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.
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)
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.
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.
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%).
Prostatic tissue and sebaceous glands have both been reported in this site.
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.
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
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.
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.
Andersen E S, Arffman E 1989 Adenocarcinoma in-situ of the uterine cervix: a clinicopathologic study of 36 cases. Gynecologic Oncology 35: 1–7.
Anderson M C, Hartley R B 1980 Cervical crypt involvement by intraepithelial neoplasia. Obstetrics and Gynecology 55: 546-550
Arends M J, Buckley C H, Wells M 1998 Aetiology, pathogenesis and pathology of cervical neoplasia Journal of Clinical Pathology 51:96-103
Ayroud Y, Gelfand MM, Ferenczy 1985 A Florid mesonephric hyperplasia of the cervix: a report of a case with review of the literature Int J Gynecol Pathol 4(3):245-54.
Betsill W G, Clark A H 1986 Early endocervical glandular neoplasia. I. Histomorphometry and cytomorphology. Acta Cytologica 30: 115–126.
Brown L J R, Wells M 1986 Cervical glandular atypia associated with squamous intraepithelial neoplasia: a premalignant lesion? Journal of Clinical Pathology 39: 22–28.
Brown L J R, Griffin N R, Wells M 1987 Cytoplasmic reactivity with the monoclonal antibody HMFG1 as a marker of cervical glandular atypia. Journal of Pathology 151: 203–208.
Bulmer J N, Griffin N R, Bates C, Kingston R E, Wells M 1990 Minimal deviation adenocarcinoma (adenoma malignum) of the endocervix: a histochemical and immunohistochemical study of two cases. Gynecologic Oncology 36: 139–146.
Christopherson W M, Nealson N, Gray L A 1979 Non-invasive precursor lesions of adenocarcinoma and mixed adenosquamous carcinoma of the cervix uteri. Cancer 44: 975–983.
Chumas JC, Nelson B, Mann WJ, Chalas E, Kaplan CG1985. Microglandular hyperplasia of the uterine cervix. Obstet Gynecol 66(3):406-9
Cina S J, Richardson M S, Austin R M 1997 Immunohistochemical staining for Ki-67 antigen, carcinoembryonic antigen and p53 in the differential diagnosis of glandular lesions of the cervix Modern Pathology 10:176-180
Clement P B, Young R H 1989 Deep nabothian cysts of the uterine cervix. International Journal of Gynecological Pathology 8: 340-348
Colgan T J, Lickrish G M 1990 The topography and invasive potential of cervical adenocarcinoma in situ with and without associated squamous dysplasia Gynecologic Oncology 36:246-249
Duk J M, Aalders J G, Fleuren G J, Kraus M, de Bruijn H W A 1989 Tumor markers Ca125, squamous cell carcinoma antigen and carcinoembryonic antigen in patients with adenocarcinoma of the uterine cervix. Obstetrics and Gynecology 73: 661–688.
Ferry JA, Scully RE 1990 Mesonephric remnants, hyperplasia, and neoplasia in the uterine cervix. American Journal of Surgical Pathology 14: 1100-1111
Fluhmann CF 1961. Focal hyperplasia (tunnel clusters) of the cervix uteri. Obstet Gynecol 17:206-214
Fichera G, Santanocito A. 1989 Pilo-sebaceous cystic ectopy of the uterine cervix. Clin Exp Obstet Gynecol.;16:21-5
Gilks C B, Young R H, Aguirre P, DeLellis R A, Scully R E 1989 Adenoma malignum (minimal deviation adenocarcinoma) of the uterine cervix: a clinicopathological and immunohistochemical analysis of 26 cases. American Journal of Surgical Pathology 13: 717–729.
Gloor E, Hurlimann J 1986 Cervical intraepithelial glandular neoplasia (adenocarcinoma in-situ and glandular dysplasia). Cancer 58: 1272–1280.
Gloor E, Ruzicka J 1982 Morphology of adenocarcinoma in-situ of the uterine cervix: a study of 14 cases. Cancer 49: 294–302.
Goldstein N S, Ahmad E, Hussain M, Hankin R C, Perez-Reyes N 1998 Endocervical Glandular atypia. Does a preneoplastic lesion of adenocarcinoma in situ exist American Journal of Clinical Pathology 110:200-209
Jones MA, Andrews J, Tarraza HM 1993. Mesonephric remnant hyperplasia of the cervix: a clinicopathologic analysis of 14 cases. Gynecol Oncol 49(1):41-7
Hurlimann J, Gloor E 1984 Adenocarcinoma in-situ and invasive adenocarcinoma of the uterine cervix: an immunohistologic study with antibodies specific for several epithelial markers. Cancer 54: 103–109.
Ishii K, Hidaka E, Katsuyama T, Ota H, Shiozawa T, Tsuchiya S 1999 Ultrastructural features of adenoma malignum of the uterine cervix: demonstration of gastric phenotype. Ultrastructural Pathology 23: 375-381
Jones MA, Young RH, Scully RE 1991. Diffuse laminar endocervical glandular hyperplasia. A benign lesion often confused with adenoma malignum (minimal deviation adenocarcinoma). Am J Surg Pathol 15(12):1123-9
Jones M W, Kounelis S, Papadaki H, Bakker A, Swalsky P A, Woods J, Finkelstein S D 2000 Well differentiated adenocarcinoma of the uterine cervix: Oncogene/tumour suppressor gene alterations and human papillomavirus genotyping. International Journal of Gynecological Pathology 19: 110-117
Kaku T, Enjoji M 1983 Extremely well differentiated adenocarcinoma (“adenoma malignum”) of the cervix. International Journal of Gynecological Pathology 2: 28–41.
Kashimura M, Shinohara M, Oikawa K, Hamasaki K, Sato H 1990 An adenocarcinoma in-situ of the uterine cervix that developed into invasive adenocarcinoma after 5 years. Gynecologic Oncology 36: 128–133.
Kashimura M, Shinohara M, Oikawa K, Hamasaki K, Sato H 1990 An adenocarcinoma in-situ of the uterine cervix that developed into invasive adenocarcinoma after 5 years. Gynecologic Oncology 36: 128–133.
Larraza-Hernandez O, Molberg KH, Lindberg G, Albores-Saavedra J 1997 Ectopic prostatic tissue in the uterine cervix. Int J. Pathol 16(3):291-3
Lesack D, Wahab I, Gilks C B 1996 Radiation-induced atypia of endocervical epithelium: a histological immunohistochemical and cytometric study International Journal of Gynecological Pathology 15:242-247
Luesley D M, Jordan J A, Woodman C B J, Watson N, Williams D R, Waddell C 1987 A retrospective review of adenocarcinoma in situ and glandular atypia of the uterine cervix. British Journal of Obstetrics and Gynaecology 94: 699–703.
McCluggage G, McBride H, Maxwell P, Bharucha H 1997 Immunohistochemical detection of p53 and bcl2 proteins in neoplastic and non-neoplastic endocervical glandular lesions International Journal of Clinical Pathology 16:22-27
McCluggage W G, Maxwell P, McBride H A, Hamilton P W, Bharucha H 1995 Monoclonal antibodies Ki-67 and MIB1 in the distinction of tuboendometrioid metaplasia from endocervical adenocarcinoma and adenocarcinoma in situ in formalin-fixed material International Journal of Gynecological Pathology 14:209-216
Marques T, Andrade LA, Vassallo J 1996 Endocervical tubal metaplasia and adenocarcinoma in situ: role of immunohistochemistry for carcinoembryonic antigen and vimentin in differential diagnosis. Histopathology 28:549-550
Maruyama R, Nagaoka S, Terao K, Honda M, Koita H 1995 Diffuse laminar endocervical glandular hyperplasia. Pathol Int (4):283-6
McCluggage G, McBride H, Maxwell P, Bharucha H. 1997 Immunohistochemical detection of p53 and bcl-2 proteins in neoplastic and non-neoplastic endocervical glandular lesions. Int J Gynecol Pathol Jan;16(1):22-7
Mikami Y, Hata S, Fujiwara K, Imajo Y, Kohno I, Manabe T 1999 Florid endocervical glandular hyperplasia with intestinal and pyloric gland metaplasia: worrisome benign mimic of “adenoma malignum” Gynecologic Oncology 74: 504-511
Moritani S, Ioffe OB, Sagae S, Dahmoush L, Silverberg SG, Hattori T. 2002 Mitotic Activity and Apoptosis in Endocervical Glandular Lesions Int J Gynecol Pathol 21(2):125-133.
Nucci M R, Clement P B, Young R H 1999 Lobular endocervical glandular hyperplasia, not otherwise specified: a clinicopathological analysis of thirteen cases of a distinctive pseudoneoplastic lesion and comparison with fourteen cases of adenoma malignum. American journal of surgical pathology 23: 886-891
Nucci MR, Ferry JA, Young RH. 2000 Ectopic prostatic tissue in the uterine cervix: a report of four cases and review of ectopic prostatic tissue Am J Surg Pathol 24(9):1224-30.
Oliva E, Clement PB, Young RH. 1995 Tubal and tubo-endometrioid metaplasia of the uterine cervix. Unemphasized features that may cause problems in differential diagnosis: a report of 25 cases. Am J Clin Pathol;103:618-23
Ostor A G 2000 Early invasive adenocarcinoma of the uterine cervix. International Journal of Gynecological Pathology 19: 29-38
Ostor A G, Pagan R, Davoren R A M, Fortune D W, Chanen W, Rome R 1984 Adenocarcinoma in-situ of the cervix. International Journal of Gynecological Pathology 3: 179–190.
Ostor A G, Rome R, Quinn M 1997 Microinvasive adenocarcinoma of the cervix: a clinicopathological study of 77 women. Obstetrics and Gynecology 89:88-93
Pirog EC, Isacson C, Szabolcs MJ, Kleter B, Quint W, Richart RM. 2002 Proliferative activity of benign and neoplastic endocervical epithelium and correlation with HPV DNA detection. Int J Gynecol Pathol. 21:22-6.
Polacarz S V, Darne J, Sheridan E G, Ginsberg R, Sharp F 1991 Endocervical carcinoma and precursor lesions: c-myc expression and demonstration of field changes. Journal of Clinical Pathology 44: 896–899.
Rahilly M A, Williams A R, al-Nafussi A 1992 Minimal deviation endometrioid adenocarcinoma of the cervix: a clinicopathological and immunohistochemical study of two cases. Histopathology 20: 351–354.
Rollason T P, Cullimore J, Bradgate M G 1989 A suggested columnar cell morphological equivalent of squamous carcinoma in-situ with early stromal invasion. International Journal of Gynecological Pathology 8: 230–236.
Segal GH, Hart WR 1990 Am J Surg Pathol Cystic endocervical tunnel clusters. A clinicopathologic study of 29 cases of so-called adenomatous hyperplasia..14(10):895-903
Seidman JD, Tavassoli FA. 1995 Mesonephric hyperplasia of the uterine cervix: a clinicopathologic study of 51 cases Int J Gynecol Pathol;14(4):293-9.
Teshima S, Shimosata Y, Kishi K, Kasamatou T, Ohmi K, Uei Y 1985 Early stage adenocarcinoma of the uterine cervix: histopathologic analysis with consideration of histogenesis. Cancer 56: 167–172.
Toki T, Shimizu M, Takagi Y, Ashida T, Konishi I. 2002 CD10 is a marker for normal and neoplastic endometrial stromal cells. Int J Gynecol Pathol 21:41-7.
Trowell JE 1985 Intestinal metaplasia with argentaffin cells in the uterine cervix. Histopathology 9:551-559
Wells M, Brown L J R 1986 Glandular lesions of the cervix: the present state of our knowledge. Histopathology 10:777-792
Young R H, Clement P B 1991 Pseudoneoplastic glandular lesions of the uterine cervix Seminars in Diagnostic Pathology 8:234-249
Young R H, Scully R 1989 Atypical forms of microglandular hyperplasia of the cervix simulating carcinoma. Am J Surg Pathol 13:50-56