Histopathology 2001, 39, 364±372
Lobular endocervical glandular hyperplasia is a metaplastic process with a pyloric gland phenotype Y Mikami, S Hata, J Melamed,2 K Fujiwara1 & T Manabe
Department of Pathology and 1Obstetrics and Gynaecology, Kawasaki Medical School Hospital, Okayama, Japan, and 2 Department of Pathology, New York University Medical Center, New York, NY, USA Date of submission 28 July 2000 Accepted for publication 9 April 2001
Mikami Y, Hata S, Melamed J, Fujiwara K & Manabe T (2001) Histopathology 39, 364±372
Lobular endocervical glandular hyperplasia is a metaplastic process with a pyloric gland phenotype Aims: Lobular endocervical glandular hyperplasia of the uterine cervix is a rare pseudoneoplastic lesion of the uterine cervix, described recently. Our aim was to characterize the clinicopathological and immunohistochemical features of lobular endocervical glandular hyperplasia, to elucidate its pyloric gland phenotype, and to distinguish it from adenoma malignum of the uterine cervix. Methods and results: Nine cases of lobular endocervical glandular hyperplasia were studied histologically and immunohistochemically. The average age of the nine patients was 48.8 years (range 38±64 years). Six cases were found incidentally, whereas in three cases a watery vaginal discharge and imaging studies suggested adenoma malignum preoperatively. Microscopically, lobular endocervical glandular hyperplasia ranged from 1 mm to 20 mm (mean 6.8 mm) in the largest horizontal extent and 1 mm to 10 mm (mean 3.9 mm) in depth, and was characterized by lobular arrangements of small glands composed of low columnar cells
with pale eosinophilic cytoplasm and bland nuclei. Three cases showed a pseudo-invasive growth. Intracytoplasmic mucin was predominantly PAS-positive, and seven cases showed immunoreactivity for M-GGMC-1, an antibody that reacts with pyloric glandtype mucin. Only focal and faint reactivity for CEA was seen, and ER was negative in all cases. The cytokeratin pro®le was CK7+/20± in all cases, in keeping with their MuÈllerian derivation. All three lesions examined contained chromogranin-positive endocrine cells. After surgery all patients are well without recurrent disease (mean follow-up was 48.4 months). Conclusions: Lobular endocervical glandular hyperplasia is a morphologically distinct pseudoneoplastic glandular lesion, which has unique phenotypic characteristics shared by pyloric glands of the stomach. Although most are found incidentally, some cases may show clinical and radiological features resembling those of adenoma malignum.
Keywords: lobular endocervical glandular hyperplasia, pyloric gland metaplasia, uterine cervix, adenoma malignum, clinicopathologic study
Introduction Recently, we have described three cases of pyloric gland metaplasia of the uterine cervix, emphasizing the diagnostic problem.1 This pseudoneoplastic glandular lesion seems to correspond to lobular endocervical Address for correspondence: Dr Y Mikami, Assistant Professor, Department of Pathology, Kawasaki Medical School Hospital, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan. e-mail:
[email protected] Ó 2001 Blackwell Science Limited.
glandular hyperplasia, not otherwise speci®ed, that was recently described and named by Nucci et al.2,3 Because of the ¯orid proliferation of glandular components, presence of pseudo-invasion, and more importantly the absence of established criteria for this epithelial disorder, lobular endocervical glandular hyperplasia, as well as a variety of pseudoneoplastic endocervical glandular lesions,4 may have been misdiagnosed in the past as adenoma malignum, a well-differentiated form of endocervical adenocarcinoma. In 1998, Ishii et al. ®rst focused on the gastric
Pyloric gland metaplasia of the uterine cervix
phenotype of adenoma malignum, and emphasized that this phenotypic change is a powerful diagnostic feature supporting the diagnosis of adenoma malignum.5 Thereafter, the relationship between adenoma malignum and pyloric gland metaplasia has become controversial, particularly whether pyloric gland metaplasia is a precursor of adenoma malignum or `adenoma malignum in situ' or whether it is a benign lesion distinct from adenoma malignum. The current study was carried out to determine the clinicopathological signi®cance of lobular endocervical glandular hyperplasia and its histopathological spectrum.
Materials and methods Clinicopathological and immunohistochemical features were determined for lobular endocervical glandular hyperplasia, based on eight cases identi®ed in a review of 1169 consecutive hysterectomy specimens (0.7%) from the records of the Department of Pathology, Kawasaki Medical School Hospital. Some of the clinicopathological features of three of these cases were reported previously.1 One additional case was included in the present series, which the authors encountered after the review. Reviewed cases included a variety of benign and malignant diseases including leiomyoma, prolapsed uteri, carcinomas, adenomyosis, and ovarian tumours. The lobular endocervical glandular hyperplasia was de®ned as follows: (i) proliferation of small glands in a lobular fashion; (ii) abundant intracytoplasmic mucin of the glandular epithelium, which stained pale eosinophilic with haematoxylin and eosin (H&E); (iii) basally located round nuclei without anaplasia; and (iv) absence of distinct evidence of destructive stromal invasion (Figure 1). In the reviewed cases, there were 15 adenocarcinomas of the uterine cervix including one adenoma malignum, in which coexisting pyloric gland metaplasia was not identi®ed. Ten cases of endocervical glandular hyperplasia, not otherwise speci®ed, were selected as external controls for immunohistochemical studies. At least two representative specimens were taken from the cervical portion of the resected uterus, and were ®xed in 10% buffered formalin, routinely processed, and embedded in paraf®n. Sections (4 lm thick) were prepared and stained with H&E, PAS, and Alcian blue for light microscopic examination. Immunohistochemical studies were performed on formalin-®xed and paraf®n-embedded tissues employing the following antibodies: M-GGMC-1 (1 : 20; Kanto Kagaku, Tokyo, Japan), an antibody which reacts with pyloric glandtype mucin, and antibodies to CEA (polyclonal, 1 : 50; Dako, Carpinteria, CA, USA), cytokeratin (CK)7 (1 : 50; Ó 2001 Blackwell Science Ltd, Histopathology, 39, 364±372.
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Dako) and 20 (1 : 50; Dako), chromogranin A (1 : 200; Shandon-Lepshaw, Pittsburgh, PA, USA), and oestrogen receptor (ER) (1 : 100; Dako). A streptavidin± biotin peroxidase complex method was used. All antibodies except ER were incubated with the sections after treatment using a microwave antigen retrieval technique with 10 mM citrate buffer pH 6.0, at high temperature for 10 min, and ER using a pressure cooker method with 10 mM citrate buffer pH 6.0.
Results CLINICAL FEATURES
Clinical information and the preoperative diagnosis for each patient are summarized in Table 1. The average age of nine patients was 48.8 years (range 38±64 years). Six examples were found incidentally in cases with a preoperative diagnosis of leiomyoma, ovarian tumour, or glandular dysplasia of the cervix, whereas in three cases a watery vaginal discharge and/or imaging studies suggesting ¯orid glandular lesions made adenoma malignum a serious diagnostic concern preoperatively. In one of these three cases, a patient with stage IIb squamous cell carcinoma underwent hysterectomy because of a residual carcinoma and suspicion of a concomitant adenoma malignum. This patient had two courses of neoadjuvant chemotherapy using carboplatin and mitomycin C and intracavitary irradiation. In seven patients information on hormonal therapy was available. One patient had a history of 11 years of oestrogen replacement therapy. Two patients with leiomyoma were treated with norgestrel-ethinyl and oestradiol, and danazol, respectively, before the hysterectomy. Follow-up information was available in seven cases. In these, all patients had no evidence of recurrent cervical disease after an average length of 48.4 months of follow-up (range 4±107 months). PATHOLOGICAL FEATURES
Gross examination revealed that the cervix was unremarkable in seven cases, but in two cases there was bulging of the posterior wall predominantly at the level of the internal os, as well as cysts of variable sizes on the cut surface of the thickened wall. Microscopically, lobular endocervical glandular hyperplasia ranged from 1 mm to 20 mm (mean 6.8 mm) in the largest width and 1 mm to 10 mm (mean 3.9 mm) in depth (Table 2), and was characterized by lobular arrangements of small glands composed of low columnar cells with pale eosinophilic cytoplasm and bland nuclei
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Figure 1. Lobular endocervical glandular hyperplasia. a, Florid glandular lesion characterized by small glands arranged in lobular fashion, surrounding dilated larger glands. b, Small glands composed of low-columnar cells with bland nuclei. c, Immunohistochemistry using M-GGMC-1.
(Figure 1). Three patients, who had larger lesions, up to 20 mm in width and 10 mm in depth, associated with ¯orid endocervical glandular hyperplasia, not otherwise speci®ed, were suspected of having adenoma malignum preoperatively. Neither distinct nuclear
anaplasia nor evidence of stromal invasion was noted (Figure 1). The smaller lesions tended to be located super®cially. Columnar epithelium lining dilated glands in lobular endocervical glandular hyperplasia showed intestinal metaplasia in four cases (Figure 2). In some Ó 2001 Blackwell Science Ltd, Histopathology, 39, 364±372.
Ó 2001 Blackwell Science Ltd, Histopathology, 39, 364±372.
47
43
38
49
46
55
48
49
64
1
2
3
4
5
6
7
8
9
Vaginal discharge
Vaginal discharge
±
±
Hypermenorrhoea
Intra-abdominal mass
Intra-abdominal mass
Hypermenorrhoea before hysterectomy
Hypermenorrhoea
Presentation
Suspicious for adenoma malignum Adenoma malignum*
Squamous cell carcinoma Invasive squamous cell carcinoma of the cervix Suspicious for adenoma malignum
Glandular dysplasia
Low-grade endometrial stromal sarcoma
Suspicious for ovarian tumour Suspicious for adenocarcinoma
Mucinous cystadenoma of the ovary
Leiomyoma of the uterus Cervical intraepithelial neoplasia (CIN)2
Leiomyoma of the uterus Adenomyosis
Leiomyoma of the uterus
Original primary histopathological diagnosis
Ovarian tumour
Leiomyoma of the uterus Prolapse uteri
Leiomyoma of the uterus
Leiomyoma of the uterus
Preoperative diagnosis
Oestrogen replacement Suspicious for adenoma malignum Pyloric gland metaplasia therapy for 11 years Florid endocervical glandular hyperplasia
±
NA
NA
Danazol for 1 week before hysterectomy
±
±
Norgestrel-ethinyl oestradiol
±
Hormonal therapy
AWD (4)
AWD (39)
AWD (22)
AWD (50)
AWD (107)
NA
NA
AWD (31)
AWD (86)
Outcome (months)
NA, Not available; AWD, alive without disease. *The diagnosis was changed to pyloric gland metaplasia in association with endocervical glandular hyperplasia after the current review of the sections.
Age (years)
Case
Table 1. Clinical features, and preoperative and original histopathological diagnosis of nine patients with pyloric gland metaplasia
Pyloric gland metaplasia of the uterine cervix 367
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Table 2. Pathological features of pyloric gland metaplasia Case
Size (mm)/depth (mm)
PAS/alcian blue
M-GGMC-1
CGA
CEA
ER
CK7
CK20
1
1/1
PAS ³ AB
)
NA
)
)
+
)
2
6/4
PAS > AB
+
NA
)
)
+
)
3
3/1
PAS > AB
+
NA
Focal+
)
+
)
4
5/5
PAS > AB
+
NA
Focal+
)
+
)
5
1/3 (2 foci)
PAS > AB
)
NA
Focal+
)
+
)
6
3/2
PAS > AB
+
+
)
)
+
)
7
13/2
PAS > AB
+
NA
Focal+
)
+
)
8
9/10
PAS > AB
+
+
Focal+
)
+
)
9
20/7
PAS > AB
+
+
Focal+
)
+
)
CGA, Chromogranin A; NA, not available.
areas released mucin from disrupted benign-looking glands elicited a granulation tissue-type stromal reaction with in®ltration of lymphocytes and histiocytes, which resembled a desmoplastic reaction (Figure 3). In addition, the lesion in these cases showed a pseudoinvasive growth characterized by distorted but aggregated small glands intermingled with haphazardly arranged collagen bundles without a distinct desmoplastic reaction (Figure 3). Extracervical lesions diagnosed included leiomyoma of the uterus, adenomyosis, mucinous cystadenoma of the ovary, and low-grade endometrial stromal sarcoma of the uterus (Table 1). Associated cervical lesions con®rmed histologically in the study group included moderate squamous dysplasia (CIN2) in one case, invasive squamous cell carcinoma in another and glandular dysplasia in a third (Table 3). Six of nine cases (67%) were associated with endocervical glandular hyperplasia, not otherwise speci®ed, and seven cases (78%) were associated with Nabothian-type large cysts. In one case the original histopathological diagnosis of adenoma malignum was changed to lobular endocervical glandular hyperplasia after review by the authors. A summary of histochemical and immunohistochemical ®ndings is presented in Table 2. Intracytoplasmic mucin in lobular endocervical glandular hyperplasia was predominantly PAS-positive, and seven cases showed immunoreactivity to M-GGMC-1 (Figure 1), whereas the portion of intestinal metaplasia seen in four cases was negative for M-GGMC-1 and predominantly positive with Alcian blue. Only focal and faint reactivity for CEA along the luminal margin
of the glands was seen in limited areas (Figure 2), and staining for ER was negative in all cases. Normal and some hyperplastic glands, not otherwise speci®ed, as well as microglandular hyperplasia, tunnel clusters, and Nabothian-type cysts, in internal and 10 external controls showed moderate to marked reactivity for ER, but all were negative for M-GGMC-1 and CEA. The cytokeratin pro®le of lobular endocervical glandular hyperplasia, as well as normal and hyperplastic endocervical glands, was shown to be CK7+/20± (Figure 2), with moderate to marked staining for CK7 and completely negative staining for CK20, respectively, in all nine cases examined. There were occasional small round neuroendocrine cells positive for chromogranin A, and these were identi®ed on the basal side of the columnar cells forming lobular endocervical glandular hyperplasia (Figure 2).
Discussion The current study has demonstrated that lobular endocervical glandular hyperplasia is a hitherto unrecognized pseudoneoplastic glandular lesion with a pyloric gland phenotype. The condition can be found incidentally and occasionally misinterpreted as being adenoma malignum clinically and histologically, particularly when it is ¯orid. Adenoma malignum is a very well-differentiated adenocarcinoma which is dif®cult to diagnose,6 and a variety of benign glandular lesions including endocervical glandular hyperplasia, deep-seated Nabothian cysts, ¯orid mesonephric duct hyperplasia,4 may be erroneously regarded as adenoma malignum. After Ó 2001 Blackwell Science Ltd, Histopathology, 39, 364±372.
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Figure 2. Lobular endocervical glandular hyperplasia. a, Branching glands partially surrounded by small glands in a lobular fashion. Intestinal metaplasia can be seen in some branching glands (upper left). Small glands are positive for CK7 (b) with occasional endocrine cells positive for chromogranin A (c). d, Immunoreactivity for CEA observed in the apical side of glandular cells.
demonstrating a gastric phenotype of adenoma malignum, comprising intracytoplasmic PAS-positive and Alcian blue-negative neutral mucin which is positive for M-GGMC-1,5,7 we encountered ¯orid endocervical glandular lesions showing pyloric gland morphology and phenotype1 but lacking any evidence of malignancy. Although the gastric phenotype is suggestive of adenoma malignum,8 the histochemical and immunohistochemical ®ndings should be interpreted carefully in the context of morphological and clinical features. In this regard pyloric gland metaplasia, currently known as lobular endocervical glandular hyperplasia, is a potential diagnostic pitfall and should be put on the list of differential diagnoses of adenoma malignum. In order to establish a diagnosis of adenoma malignum, distinct nuclear anaplasia and/or evidence of destructive stromal invasion, shown by a desmoplastic reaction, should be demonstrated.9 A mixture of round, angulated, and racquet-shaped glands showing open lumina, and scattered deep in the cervical wall, are also supportive of adenoma malignum. Nuclear anaplasia is de®ned as disorientation of nuclei with irregular shapes Ó 2001 Blackwell Science Ltd, Histopathology, 39, 364±372.
and sizes, but it should be noted that certain degrees of nuclear enlargement or distinct nucleoli, as seen in some of our cases, can be observed in benign endocervical glandular lesions, and should not be interpreted as nuclear anaplasia. The deep location of the glands is also insuf®cient evidence of malignancy.10 Lobular arrangement of small round glands, as seen in our cases, is also not a feature of typical adenoma malignum and thus is against the diagnosis. Importantly, released mucin from benign glands is misleading because it can elicit a granulation tissue-type stromal reaction, mimicking a true desmoplastic reaction. It is likely that lobular endocervical glandular hyperplasia as well as intestinal metaplasia are included within the spectrum of endocervical glandular hyperplasias with unique phenotypic alterations because of the frequent and close association with endocervical glandular hyperplasia, not otherwise speci®ed. Larger glands surrounded by small glands in lobular fashion showed direct connections to the mucosal surface of the cervix. Therefore, lobular endocervical glandular hyperplasia may arise as
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Figure 3. a, Granulation tissue-type stromal reaction, secondary to release of mucin from ruptured glands at sites of lobular endocervical glandular hyperplasia. b, Irregularly arranged smaller glands with intervening collagen bundles in case 8, which was originally diagnosed as adenoma malignum (minimal deviation adenocarcinoma).
budding from these hyperplastic endocervical glands. Interestingly, Nucci et al.2 found large cysts and mucoid vaginal discharge in cases of lobular endocervical glandular hyperplasia, which were also observed in some of our cases. Mucoid vaginal discharge might represent active secretion from the metaplastic glands, which results in formation of large cysts. Some papers described watery or mucoid vaginal discharge6,9 and multicystic spaces demonstrated on computed tomography11 and magnetic resonance imaging12 that were characteristic features of adenoma malignum. However, these features are not necessarily speci®c, and it should be kept in mind that to rely only on such features could lead to a misdiagnosis of adenoma malignum. Although lobular endocervical glandular hyperplasia and adenoma malignum are distinguishable from each other morphologically, the relationship between these two conditions is a very controversial issue. Is lobular endocervical glandular hyperplasia a precursor or the
in-situ form of adenoma malignum? Do patients with lobular endocervical glandular hyperplasia carry a risk of developing adenoma malignum? Although our study could not provide a clear answer to these questions, the incidence of lobular endocervical glandular hyperplasia was too high to conclude that it is precursor or the in-situ form of adenoma malignum. The incidence of lobular endocervical glandular hyperplasia in the consecutive cases was 0.7%, and if more extensive sampling were carried out the incidence would probably be higher. On the other hand, the estimated incidence of adenoma malignum was reported to be 1±1.3% of all adenocarcinoma of the cervix.6,13 In addition, in one of nine cases lobular endocervical glandular hyperplasia was found topographically separated from glandular dysplasia, and 15 adenocarcinomas, including one adenoma malignum, were not associated with lobular endocervical glandular hyperplasia. These results do not support a link between adenoma malignum and lobular endocervical Ó 2001 Blackwell Science Ltd, Histopathology, 39, 364±372.
Pyloric gland metaplasia of the uterine cervix
Table 3. Cervical lesions in cases of pyloric gland metaplasia Lesion
Cases (%)
Glandular dysplasia
1 (11)
Cervical intraepithelial neoplasia 2
1 (11)
Invasive squamous cell carcinoma
1 (11)
Microglandular hyperplasia
2 (22)
Tunnel cluster
2 (22)
Chronic cervicitis
4 (44)
Intestinal metaplasia
4 (44)
Endocervical glandular hyperplasia
6 (67)
Nabothian-type cyst
7 (78)
glandular hyperplasia. It can be predicted, however, that `adenoma malignum in situ' may exist. If one uses such a diagnostic term, it should be de®ned as a glandular lesion showing distinct nuclear anaplasia, which is absent in lobular endocervical glandular hyperplasia. Otherwise misleading terminology could lead to unnecessary hysterectomies. In the current study, immunohistochemistry showed that lobular endocervical glandular hyperplasia is CK7+ and CK20). These ®ndings are consistent with a MuÈllerian-derivation of this condition since in the normal gastric antral mucosa, pyloric glands are negative for both CK7 and CK20.14,15 However, normal endocervical glandular epithelium as shown in our study, as well as most adenocarcinomas of the female genital tract, except mucinous carcinoma of the ovary,16,17 are almost always CK7+ and CK20). CEA was positive only in the luminal portion of the glands in limited areas in some cases. Cytoplasmic immunoreactivity for CEA has been regarded as supportive evidence for adenoma malignum, but it should be noted that positive staining can be seen along the luminal margins of benign endocervical glands. In addition, adenoma malignum can be focally positive for CEA,9 which can be easily overlooked. Therefore, both focally positive and negative ®ndings should be interpreted carefully in the context of morphology. Similarly, although loss of the expression of ER18 and existence of endocrine cells5,9,19 in cases of adenoma malignum have been reported, such ®ndings also occur in cases of lobular endocervical glandular hyperplasia. Interestingly, an unusual benign endocervical glandular proliferation described by Fetissof et al. contained chromogranin-positive endocrine cells, which partly Ó 2001 Blackwell Science Ltd, Histopathology, 39, 364±372.
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resembled the microscopic appearance of lobular endocervical glandular hyperplasia.20 In summary, we describe the clinicopathological features of lobular endocervical glandular hyperplasia of the uterine cervix, which is a rare but morphologically distinct endocervical glandular lesion showing a pyloric gland phenotype. Light microscopic and immunohistochemical ®ndings, as well as the clinical and radiological features, can be a diagnostic pitfall and may lead pathologists to an erroneous diagnosis of adenoma malignum.
References 1. Mikami Y, Hata S, Fujiwara K, Imajo Y, Kohno I, Manabe T. Florid endocervical glandular hyperplasia with intestinal and pseudopyloric gland metaplasia: worrisome benign mimic of adenoma malignum. Gyn. Oncol. 1999; 74; 504±511. 2. Nucci MR, Clement PB, Young RH. Lobular endocervical glandular hyperplasia, not otherwise speci®ed: a clinicopathologic analysis of thirteen cases of a distinct pseudoneoplastic lesion and comparison with fourteen cases of adenoma malignum. Am. J. Surg. Pathol. 1999; 23; 886±891. 3. Mikami Y, Manabe T. Lobular endocervical glandular hyperplasia represents pyloric gland metaplasia? Am. J. Surg. Pathol. 2000; 24; 323±324. 4. Young RH, Clement PB. Pseudoneoplastic glandular lesions of the uterine cervix. Semin. Diagn. Pathol. 1991; 8; 234±249. 5. Ishii K, Hosaka N, Toki T et al. A new view of the so-called adenoma malignum of the uterine cervix. Virchows Arch. 1998; 432; 315±322. 6. Kaminski PF, Norris HJ. Minimal deviation carcinoma (adenoma malignum) of the cervix. Int. J. Gynecol. Pathol. 1983; 2; 141±152. 7. Ota H, Nakayama J, Momose M et al. New monoclonal antibodies against gastric gland mucous cell-type mucins: a comparative immunohistochemical study. Histochem. Cell Biol. 1998; 110; 113±119. 8. Hayashi I, Tsuda H, Shimoda H. Reappraisal of orthodox histochemistry for diagnosis of minimal deviation adenocarcinoma of the cervix. Am. J. Surg. Pathol. 2000; 24; 559±562. 9. Gilks CB, Young RH, Aguirre P, DeLellis RA, Scully RE. Adenoma malignum (minimal deviation adenocarcinoma) of the uterine cervix. A clinicopathological and immunohistochemical analysis of 26 cases. Am. J. Surg. Pathol. 1989; 13; 717±729. 10. Daya D, Young RH. Florid deep glands of the uterine cervix. Another mimic of adenoma malignum. Am. J. Clin. Pathol. 1995; 103; 614±617. 11. Tsuruchi N, Tsukamoto N, Kaku T, Kamura T, Nakano H. Adenoma malignum of the uterine cervix detected by imaging methods in a patient with Peutz±Jeghers syndrome. Gynecol. Oncol. 1994; 54; 232±236. 12. Doi T, Yamashita Y, Yasunaga T et al. Adenoma malignum: MR imaging and pathologic study. Radiology 1997; 204; 39±42. 13. Hirai Y, Takeshima N, Haga A, Arai Y, Akiyama F, Hasumi K. A clinicocytopathologic study of adenoma malignum of the uterine cervix. Gynecol. Oncol. 1998; 70; 219±223. 14. Schwerer MJ, Baczako K. Expression of cytokeratins typical for ductal and squamous differentiation in the human stomach: an immunohistochemical study of normal foveolar epithelium,
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Helicobacter pylori gastritis and intestinal metaplasia. Histopathology 1996; 29; 131±137. 15. Schwerer MJ, Baczako K. Immunohistochemical evaluation of keratin 20 expression in intestinal metaplasia types I to III. J. Clin. Pathol. 1996; 49; 791±794. 16. Ramaekers F, van Niekerk C, Poels L et al. Use of monoclonal antibodies to keratin 7 in the differential diagnosis of adenocarcinomas. Am. J. Pathol. 1990; 136; 641±655. 17. Wang NP, Zee S, Zarbo RJ, Bacchi CE, Gown AM. Coordinate expression of cytokeratin 7 and 20 de®nes unique subsets of carcinomas. Appl. Immunohistochem. 1995; 3; 99±107.
18. Toki T, Shiozawa T, Hosaka N, Ishii K, Nikaido T, Fujii S. Minimal deviation adenocarcinoma of the uterine cervix has abnormal expression of sex steroid receptors, CA125, and gastric mucin. Int. J. Gynecol. Pathol. 1997; 16; 111±116. 19. Fetissof F, Berger G, Dubois MP, Philippe A, Lansac J, Jobard P. Female genital tract and Peutz±Jeghers syndrome: an immunohistochemical study. Int. J. Gynecol. Pathol. 1985; 4; 219±229. 20. Fetissof F, Heitzman A, Machet MC, Lansac J. Unusual endocervical lesions with endocrine cells. Pathol. Res. Pract. 1993; 189; 928±939.
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