses are infrequent. The histological characteristics of clear cell carcinoma of the female genital tract are similar regardless of its location (cervix, vagina, ovary or endometrium).

Serous papillary type

These rare tumours arise from the superficial epithelium of the endocervix and are composed of papillae with fine librovascular cores, identical to ovarian serous papillary carcinomas. The exclusion of metastasis or direct extension from a primary serous papillary carcinoma of the ovary, fallopian tube or endometrium is a prerequisite for diagnosis.’

Intestinal type

These neoplasms are morphologically similar to the adenocarcinomas common to the colon and rectum. The tumour is composed of glands lined by pseudos- tratilied columnar epithelial cells containing small amounts of mucin and occasional signet ring cells and goblet cells. Some of these tumours show differentia- tion towards small intestinal epithelium and contain numerous Paneth cells.‘? Exclusion of direct extension or metastasis from a primary adenocarcinoma of the gastrointestinal tract is a prerequisite for diagnosis.

Intestinal metaplasia is frequently seen within foci of cervical glandular intraepithelial neoplasia.

Adenoid cystic and adenoid basal carcinoma

These rare neoplasms have often been regarded as a single entity, but are clinically and histologically dis- tinct. The majority present with postmenopausal bleeding. They are less common in Caucasians than in other races.

Adenoid basal carcinomas occur in postmenopausal women (mean age, 64 years), and the cervix is usually normal on examination. The majority of cases are associated with squamous cell carcinoma or CIN grade 3. Microscopically, the tumour is composed of small cells with uniform dark oval nuclei and scant cytoplasm. These cells show peripheral palisad- ing and are arranged in nests resembling basal cell carcinoma of the skin. Focal squamous metaplasia is common. The tumour does not elicit a stromal reaction, and vascular channel invasion is rare. The tumour has an excellent prognosis.23

In contrast, adenoid cystic carcinoma is a poorly differentiated tumour that occurs in older women (mean age, 72 years). A cervical mass is present in the

1~~5 Current Obstetrics di Gynaecology

majority of cases. Microscopically, the tumour is composed of sheets, cords, trabeculae and nests of cells, often with a cribriform pattern. A focal cylindro- matous pattern may be present. The tumour cells are slightly larger than in adenoid basal carcinoma, with mild-to-moderate nuclear pleomorphism. The tumour ‘elicits a marked stromal reaction, with hyalinization, myxoid change or desmoplasia. Necrosis may be extensive. The tumour is aggressive and frequently fatal.”

,

Mesonephric type

These are extremely rare tumours and most cases represent misdiagnosed cases of clear-cell adenocarcinoma of Miillerian origin. True mesonephric ACC may show several infiltrative patterns (ductal, tubu- loglandular, retiform, solid nests and sex cord-like). The lesion grows deeply in the lateral cervical wall, usually without endocervical mucosal involvement. Transition from mesonephric remnants is a helpful diagnostic feature.’

PROGNOSIS

The prognosis of ACC is influenced by disease stage (as defined by the International Federation of Gynecology and Obstetrics [FIGO]), histological subtype, tumour grade, the presence of pelvic lymph node metastases and tumour volume. In contrast, obesity, gravidity, diabetes, hypertension, age less than 35 years and a history of oral contraceptive use do not affect prognosis.Z4

Chen et a1.24 observed 5 year survival rates for FIG0 stages I, II, and III/IV of 75.9,62.9, and 25.1% respectively (P < 0.001). The overall 5 year survival rate was 66.5%. Radical surgery for stages I and IIA resulted in better survival rates than radiation therapy. Clear-cell carcinoma had a worse prognosis compared with other cell types (P < 0.02), whilst endocervical, papillary and mucoid adenocarcinomas have a similar prognosis. The effect of histological subtype on prognosis is most apparent in stage I and II, but is not significant in stage III and IV disease.Z4.rs

The presence of bulky disease carries a poor prognosis.24 Depth of invasion may be difficult to assess accurately. In microinvasive disease (defined as penetration of the stroma to a depth of no more than 5 mm), the maximum tumour depth and horizontal spread are measured.‘j

Although the presence of metastatic disease is associated with decreased survival, adenocarcinoma metastatic to lymph nodes does not have a uniformly poor prognosis. In a study of 40 patients with lymph- node metastases, Cohn et al.zs observed that the median survival fell from 70 months to 24 months in patients with para-aortic lymph-node metastases, but the results did not achieve statistical significance. The dominant influence on survival in patients with

lymph-node metastases was the extent of disease at presentation. Patients with stage I disease were more likely to undergo radical hysterectomy than radio- therapy, and had a better prognosis.

CONCLUSIONS

Adenocarcinoma of the cervix consists of several histological subtypes, the majority of which are rare.

The disease has a complex pathogenesis, in which HPV infection plays a major role. The molecular pathology of ACC remains poorly understood.

Prognosis depends on disease stage, grade and histological subtype.

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adenocarcinoma of the cervix

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