Terminology

In keeping with the terminology used for squamous cervical intraepithelial neoplasia (CIN), earlier investigators recognized three grades of cervical glandular intraepithelial neoplasia (CGIN), but this has proven unrealistic. Three grades (glandular atypia, glandular dysplasia, and atypical hyperplasia), with only subtle differences among them, are not reproducible, and far less so than for corresponding squamous lesions. Even squamous intraepithelial lesions, in the Bethesda System, for example, are grouped into two categories for this reason. A more practical approach is to divide the spectrum of glandular changes into two grades. These are variously referred to as low-grade CGIN and high-grade CGIN, or endocervical glandular dysplasia and adenocarcinoma in situ (AIS).

The 2003 World Health Organization (WHO) classification included, among the precursors of invasive cervical adenocarcinoma, glandular dysplasia and AIS; however, their morphologic distinction remains unclear. Endo­cervical glandular dysplasia (atypical hyperplasia) refers to ‘glandular lesions characterized by significant nuclear abnormalities that are more striking than those in glandular atypia but fall short of the criteria for adenocarcinoma in situ .’ In other words, glandular dysplasia closely resembles AIS but differs in that the nuclei are not cytologically malignant and mitoses are less numerous. However, because of its rarity, the lack of diagnostic reproducibility, and the uncommon coexistence with AIS, the clinical and biologic significance of glandular dysplasia has not been established. Among the biomarkers used to clarify the relationship between glandular dysplasia and AIS are p16 ^INK4A , Ki-67/MIB1, and human papillomavirus (HPV) DNA determination, but results have been controversial. Besides, the relationship of HPV infection to glandular precursors differs from that of HPV and squamous precursor lesions. Whereas productive HPV infection is represented morphologically by low-grade squamous intraepithelial lesion (LSIL; mild dysplasia), a comparable lesion does not occur in glandular epithelium. Thus, it appears that productive HPV infection is closely associated with squamous but not glandular epithelium. Rather than using the term glandular dysplasia, it has been recommended to evaluate the atypical glandular lesions that fall short of AIS with p16 ^INK4A and Ki-67/MIB1. Lesions negative for p16 ^INK4A and showing a low Ki-67/MIB1 proliferation index should be diagnosed as reparative changes; on the other hand, lesions expressing a strong and diffuse p16 ^INK4A immunoreaction and a high Ki-67/MIB1 labeling index should be classified as AIS.

Definition

AIS is characterized by replacement of glandular epithelium by cytologically malignant epithelial cells with preservation of the glandular architecture. Involvement of more than one gland is required for the diagnosis.

Etiology

The evidence in favor of AIS being a precursor lesion for invasive adenocarcinoma includes the following: (1) patients with AIS are about 10–15 years younger than those with invasive adenocarcinoma, (2) AIS is commonly found in the vicinity of invasive adenocarcinoma, (3) similar HPV types are identified in both AIS and invasive adenocarcinoma, and (4) occasional cases of AIS have been documented to progress to adenocarcinoma.

General Features

AIS represents 10–20% of cervical adenocarcinomas. Compared to high-grade squamous intraepithelial lesions (HSILs), AIS is much less common, with reported ratios varying from 1 : 26 to 1 : 237. In the Surveillance, Epidemiology and End Results (SEER) registry, of 121,793 (82%) cervical lesions classified as in situ , 120,317 (99%) were squamous cell carcinoma in situ (CIS) and only 1476 (1%) were AIS. In contrast to squamous cervical lesions, the incidence of invasive glandular lesions is higher than that of noninvasive glandular lesions. The median age at diagnosis in a recent large series was 35 years compared with 41 years for women with invasive adenocarcinoma. Most AIS are asymptomatic and found in patients with abnormal cervical smears. AIS does not produce a grossly visible lesion, nor does it have a characteristic lesion like SIL by colposcopy. It involves both the surface and glands of the transformation zone in 65% of cases and is predominantly unifocal. It can extend for a distance of up to 3 cm into the endocervical canal. SIL or invasive squamous cell carcinoma coexists with AIS in 24–75% of cases and the exfoliated atypical cells lead to clinical investigation helping to identify AIS. Most AIS are associated with HPV DNA and HPV 16 and 18 are the most commonly encountered types.

Pathology

Microscopically, AIS spreads along the surface of the endocervix and does not extend below normal glands. There is neither stromal invasion nor desmoplasia. Part or all of the epithelium lining the glands shows nuclear stratification with elongated, cigar-shaped, hyperchromatic nuclei and increased mitotic activity. Based on cytoplasmic features, four subtypes of AIS have been described: (1) endocervical or mucinous type, (2) intestinal type, (3) endometrioid type, and (4) adenosquamous type. In addition, rare examples of clear cell and tubal type have been described. Although these histologic types do not have biologic significance, their distinction helps the pathologist to recognize AIS.

The most common form of AIS is the endocervical type, in which the cells resemble those of the endocervix, and glands show nuclear pseudostratification, nuclear atypia, small to moderate amounts of juxtaluminal cytoplasm containing mucin, scattered juxtaluminal mitoses (normal and/or abnormal), and apoptotic bodies ( Figures 12.1–12.5 ). Typically, there is a sharp demarcation of AIS from closely uninvolved glands and from the uninvolved epithelium of the same gland ( Figure 12.6 ). The glands of AIS can show numerous outpouchings and complex papillary infoldings and may exhibit a cribriform pattern. Intestinal-type AIS, a form of intestinal metaplasia, is characterized by the presence of goblet cells ( Figure 12.7 ). Occasionally, neuroendocrine cells, which are argentaffin positive, and even Paneth cells may also be present. Nuclear atypia is not as evident because the mucin globules compress the nuclei, reducing the degree of nuclear enlargement and pseudostratification. Endometrioid AIS is characterized by glands resembling proliferative or hyperplastic endometrium and exhibits marked nuclear pseudostratification and absent cytoplasmic mucin or mucin staining confined to the luminal border. In many ways, this distinction between endocervical and endometrioid AIS is artificial as the endometrioid features represent endocervical-type cells that have lost their intracytoplasmic mucin. Endometrioid AIS is most distinctive when it exhibits villoglandular architecture ( Figure 12.8 ). The adenosquamous type is characterized by glands containing cells exhibiting both glandular and squamous features. It is important to distinguish adenosquamous CIS from AIS, which coexists but is separate from an adjacent HSIL. The tubal type of AIS is diagnostically challenging because of its similarity to tubal metaplasia, but the cells have pseudostratification, nuclear enlargement, coarse chromatin, apoptotic bodies, and mitotic figures.

AIS compared with normal glands. The glands involved by AIS show little mucin in comparison to normal endocervical glands.

AIS. Clusters of glands involved by AIS

AIS endocervical type with numerous mitoses and apoptosis.

AIS. Stratification with elongated, cigar-shaped, hyperchromatic nuclei.

AIS compared with normal endocervical gland.

AIS. Sharp demarcation from closely uninvolved glands and from the uninvolved epithelium of the same gland.

AIS, intestinal type with numerous goblet cells.

Villoglandular AIS.

Immunohistochemistry

Most cases of AIS show diffuse nuclear and/or cytoplasmic immunoreactivity for p16 ^INK4A ( Figure 12.9 ) whereas normal endocervix demonstrates no reactivity. Overexpression of p16 ^INK4A is induced when high-risk HPV DNA integrates into the cell genome. Another useful marker is Ki-67/MIB1. The majority of AIS cells exhibit nuclear reactivity for Ki-67 and the proliferation index is usually over 30% ( Figure 12.10 ). In contrast, p53 is expressed only focally in 20% of cases. In fact, a strong p53 reaction should alert the possibility of serous carcinoma, either extending from the endometrium or as a primary endocervical tumor. Since AIS typically shows significant degrees of apoptosis, the anti-apoptotic marker bcl-2 is usually negative or only focally positive. Possibly, Ki-67/MIB1, p16 ^INK4A , and bcl-2 may serve as a diagnostic panel. Carcinoembryonic antigen (CEA) immunoreactivity occurs in 63–78% of AIS cases, whereas the endocervical epithelium is either negative or shows only luminal reaction. Vimentin immunostaining is negative. As indicated earlier, accurate application of these markers may clarify whether an atypical glandular lesion is a reparative condition or a precursor to endocervical glandular malignancy. Moreover, while these ancillary tests are useful, the mainstay of diagnosis should be careful morphologic examination.

AIS. Overexpression of p16 ^INK4A .

AIS. Nuclear reactivity for Ki-67.

Cytologic Findings

Cytologic ability to detect cervical glandular lesions is limited by both sampling and interpretation. The historical view that the Pap smear has low sensitivity for AIS is changing. While relevant studies are few, emerging evidence indicates that the sensitivity of the cervical smear for detecting AIS is in the range of 40–69%. This compares favorably with sensitivity for CIN 3, which has been reported as ranging between 43% and 75%. In the 2001 Bethesda System ‘AIS’ became a separate category. Cases showing some features suggestive but not diagnostic of AIS are ‘atypical endocervical cells, favor neoplastic.’ The lowest reporting category for abnormal endocervical cells is ‘atypical endocervical cells, NOS’ (not otherwise specified). Typical architectural features include crowded sheets of columnar cells with palisading and feathering of nuclei at group edges, pseudo­stratification, small strip-off sheets, and gland openings within the sheets ( Figure 12.11 ). In addition, rosettes are also a characteristic feature ( Figure 12.12 ). The nuclei are typically enlarged and oval shaped with coarse granular chromatin. Mitoses and apoptosis are helpful features if seen. With the use of liquid-based cytology (LBC), the cytologic appearances are different. Glandular groups with this methodology are more three-dimensional than with the usual cervical smear and show attenuation of several typical architectural features of AIS. Nuclear features are better preserved in samples collected in fluid medium. An advantage of this new methodology is the opportunity to perform immunohistochemical stains, such as p16 ^INK4A on the original cytology samples.

AIS, endocervical type (Pap smear). A crowded sheet with ragged edges. Hyperchromatic elongated nuclei show palisading and feathering at the edges of the sheet.

AIS, endocervical type (Pap smear). A rosette displays a central lumen and a ragged periphery.

Differential Diagnosis

Several benign glandular lesions simulate AIS. The most common is tubal metaplasia, which displays in varying proportions a mixture of ciliated, secretory, and resting (intercalary or peg) cells, even within a single case ( Figure 12.13 ). Glands exhibiting tubal metaplasia lack nuclear atypia and mitoses are seen only occasionally. Apoptotic bodies are inconspicuous. The glands may be associated with endometrioid-type stroma. Endometrioid metaplasia also shows bland nuclei that lack significant mitotic activity. CD10-positive endometrioid stroma may also be present. Immunohistochemically, tuboendometrioid metaplasia shows a low Ki-67/MIB1 immunoreactivity and strong widespread reaction for bcl-2. It also exhibits p16 ^INK4A in 62% of cases, but, unlike AIS, the reactivity is only focal. Tubo­endometrioid metaplasia may show reactivity for CEA in 39% of cases, but, unlike AIS, expresses vimentin. The presence of cilia usually implies a benign process, but, of note, ciliated AIS also occurs.

Tuboendometrioid metaplasia.

Superficial cervical endometriosis ( Figure 12.14 ) may be confused with AIS histologically, particularly in patients followed with cytologic smears after cone biopsy. The endometriotic foci are usually confined to the inner third of the cervical wall. The endometrioid glands are typically evenly spaced, show bland cytologic features, and are surrounded, at least focally, by endometrial-type stroma, which may show focal hemosiderin deposition. Inflammation and hemorrhage may obscure the stromal cells. Mitotic figures are seen in 37% of cases.

Superficial cervical endometriosis.

Endocervical glands may show a variety of architectural and cytologic changes in response to inflammation. This may lead to a suspicion of AIS. In inflammatory/reparative changes, the nuclei become enlarged and show chromatin clearing and prominent nucleoli. Nuclear pleomorphism may occur, but the chromatin is often smudged ( Figure 12.15 ). Pseudostratification and mitotic activity are minimal. Apoptotic bodies are generally absent. p16 ^INK4A and Ki-67/MIB1 immunoreactions are usually negative. Endocervical glands in some patients may also show mild morphologic changes during the menstrual cycle. Occasionally, a normal-appearing mitosis can be found in normal endocervical glands and should not raise concern ( Figure 12.16 ).

Endocervical gland showing inflammatory changes.

Normal endocervical gland showing a mitotic figure.

Radiation therapy results in widely spaced endocervical glands that are often dilated and lined by cells showing nuclear enlargement and pleomorphism, but the cytoplasm is finely vacuolated or granular ( Figure 12.17 ). There is often loss of nuclear polarity and the nuclei show dispersed chromatin and one or two prominent eosinophilic nucleoli. Focal cytoplasmic CEA reactivity occurs and does not distinguish it from AIS.

Radiation changes. The endocervical glands show hyperchromatic nuclei.

The Arias-Stella reaction involves the endocervical glands in 10% of gravid uteri ( Figure 12.18 ). Superficial glands are more commonly involved than deep glands. The involved glands typically have a single layer of enlarged hyperchromatic pleomorphic nuclei that protrude into the lumen producing a ‘hobnail’ appearance. The glandular cells may also show intranuclear cytoplasmic inclusions as well as optically clear nuclei. Mitoses are exceedingly rare or absent.

Arias-Stella reaction. Hyperchromatic ‘hobnail’ nuclei protruding into the gland lumina.

In contrast to AIS, microglandular hyperplasia lacks significant nuclear atypia ( Figure 12.19 ), lacks pseudostratification, has rare mitotic figures, and p16 ^INK4A immunoreaction is negative. AIS, however, may occasionally involve areas of microglandular hyperplasia and, in such cases, the presence of residual microglandular hyperplasia uninvolved by AIS is the key to establishing the diagnosis. Similarly, AIS may also extend into other benign endocervical glandular lesions, such as tunnel clusters.

Microglandular hyperplasia. The small glands lack significant nuclear atypia, pseudostratification, and mitotic figures.

A stratified mucin-producing intraepithelial lesion (SMILE) exhibits stratified epithelium resembling CIN in which there is conspicuous mucin production ( Figure 12.20 ). Mucin is present throughout the epithelium, varying from indistinct cytoplasmic clearing to discrete vacuoles. The lesion shows a rounded or lobulated contour at the epithelial–stromal interface and a high Ki-67/MIB1 index. SMILE is an unusual cervical intraepithelial lesion best regarded as a variant of cervical columnar cell neoplasia based on phenotype. SMILE is frequently associated with CIN, AIS, or invasive carcinoma.

SMILE in a case also with AIS and CIN 3 elsewhere in the cervix.

Biologic Behavior and Treatment

AIS is treated either by conization or by hysterectomy. Because of the multicentric distribution of AIS, recurrence occurs more often after conization than after hysterectomy, particularly if the lesion involves the margins of the cone. Even though in young women who are desirous of preservation of fertility cone biopsy may be selected, currently the definitive therapy for AIS remains hysterectomy. In a meta-analysis, 27% of patients treated with conization where the margins were free of abnormality had residual AIS in the subsequent hysterectomy specimen. This figure reached 59% if the margins on cone biopsy were positive. Some authors believe that the disease-free endocervical margin in a cone biopsy must be at least 10 mm to consider the lesion completely excised. If a lesser procedure is performed, cold knife or laser cone biopsy is more effective than loop electrosurgical excision, especially for the endocervical margin. Furthermore, patients with AIS and positive margins on cone biopsy are at moderate risk of harboring an occult invasive endocervical adenocarcinoma that has already developed. The optimal management of the atypical glandular lesions that fall short of AIS is even more controversial, with treatment options including cytologic follow-up or management along the lines of AIS.

Definition

Microinvasive adenocarcinoma refers to the earliest form of invasive adenocarcinoma and is classified generally in a manner similar to microinvasive squamous cell carcinoma.

Pathology

In contrast to microinvasive squamous cell carcinoma, the glandular counterpart has received little attention in the literature. The ideal definition of microinvasive adenocarcinoma should guarantee the safety of conservative therapy; it should describe an invasive adenocarcinoma small enough not to be associated with metastasis. The main diagnostic problems are, first, to distinguish microinvasive adenocarcinoma from AIS and, second, how to measure the depth of invasion.

The criteria for microinvasion include: (1) obvious stromal invasion by epithelial finger-like processes arising from glands involved by AIS or detached cellular clusters with abundant pink cytoplasm lying free in the stroma; (2) obliteration of the normal endocervical crypts; (3) complex intraglandular cribriform or papillary growth patterns; (4) stromal edema, inflammation, and desmoplasia; and (5) extension below the deep margin of normal endocervical glands ( Figures 12.21 and 12.22 ). If the distance between neoplastic glands and thick-walled blood vessels is less than the thickness of the vessel wall, invasion should be suspected ( Figure 12.23 ). Not all of these features are present in every case and invasion is indicated by the gland pattern and haphazard distribution on low-power examination. The depth of invasion is usually measured from the surface epithelium (tumor thickness) rather than from the point of origin. This is due to the difficulty to determine where AIS ends and stromal invasion begins ( Figure 12.24 ). Indeed, the identification of early invasion in cervical glandular lesions may not always be possible, and in approximately 10–15% of patients the pathologist may be uncertain.

Microinvasive adenocarcinoma. The irregular growth pattern and irregular outlines of the glands are indicative of early invasive carcinoma.

Microinvasive adenocarcinoma. Numerous irregular glands with cribriform pattern.

Microinvasive adenocarcinoma. A tumor gland appears adjacent to a thick-walled blood vessel.

Microinvasive adenocarcinoma. In some cases it may be difficult to distinguish AIS from invasive adenocarcinoma. The deeply invasive glands suggest this tumor is invasive.

The FIGO system (2009) for staging carcinoma of the cervix makes no distinction between squamous and glandular lesions. Stage IA1 defines invasion to less than 3 mm in depth and less than 7 mm in width; stage IA2 defines invasion between 3 and 5 mm in depth and less than 7 mm in width. Vascular space invasion does not alter the stage.

Cytologic Correlation

Microinvasive adenocarcinoma can sometimes be predicted cytologically. Features include those of AIS, which are always present. Syncytia of glandular cells, small cells in supercrowded sheets, papillary groupings, and dissociated cells are suggestive of the diagnosis. Nuclear features include pleomorphism with irregular chromatin and nucleoli. Tumor diathesis may also be present. Collectively, these criteria help predict microinvasion in over two-fifths of cases. In practical terms, microinvasion can be accurately defined only histologically. The major role of cytology in this circumstance is identifying the existence of high-grade neoplasia of endocervical columnar cell origin.

Biologic Behavior and Treatment

It appears that microinvasive adenocarcinoma behaves in the same way as its squamous counterpart. What is uncertain is the maximum size at which less than radical treatment is safe. When microinvasive adenocarcinoma does not invade beyond 5 mm, the margins are free, and the conization specimen has been totally embedded, conservative treatment is acceptable. A review of the literature revealed that only five (2%) of 219 patients with microinvasive adenocarcinoma invading less than 5 mm were found to have metastasis after pelvic lymph node dissection. Of these patients, 3.4% developed recurrences and 1.4% died. No patient treated by radical hysterectomy had parametrial involvement. The relationship of capillary–lymphatic space involvement, lymph node metastasis, and recurrence remains uncertain. Conization is considered acceptable treatment only if the specimen has been adequately sampled and the margins free. Fifty percent of patients with positive margins had residual disease in the subsequent hysterectomy specimen.

In a SEER database review of 301 cases of microinvasive adenocarcinoma of which 131 were FIGO stage IA1 and 170 were stage IA2, only one of 140 women who had lymphadenectomy had a single positive lymph node. This patient had stage IA2 disease. Moreover, of four women with tumor-related deaths, three were stage IA2. Overall, the prognosis for microinvasive adenocarcinoma is excellent and, in 96 cases, simple hysterectomy alone proved adequate. In a more recent study evaluating depth of invasion, none of 48 patients with tumor under 5 mm invasion had involved parametria or nodes; whereas eight of the 36 with invasion greater than 5 mm had nodal metastases. None of the former developed a recurrence whereas one-sixth of the latter had recurrent disease. These data argue that, for patients with tumor less than 5 mm invasion and negative margins, pelvic lymphadenectomy may be omitted. Similarly, in a study of 32 patients with FIGO stage IA1 and IA2 adenocarcinomas of the cervix where invasion was strictly defined, the method of measurement was standardized and villoglandular, serous, and clear cell carcinomas were excluded, no recurrences have been reported to date. Clearly, some young women with early invasive adenocarcinomas might best be served by treating the tumor in the same way as microinvasive squamous cell carcinoma.

Definition

An adenocarcinoma in which the tumor cells resemble those lining the endocervical glands and contain varying amounts of cytoplasmic mucin. This is the most common type of adenocarcinoma accounting for almost 80% of all cervical adenocarcinomas.

Pathology

Grossly, half of cervical adenocarcinomas are exophytic, usually as a polypoid or papillary mass. Some may be nodular, with diffuse enlargement ( Figure 12.25 ) or ulceration, and some tumors present as a barrel-shaped cervix. About one-sixth are small and not visible, usually because of their location within the endocervical canal. Even in the absence of visible signs or symptoms, the tumor may infiltrate deeply into the wall ( Figure 12.26 ). Generally, the gross appearance is not helpful in predicting the histologic appearance.

Adenocarcinoma. Diffuse enlargement of the cervical wall.

Adenocarcinoma. Perivascular infiltration deep into the cervical wall.

As indicated earlier, most tumors are moderately differentiated and show little intracytoplasmic mucin; thus, the tumor glands resemble those of endometrioid carcinoma or exhibit a mixed endocervical and endometrioid appearance. This has led to confusion, with these tumors regarded as endometrioid adenocarcinomas. Gland size may vary from small to cystic, and the glands may be widely spaced or closely packed, often with a cribriform pattern. Papillae may be present, but are rarely conspicuous ( Figure 12.27 ). Mitoses are readily found and apoptotic bodies are commonly seen ( Figure 12.28 ). The tumors are usually associated with a desmoplastic or a prominent fibromatous stroma. Some tumors show prominent numbers of acute inflammatory cells within both the stroma and the gland lumens.

Adenocarcinoma, usual-type. The glands are arranged in a complex pattern. Stroma is abundant.

Adenocarcinoma, usual-type. The papillae are lined by stratified epithelial cells showing numerous mitoses and apoptotic bodies. The stroma contains abundant chronic inflammatory cells.

Well-differentiated endocervical adenocarcinomas show complex glandular arrangement resembling the tunnel configuration of the normal endocervical mucosa. The tumor cells have basal nuclei and abundant pale cytoplasm, which stains positively with mucicarmine stains. There is significant nuclear atypia and mitotic figures. Large amounts of mucin may be found in the stroma, forming mucin lakes or pools in the so-called colloid carcinoma.

Grading of the tumors follows the general FIGO system for glandular tumors as described elsewhere for endometrium and ovary. Grade 1 tumors (well-differentiated tumors) grow in glandular formations with less than 5% of areas being solid. Grade 3 tumors (poorly differentiated tumors) are more than 50% composed of solid tumor nests; the cells may show pseudorosette formation or palisading of nuclei.

The distinction of endocervical adenocarcinomas from endometrial adenocarcinomas may be difficult particularly when a fractional curettage has not been performed or when tumor is present in both samples of the curettage. The presence of abundant intracellular mucin favors an endocervical origin, but most endometrial adenocarcinomas show focal mucinous differentiation and some of them are largely mucinous. The stroma of the tumor may be helpful; in cervical tumors it is typically fibrous whereas endometrial carcinomas usually contain very little stroma. Hysteroscopy is often helpful in identifying the site of origin of the tumor ( Table 12.2 ).

Coexistent CIN occurs in up to 40% of cases , and AIS is also common. Synchronous mucinous tumors may be found elsewhere in the female genital tract.

Immunohistochemistry

Approximately 90% of endocervical adenocarcinomas are HPV related and show diffuse and moderate/strong immuno­reaction for p16 ^INK4A ( Figure 12.29A ). Apparently, high-risk E6 and E7 HPV transforming proteins interact with cell cycle regulatory proteins (p53, Rb) and cause p16 ^INK4A overexpression. In contrast, endometrioid carcinomas are etiologically unrelated to HPV and exhibit usually patchy p16 ^INK4A immunoreaction of variable intensity. Typical endocervical adenocarcinomas are often, but not always, cytoplasmic CEA positive and are negative for vimentin ( Figure 12.29B ). Estrogen (ER) and progesterone (PR) receptors are also generally negative ( Figure 12.29C ); however, focal weak reactivity for ER may be present. In contrast, primary endometrial adenocarcinomas of endometrioid type are strongly immunoreactive for both vimentin and ER and PR and are negative for CEA. However, endometrial tumors showing mucinous differentiation may be strongly positive for CEA.

Adenocarcinoma. (A) Diffuse and strong immunoreaction for p16. (B) Negative vimentin. (C) Negative estrogen receptors.

Thus, it appears that tumors that show strong positive immunoreaction for vimentin and ER, and weak or negative immunostaining for p16 ^INK4A , are almost invariably of endometrial origin.

In situ Hybridization

In situ hybridization for high-risk HPV types is the most specific test available for distinguishing endocervical from endometrial adenocarcinoma. At least 90% of cervical adenocarcinomas contain high-risk HPV types, whereas endometrial carcinomas are negative.

Cytologic Correlation

Invasive endocervical adenocarcinoma shares many features with AIS. Features helpful in correctly predicting histologic invasion include: heavy blood staining, abundant abnormal glandular epithelium, supercrowding of sheets, small three-dimensional groups, papillary clusters, tumor diathesis, single malignant cells with nuclear pleomorphism and macronucleoli, and mitotic figures ( Figure 12.30 ). LBC may be more sensitive than conventional cytology in detection of cervical adenocarcinoma. The reduction in screening false negatives has been attributed to enhanced cytologic detail and the elimination of obscuring elements such as blood.

Adenocarcinoma (ThinPrep) showing a group of malignant glandular cells with lysed blood in the background.

Differential Diagnosis

The histologic differential diagnosis of cervical adenocarcinoma includes benign glandular lesions (see Chapter 8 ) including tunnel clusters (types A and B), microglandular hyperplasia, lobular endocervical glandular hyperplasia, diffuse laminar endocervical glandular hyperplasia, and deep nabothian cysts, as well as secondary adenocarcinoma metastatic to the cervix. In general, when faced with a problematic endocervical glandular lesion, features that favor a benign lesion include: (1) superficial location and lack of deep infiltration, (2) lobulation, (3) well-defined margins, (4) bland nuclear features, (5) inconspicuous mitotic and apoptotic activity, and (6) absence of a stromal reaction. However, benign glandular lesions may coexist with adenocarcinoma and, ultimately, assessment of the overall cytologic and architectural features facilitates the correct diagnosis.

An Arias-Stella reaction involving endocervical glands is found in 10–50% of pregnant uteri. These glands show markedly pleomorphic cells with large abnormal nuclei; prominent nucleoli; and pale, vacuolated cytoplasm. Knowledge of the patient’s pregnant status is very important to prevent a false-positive diagnosis of adenocarcinoma. Occasionally glandular changes similar to the Arias-Stella reaction occur in nonpregnant women, usually in patients taking exogenous hormones. Whereas the characteristic nuclear atypicality may suggest malignancy, lack of mitoses and partial gland involvement help to establish the correct diagnosis. Both atypical oxyphilic metaplasia and radiation-induced atypia show enlarged, hyperchromatic nuclei exhibiting smudged chromatin, cytoplasmic vacuolation, and preservation of the nuclear to cytoplasmic ratio.

Tunnel clusters mimic cervical adenocarcinoma with a microcystic pattern. High-power examination, however, reveals the presence of cytologic atypia and the malignant nature of the lesion. Other benign lesions that may simulate invasive adenocarcinoma of the cervix are microglandular hyperplasia and hyperplastic mesonephric remnants. Microglandular hyperplasia tends to occur in young women and is frequently polypoid. In contrast to cervical adenocarcinoma, microglandular hyperplasia is composed of small and uniform glands lined by a single layer of bland epithelium with few mitoses. Mesonephric remnants show lobular arrangement in the vicinity of mesonephric ducts, and are deep in the cervical stroma. The epithelium lining the tubules is usually cuboidal, lacks mucin, and shows minimal cytologic atypia.

Endometrial carcinoma may extend to the endocervix, but, when it does, it has usually invaded the myometrium and has become sufficiently bulky to enlarge the uterus. Microscopically, endocervical adenocarcinoma can be distinguished from endometrial adenocarcinoma extending to the cervix by the presence of squamous metaplasia and foamy histiocytes in the latter. Immunohistochemical stains may be helpful in difficult cases (see earlier) ( Table 12.2 ). Metastatic adenocarcinoma of the cervix usually occurs in patients with known widely spread tumors and typically shows lack of surface involvement and widespread lymphovascular invasion. Metastatic carcinomas involving the cervix arise most commonly from gastrointestinal tract, ovary, and breast and are characterized by a clean background. In contrast, bowel and bladder carcinomas, which directly invade the female genital tract, often have a necro-inflammatory diathesis due to fistula formation. In assessing whether a carcinoma is of primary endocervical origin or is metastatic in the cervix, the finding of a transition between in situ and invasive carcinoma provides the strongest evidence for a primary cervical origin and is found in approximately 50% of cases.

Biologic Behavior and Treatment

Although older studies suggested that the prognosis of adenocarcinomas of the cervix was worse than that of squamous cervical cancer, more recent studies adjusting for depth, stage, and therapy have not found a significant difference. Collectively, the prognosis for adenocarcinoma is essentially that of squamous carcinoma or slightly worse, and, in general, both squamous carcinomas and adenocarcinomas are treated similarly. Differences in survival rates for squamous cell carcinoma and adenocarcinoma in stage I and II disease may be due to the relative ineffectiveness of radiotherapy as a primary treatment in cases of adenocarcinoma. The features that influence prognosis are similar to those for squamous cell carcinoma, mainly histologic grade, tumor size, depth of invasion, lymphatic–capillary space involvement, stage, age, and lymph node status. In addition, the ratio of mitotic index to apoptotic index is also of prognostic significance. Young age at presentation has been associated with a good prognosis in several series. Infection with HPV 18 has been associated with poor survival. The 5 year survival for adenocarcinoma according to stage is stage IA1, 100%; stage IA2, 93%; stage IB, 83%; stage II, 37–62.9%; stage III, 13–31%; and stage IV, 0–6%. Longest survival is seen in patients with early stage disease, younger patients, and those treated with primary surgery.

Definition

This unusually well-differentiated mucinous adenocarcinoma was initially designated as adenoma malignum to emphasize its bland histologic appearance in spite of its highly malignant behavior. Today, the term ‘minimal deviation adenocarcinoma’ is often used synonymously with ‘adenoma malignum.’ The concept of minimal deviation adenocarcinoma has been expanded to include endometrioid and clear cell variants.

Recent studies have shown that minimal deviation adenocarcinoma frequently exhibits a gastric immunophenotype, as demonstrated by immunoreactivity for HIK1083 and/or anti-MUC6 antibodies which recognize pyloric gland mucin.

Clinical Features

It is a rare tumor accounting for only 1–3% of adenocarcinomas of the cervix. The age range of patients is 25–72 years (mean age, 42 years). Synchronous or metachronous ovarian mucinous tumors with histologic features resembling cystadenoma, borderline tumor, and well-differentiated adenocarcinoma may also occur and have been interpreted as representing independent primary ovarian tumors or metastases. A minority of cases are associated with the Peutz–Jeghers syndrome. Other ovarian neoplasms associated with minimal deviation adenocarcinoma of the cervix in patients with the Peutz–Jeghers syndrome are sex cord tumors with annular tubules. In these patients, benign mucinous epithelium may be seen in the endometrium and fallopian tubes and should not be interpreted as metastasis. Therefore, close follow-up of patients with Peutz–Jeghers syndrome is recommended, including periodic endocervical cytologic examination and curettage. The most common presenting sign, as with most cervical carcinomas, is abnormal vaginal bleeding. A mucoid, watery, or purulent vaginal discharge may be present.

Pathology

Grossly, adenoma malignum resembles and is indistinguishable from other types of endocervical adenocarcinoma. It may be polypoid or ulcerative and the cervical wall is typically firm or indurated. In early lesions, the cervix may even look normal. The mucosa is usually hemorrhagic, friable, or mucoid. On section, the cervix usually shows thickening by yellow or tan-white tumor tissue and mucin-filled cysts are occasionally prominent ( Figure 12.34 ).

Minimal deviation adenocarcinoma (‘adenoma malignum’). The tumor diffusely infiltrates the entire thickness of the cervical wall.

The tumor shows glands lined by a single layer of columnar cells with clear and/or pale eosinophilic and voluminous cytoplasm, with distinct cell borders and basal uniform nuclei with inconspicuous nucleoli. Features that help in arriving at the correct diagnosis include: (1) variability in gland shape and size, often exhibiting large branching glands ( Figures 12.35 and 12.36 ); (2) desmoplastic or edematous stroma; and (3) mitotic figures. Nevertheless, large areas of invasive tumor may be devoid of any stromal reaction. In such areas, the presence of glands adjacent to thick-walled blood vessels is a helpful finding in determining that stromal invasion is present ( Figure 12.37 ). Furthermore, areas of clearly malignant glands, vascular invasion, or perineural invasion ( Figure 12.38 ), which help to confirm the diagnosis, are present in approximately half of the cases. In most cases the tumor deeply invades the cervical wall and spreading to the parametrium is seen in approximately 40% of patients. The most reliable criterion to assess the malignant nature of minimal deviation adenocarcinoma is the haphazard arrangement of glands that extend beyond the level of normal endocervical glands (over 8 mm). Thus, a histologic diagnosis of minimal deviation adenocarcinoma may be impossible in small superficial biopsies; it instead requires cone biopsy or hysterectomy specimen.

Gastric-type or minimal deviation adenocarcinoma (‘adenoma malignum’). There are numerous branching glands of varying size and shape.

Gastric-type or minimal deviation adenocarcinoma (‘adenoma malignum’). Well-differentiated and excessively convoluted endocervical-type glands.

Gastric-type or minimal deviation adenocarcinoma (‘adenoma malignum’). Tumor gland adjacent to thick-walled blood vessel.

Gastric-type or minimal deviation adenocarcinoma (‘adenoma malignum’). Extensive perineural invasion.

Cytologic diagnosis of adenoma malignum is challenging. Smears display many large branching sheets of enlarged glandular cells with retention of the honeycomb pattern and peripheral palisading. Nuclei can be enlarged but are uniform, with smooth nuclear membranes, occasional irregularities in shape, and fine chromatin. Small nucleoli may be present. Cytoplasm is abundant and vacuolated or lacy. The presence of more usual type adenocarcinoma cells with increased nuclear atypia and pleomorphism may provide a useful clue.

Immunohistochemistry

Immunohistochemical staining for estrogen and progesterone receptors is uniformly negative in minimal deviation adenocarcinoma, and this finding helps to distinguish these tumors from variants of normal endocervical glands. Stains for p16 ^INK4A are negative or only focally positive since minimal deviation adenocarcinoma is not associated with high-risk HPV infection and the Ki-67/MIB1 proliferation index is often low. HIK1083 and MUC6, two markers for pyloric gland phenotype, are frequently positive with 75% and 65% rates, respectively. Up to 95% of cases are positive for at least one of these two markers. MUC6 can also be positive in intestinal-type adenocarcinoma.

Somatic Genetics

Somatic mutations of the STK11 gene, the gene responsible for Peutz–Jeghers syndrome, are characteristic of minimal deviation adenocarcinoma. They were found in 55% of patients with minimal deviation adenocarcinoma and in only 5% of other types of mucinous adenocarcinoma of the cervix. In the sporadic form of adenoma malignum, a putative tumor suppressor gene is located at D19S216 on chromosomal band 19p13.3 and plays an important role in adenoma malignum tumor genesis.

DNA measurements of the glands of adenoma malignum disclose patterns similar to those of normal endocervical glands. Reports of HPV identification strongly suggest that HPV is involved in only rare cases.

Differential Diagnosis

Benign lesions which must be distinguished from adenoma malignum include tunnel clusters, deep nabothian cysts, diffuse laminar endocervical glandular hyperplasia, microglandular hyperplasia, and mesonephric hyperplasia.

Tunnel clusters are benign, lobulated proliferations of small, nondilated, closely packed glands found virtually always as an incidental finding. While most glands are arranged around a central primary or secondary endocervical cleft and as a group are well circumscribed, occasionally the borders may be irregular and have a pseudoinvasive appearance. Rarely, some areas may show cytologic atypia.

Diffuse laminar endocervical glandular hyperplasia is also an incidental finding in hysterectomy or cone biopsy specimens. Moderate-sized, evenly spaced, extremely well-differentiated endocervical glands are present within the inner one-third of the cervical wall and are sharply demarcated from the underlying cervical stroma. A marked inflammatory response is often present. Occasionally, entirely normal endocervical glands can be found deep in the wall as an incidental finding. Usually the glands are few in number, but rarely may be florid.

Endocervicosis, a condition that usually involves the urinary bladder, but may also involve the deep cervix, is of unknown pathogenesis. In the few cases described, the lesion grossly consisted of firm rubbery masses 1–2.5 cm in size, and was located in the outer half of the anterior cervical wall and separate from the normal endocervical glands lining the endocervix. Microscopically, the mucinous glands are of variable size and shape, and exhibit endocervical-type glands with bland cytologic features. Desmoplasia is absent.

Histochemistry using a combined Alcian blue (pH 2.5)/periodic acid–Schiff (PAS) stain may be useful. Normal endocervical glands with their high content of acid and neutral mucins stain a purple to violet color, whereas the glands of cervical adenoma malignum (and conventional adenocarcinomas) stain red because of the almost exclusive presence of neutral mucin.

In a recent study, both adenoma malignum and well-differentiated adenocarcinoma of usual type could be distinguished from endocervical glandular hyperplasia by identifying surrounding α-smooth muscle actin-positive stromal cells and by the absence or decreased number of ER-positive stromal cells in the malignant tumors.

Biologic Behavior and Treatment

Despite its histologically bland appearance, adenoma malignum invades deeply and commonly metastasizes to lymph nodes. In a literature review of tumors that were clinically staged before treatment, 50% of patients with stage I tumors and 80% of patients with stage II tumors died of recurrent tumor despite radical treatment in most cases. Hematogenous dissemination of tumor is exceptional and tumor recurrence is most commonly in the abdominopelvic region.

Definition and Clinical History

Villoglandular adenocarcinoma is an uncommon variant of cervical adenocarcinoma that shows well-differentiated villo­glandular fronds resembling villoglandular adenoma of the colon. It occurs mostly in young women (average age, 35–45 years) and is associated with excellent prognosis. A link with oral contraceptive use has been suggested.

Pathology

The tumor is grossly distinctive and usually appears as a broad-based, papillary, and friable cervical polyp ( Figure 12.39 ). Microscopically, it shows by a surface papillary component of variable thickness ( Figure 12.40 ). The papillae are long and slender, occasionally short and broad, and covered by endocervical, endometrioid, or intestinal epithelia with at most mild to moderate cytologic atypia ( Figures 12.41–12.43 ). The amount of stroma in the villi may be substantial or minimal, and often contains many acute and chronic inflammatory cells. The epithelium may be pseudostratified, but lacks tufting and solid areas. The invasive portion of the tumor, if present, is composed of elongated branching glands separated by a fibrous stroma like that seen in the stroma of the papillae but sometimes it may be myxoid or desmoplastic. Most tumors are either entirely exophytic or show only superficial invasion, confined to the inner third of the cervical wall. The tumor cells usually exhibit mild to moderate nuclear atypicality and contain scattered mitotic figures. Lymphatic or vascular invasion is rarely observed. Associated SIL or AIS is common. Lymph node metastases are rare.

Villoglandular adenocarcinoma. The tumor appears as a broad-based, papillary, and friable cervical polyp.

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