The Diagnosis of Cervical Glandular Intraepithelial Neoplasia (CGIN).


Laurence Brown, Consultant Histopathologist, University Hospitals of Leicester.


The pre-invasive stage of adenocarcinoma of the cervix is recognised as a spectrum of changes termed cervical glandular intraepithelial neoplasia (CGIN).  By analogy with squamous intraepithelial lesions this terminology includes adenocarcinoma in situ, cervical glandular atypia and cervical intraepithelial glandular neoplasia.  Because of the difficulties of grading columnar neoplasia, this classification is divided into high (H-CGIN) and low (L-CGIN) grade.

High grade CGIN includes adenocarcinoma in situ and features nuclei that may be morphologically indistinguishable from invasive adenocarcinoma.  The involved glands may be strikingly hyperchromatic at low power, drawing attention to the presence of the lesion even when the glandular profile is normal.  The glands may also be complex with branched, budded or cribriform areas.  Characteristically, there may be an abrupt change from normal to neoplastic epithelium within the same gland.  The range of cytological changes includes atypical nuclei with increased, abnormal mitoses stratified for the whole epithelial height.  Apoptotic bodies are increased and may be useful in distinguishing CGIN from reactive conditions.  Other markers of increased cellular turnover include epithelial budding with intraluminal projections and increased Ki-67 and MIB-1 indices (>16% for Ki-67 and >30% for MIB-1.

In low grade CGIN (L-CGIN) the most obvious feature may be increased hyperchromasia accompanied by minor degrees of nuclear enlargement, nuclear variation, loss of polarity and increased mitoses.  The nuclei are generally limited to the basal two-thirds of the epithelium and there may be altered glandular profiles.  L-CGIN is most often seen accompanying H-CGIN but may exist alone and be the sole explanation for abnormal cervical cytology.

One of the difficulties of diagnosing glandular intraepithelial neoplasia is identifying an in situ lesion by excluding invasion. Normal glands are limited to a maximum depth of 7.8 mm and the intraepithelial lesion will only involve glandular profiles.  Glands outside the normal glandular field should always raise a suspicion of invasion. The most recognisable stage of superficial invasion features small squamoid buds invading though the basement membrane, as in squamous carcinoma.  Some workers have claimed that cribriform areas define invasion and there is little doubt that complex glandular and solid areas are more common in adenocarcinomas.  However. cribriform glands are seen in benign conditions such as microglandular hyperplasia and the presence of such architecture cannot be taken as diagnostic of invasion.  Furthermore, a desmoplastic stromal response accompanies invasion, but this may not always be present.  Inflamed normal glands may also excite a stromal response. 

Although in most cases it appears that CGIN arises in the transformation zone through a process of atypical reserve cell hyperplasia and then extends up the endocervical canal, some workers have observed skip lesions.  This may be a true occurrence or may be explained by tangential sectioning through the involved circumference of the endocervical canal. 

The glandular epithelium usually adopts an endocervical morphology but when stratified can be extremely difficult to differentiate from endometrioid epithelium.  Less than 4% of reported instances show enteric, adenosquamous or clear cell differentiation.

Intestinal metaplasia

The original accounts of intestinal metaplasia illustrated atypical epithelium.  It would seem that intestinal metaplasia is rarely, if ever, seen in the absence of CGIN and can be regarded as a powerful marker of its presence. 


Stratified Mucinous Intraepithelial Lesion (SMILE)

This shows a similar spectrum of nuclear morphology to CGIN but in this variant, mucin production is preserved with vacuoles distributed throughout the whole height of the dysplastic epithelium.  In most instances, SMILE is associated with CIN or H-CGIN and, if seen on biopsy, should be an indication for further sampling of the cervix. 


Ciliated CGIN


The presence of cilia may cause considerable confusion with tuboendometrioid metaplasia.  Dysplastic nuclear features are the most helpful in distinguishing these conditions but the glandular morphology may also be more abnormal in CGIN than in metaplasia. 


The Evidence for CGIN as a precursor of adenocarcinoma


CGIN exhibits similar morphological and morphometric appearances to adenocarcinoma, is found in a similar distribution and is found adjacent to areas of invasion.  18% of microinvasive adenocarcinomas also features associated L-GCIN.


H-CGIN may, if ignored or treated inadequately, progress to invasion within one year or by fourteen years on average.  The mean ages of 39 years for L-CGIN, 43 for H-CGIN and 48 years for microinvasive adenocarcinoma, are consistent with this. 


CGIN shows further similarities to adenocarcinoma in the expression of telomerase activation, lactoferrin mRNA, proliferation markers, lectin histochemistry, nucleolar organiser regions, epithelial membrane antigens, CEA expression, mucin histochemistry and CA125.  Tetraploidy has been reported in CGIN and the expression of c-myc oncogene is similar to adenocarcinoma. 




Normal cyclical changes


The endocervical epithelium undergoes a cycle of proliferation and secretion under hormone control.  During the course of this cycle there may be stratification of the nuclei.  This is readily distinguished from CGIN by the absence of the nuclear features of dysplasia.  Occasional normal mitoses may be seen. 


Tuboendometrioid Metaplasia


Crypts lined by tubal or endometrioid type epithelium, commonly arising in response to trauma, may appear worryingly hyperchromatic at low power.  However, the glandular profiles are usually normal and although there may occasional mitoses, abnormal figures are not present.  Tubal epithelium includes ciliated secretory and resting (intercalated) cells.  This heterogeneity may be misleading at low power.  An endometriotic stroma, reacting with CD10, may accompany these lesions.  Low MIB-1 and Ki-67 indices favour a diagnosis of tuboendometrioid metaplasia as does diffuse cytoplasmic reactivity for BCL-2 and a luminal reaction with HMFG.  Unlike H-CGIN, tuboendometrioid metaplasia is positive for Vimentin but the reaction with CEA in 39% of cases may not be sufficiently discriminatory to separate these lesions from CGIN (+ve in only 67%).


Rare metaplasias


Prostatic tissue and sebaceous glands have both been reported in this site. 


Tunnel clusters


Collections of small or variably sized cystically dilated glands (Type A) or branched, budded, lobular proliferations without dilatation (Type B) are commonly seen, usually in women over 30.  These glands may result from involution following hyperplasia but do not appear to be due to obstruction of the crypt duct.  Marked glandular proliferation may cause gross enlargement of the cervix that can be confused with carcinoma on clinical examination.  Inflammation may cause a degree of nuclear atypia but these lesions lack mitotic activity, coarse chromatin or apoptotic bodies. 


Microglandular hyperplasia


Closely packed collections of small glands may form polypoid projections into the endocervical canal that may cause bleeding or clinical confusion with carcinoma.  Microscopically, cuboidal, columnar or squamoid cells may form acini or solid sheets typically supported by lacy subcolumnar reserve cells.  The epithelium may be vacuolated with occasional signet ring cells.  Typically the epithelium and gland lumina contain neutrophils with mixed inflammatory cells in the stroma.  Mitoses may be present (usually less than 1 per 10 high power fields) but apoptotic bodies are rare and there should be no severe nuclear atypia.  The differential diagnosis includes adenosquamous carcinoma and clear cell carcinoma but in contrast to the latter, microglandular hyperplasia lacks cytoplasmic glycogen.  Immunohistochemistry shows luminal activity of HMFG and CEA 125 with lack of significant reaction for CEA in the epithelial cells contrasting with the cytoplasmic reaction in most adenocarcinomas.  The subcolumnar reserve cell may be +ve for CEA.


Lobular endocervical hyperplasia


This features a proliferation of simple tubular glands forming lobules exending deeply into the cervical stroma but limited to the inner half of the wall of the cervix.  The glandular epithelium is banal, tall or cuboidal, mucin secreting, lacking atypia with indistinct nucleoli.  Rare mitoses may be present.  This must be distinguished from adenoma malignum by the lack of deep infiltration or irregularly shaped glands. 


Laminar endocervical hyperplasia


In this, endocervical glands form a sharply delineated layer up to two-thirds into the depth of the cervical stroma.  The glands show some similarities with lobular endocervical hyperplasia, lacking nuclear features of malignancy. 


Gartner’s duct remnants/mesonephric hyperplasia


These embryological remnants of the analague of the testicular efferent ducts may product ramifying ductular outgrowths extending beyond the lateral portions of the cervix to involve any quadrant.  The glands may proliferate in lobular or diffuse growth patterns composed of small acini formed by low columnar or cuboidal cells with pale vesicular nuclei.  A characteristic eosinophilic intra-acinar product may be present.


Arias Stella change


 Hypersecretory endocervical glands may be seen in up to 9% of pregnancies.  The appearances are similar to the endometrium, where nuclear hyperchromasia and pleomorphism may cause confusion with neoplasia.  An awareness of the condition is the best defence against misdiagnosis.


Atypical Endocervical Oxyphilic metaplasia


The endocervical epithelium is oxyphilic with some apical blebbing, similar to apocrine metaplasia.  This is usually an incidental finding associated with inflammation.  The nuclei may be enlarged, hyprchromatic or poylobated, but the is no stratification or mitoitc activity

Papillary cervicitis

The normal crypt pattern may be exaggerated to produce blunt-tipped papillae projecting into the endocervical canal where they become congested, haemorrhagic and inflamed.  There is no dysplasia or epithelial proliferation.

Florid Cystic Endosalpingiosis

This is a proliferation of cysts lined by tubal type epithelium in the outer part of the cervical wall. There may be similar deposits of endosalpingiosis on the serosa of the uterus and on the ovaries.  There is no atypia or stromal response.

Radiation atypia

The crypts that may be atrophic lined by atypical epithelium, but with no more than a slight increase in nuclear cytoplasmic ratio and loss of polarity, without hyperchromasia. Atypical stromal fibroblasts may indicate the aetiology.  The epithelium may be reactive for CEA.


 Minimal deviation adenocarcinoma


Adenoma malignum or minimal deviation adenocarcinoma features glands that invade deeply into the cervical stroma, displaying abnormally shaped, branched, budded or characteristic claw shaped profiles.  The epithelium is very well differentiated and may show a pyloric phenotype.  This condition is associated with Peutz-Jeghers syndrome, sex cord tumours with annular tubules and mucinous ovarian tumours.  The diagnosis may be extremely difficult to make on biopsy but the presence of rare focal cytological atypia with rare normal mitotic figures helps.  The most important diagnostic characteristics are deep invasion, stromal response, focal atypia, invasion around medium sized arterioles and lymphatic permeation.  The immunohistochemical reactions are similar to those of adenocarcinoma.


Other differential diagnoses to be considered include change, atypical endocervical oxyphilic metaplasia, florid cystic endosalpingiosis, papillary cervicitis, radiation atypia and endocervical adenomyoma. 





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