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Florid Endocervical Glandular Hyperplasia with Intestinal and Pyloric Gland Metaplasia: Worrisome Benign Mimic of “Adenoma Malignum”
Gynecologic Oncology 74, 504 –511 (1999) Article ID gyno.1999.5462, available online at http://www.idealibrary.com on
CASE REPORT Florid Endocervical Glandular Hyperplasia with Intestinal and Pyloric Gland Metaplasia: Worrisome Benign Mimic of “Adenoma Malignum” Yoshiki Mikami, M.D.,* ,1 Sakae Hata, C.T.,* Keiichi Fujiwara, M.D.,† Yoshinari Imajo, M.D.,‡ Ichiro Kohno, M.D.,† and Toshiaki Manabe, M.D.* *Department of Pathology, †Department of Obstetrics and Gynecology, and ‡Department of Radiology, Kawasaki Medical School Hospital, 577 Matsushima, Kurashiki, Okayama 701-01, Japan Received January 27, 1999
encountered a hitherto undescribed pseudoneoplastic glandular proliferation distinguishable from these lesions, which is characterized by densely packed glands showing morphologic and immunophenotypic resemblance to pyloric glands of the stomach. Recently, Ishii et al. [2] also mentioned the existence of gastric metaplasia of the cervix, resembling the pyloric gland, in their article on adenoma malignum. We herein describe clinical, morphologic, histochemical, and immunophenotypic features of three examples of gastric metaplasia with discussion of its diagnostic problems.
We describe three cases of florid endocervical glandular hyperplasia with intestinal and pyloric gland metaplasia, which can be a benign mimic of adenoma malignum. In two cases, adenoma malignum was seriously considered preoperatively because of watery vaginal discharge and the results of imaging studies. The three cases shared common histopathological features, i.e., (i) proliferating endocervical glands surrounded by clusters of smaller glands, resembling the pyloric glands of the stomach; (ii) occasional intestinal metaplasia; (iii) bland nuclear features; and (iv) predominantly PAS-positive neutral mucin in the glandular epithelium. In two cases, glands were densely and irregularly arranged in some areas. Immunohistochemistry disclosed that the intracytoplasmic mucin of the metaplastic epithelium was positive for M-GGMC-1 (HIK1083), which reacts with mucin of pyloric glands. Monoclonal CEA was negative in all cases. This pseudoneoplastic benign condition should be recognized by both gynecologists and pathologists, although it might be difficult to establish a definite diagnosis preoperatively even with deep cone biopsy. © 1999 Academic Press Key Words: pyloric gland metaplasia; uterine cervix; adenoma malignum; pathology.
CASE PRESENTATION Case 1
INTRODUCTION
A 55-year-old, gravida 3, para 2, Japanese woman, who had been healthy except for having well-controlled hyperlipidemia, was referred to our hospital because atypical glandular cells were found on Pap smear at the time of annual check-up. At the presentation, her uterus was small and her cervix was unsatisfactory for colposcopic findings. Transvaginal ultrasonography showed one cervical cyst measuring 1.2 cm in diameter, suggesting a deep nabothian cyst. A cervical smear using a cotton swab and an endocervical brushing smear again disclosed atypical glandular cells. Vaginal smears were positive for human papillomavirus type 18. Magnetic resonance imaging (MRI) suggested the presence of deep nabothian cysts, but gadolinium enhancement failed to reveal any other abnormalities. Microscopic examination of a cervical specimen obtained by a loop electric excision procedure disclosed glandular dysplasia. Under the suspicion of coexisting adenocarcinoma, abdominal total hysterectomy with bilateral salpingo-oophorectomy was performed. No grossly identifiable abnormalities were found during the surgery. She has been uneventful for 36 months following surgery without any additional therapy.
Adenoma malignum of the uterine cervix, alternatively called minimal deviation adenocarcinoma, can be a histopathologic diagnostic problem, although clinical manifestations of mucoid vaginal discharge or irregular bleeding and existence of florid glandular proliferations extending deep into the cervical wall are suggestive of this very-well-differentiated form of adenocarcinoma. There are benign glandular lesions that can be misinterpreted as adenoma malignum. Such lesions include endocervical glandular hyperplasia, deep-seated nabothian cysts, and florid mesonephric duct hyperplasia [1]. We have 1
To whom correspondence and reprint requests should be addressed. Fax: 181-86-462-1199. E-mail: [email protected]. 0090-8258/99 $30.00 Copyright © 1999 by Academic Press All rights of reproduction in any form reserved.
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Case 3
FIG. 1. An MRI image from case 2. A sagittal T2-weighted image showing enlargement of the cervical contour and widening of the endocervical canal, which contains a multicystic high-signal-intensity mass anteriorly and a solid slightly high-signal-intensity mass posteriorly.
Case 2 A 48-year-old, gravida 5, para 3, Japanese woman visited a local clinic because of increased vaginal discharge. Her past history and family history were not contributory. Since invasive squamous cell carcinoma of the uterine cervix was found, she was referred to our hospital for further treatment. MRI findings revealed a tumor occupying the cervical wall, extending deeply into both parametria. In addition, a sagittal T2weighted image showed enlargement of the cervical contour and widening of the endocervical canal between the internal and the external ostia of the uterus. The endocervical canal contained a multicystic high-signal-intensity mass anteriorly and a solid slightly high-signal-intensity mass posteriorly (Fig. 1). The multicystic mass was demarcated from the stromal ring, but the solid mass located in the posterior cervical lip was later proved to be invasive squamous cell carcinoma by microscopic examination of a biopsy specimen. Based on the diagnosis of stage IIB cervical cancer, two courses of neoadjuvant intra-arterial chemotherapy using carboplatin and mitomycin C were given, followed by standard pelvic and intracavitary irradiation. A partial response was obtained with chemotherapy. After radiotherapy, the tumor was shrunken, but multicystic glandular lesions were still recognizable. Since residual squamous cell carcinoma was strongly suspected, and watery discharge and image studies made concomitant adenoma malignum a serious diagnostic consideration, a total abdominal hysterectomy was performed. Thereafter she has been well for 8 months without evidence of recurrent disease.
A 49-year-old, gravida 3, para 2, Japanese woman consulted a local gynecologist because of profuse watery vaginal discharge and was found to have multiple cystic lesions in the uterine cervix by ultrasonography. Since adenoma malignum was suspected, she was referred to our hospital. At presentation, she had a massive watery discharge from the enlarged cervix. Otherwise, she had no significant physical findings. She had a previous history of acute glomerulonephritis at the age of 11, surgery for a right tubal pregnancy at 27, and acute cholecystitis at 38. Her family history was unremarkable. A colposcopic examination showed that the vaginal canal was filled with a massive amount of a clear, translucent mucus substance that discharged from the external ostium of the cervix. The cervix was mildly enlarged. A cervical smear showed atypical mucus cells, although a subsequent biopsy failed to reveal any abnormalities. Her MRI showed multiple cysts, mostly with low T1, high T2, and high FLAIR (fluid attenuated inversion recovery) fluid content. The T2-weighted images parallel to the uterine long axis disclosed multiple irregular cystic lesions with high signal intensity, varying in size from several millimeters to several centimeters (Fig. 2). These lesions showed mainly an endophytic growth pattern, but partly an encroaching pattern on the cervical stroma. Widening of the internal ostium and endocervical canal could also be observed. There were several cysts showing slightly higher T1, high T2, and high FLAIR content.
FIG. 2. An MRI image from case 3. A sagittal T2-weighted image parallel to the uterine long axis revealing multiple irregular cystic lesions with high signal intensity, varying in size from several millimeters to several centimeters. These lesions show predominantly an endophytic growth pattern, but partly an encroaching pattern on the cervical stroma.
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FIG. 3. Gross features in cases 1 and 3. (A) Case 1 shows slight elevation of the posterior wall with some translucent cystic areas (status: postconization). (B and C) In case 3, a dome-shaped elevation of the posterior wall measuring 3 cm in its largest dimension was located predominantly at the internal ostium away from the transition zone. The horizontal section shows nabothian cysts up to 1.8 cm in diameter with tiny dilated glands scattered at the superficial portion of the wall.
Gadolinium-enhanced T1-weighted imaging could not be taken because the patient was allergic to contrast materials. Deep nabothian cysts were considered most likely but adenoma malignum could not be ruled out with confidence. Therefore, laparoscopy-assisted vaginal simple hysterectomy with right salpingo-oophorectomy was performed. The patient has been followed after surgery for 24 months with no evidence of recurrent disease. Gross Findings In cases 1 and 3, the resected uterus showed dome-shaped elevations, each measuring 2 and 3 cm in diameter, predom-
inantly on the posterior portion of the internal ostium of the cervical wall (Figs. 3A and 3B). The mucosal surface was smooth, although several translucent cystic areas were seen on the surface. In case 3, the cut surface of the cervical wall also showed thickening of the posterior wall, with macroscopically recognizable cystic cavities up to 1.8 cm in diameter (Fig. 3C). Small cystic areas less than 1 mm in diameter were also observed between these large cystic cavities. Case 2 showed no discernible elevation of the mucosal surface, although multicystic lesions could be observed predominantly at the portion of the internal ostium.
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FIG. 4. Case 1. Endocervical glandular hyperplasia with pyloric gland metaplasia. (A) Low-power magnification showing densely packed glands with some dilated glands. (B) Dilated glands surrounded by clusters of smaller glands showing lobular appearance. (C) Immunohistochemistry showing that the smaller glands forming clusters are positive for M-GGMC-1.
Microscopic Findings Histologically, glandular dysplasia was seen in case 1, residual invasive squamous cell carcinoma with radiation-induced necrosis and bizarre morphology was observed in case 2, and high-grade squamous intraepithelial lesions were seen in case 3. In addition, all three cases showed a glandular lesion in the cervix (Figs. 4 –7), which was characterized by a mixture of nabothian cysts and florid glandular proliferation with or without intestinal metaplasia, although the degree of proliferation was remarkable and the pattern was rather irregular in some areas in cases 2 and 3 (Figs. 5 and 6). These glandular lesions, predominantly located in the portion of the internal ostium distant from the transition zone, were either separated from or partly adjacent to the above-mentioned neoplastic lesions. Proliferating glands lined by columnar cells with pale eosinophilic cytoplasm, which were tightly arranged in clusters with a back-to-back appearance, resembling pyloric glands of the stomach (Figs. 4 and 5), were commonly seen. As illustrated
for case 1, clusters of smaller glands surrounded mildly or moderately dilated ducts (Fig. 4), some of which were connected to the mucosal surface. In general, nuclei were located basally and showed neither discernible nuclear atypia nor mitotic figures (Fig. 5). In some areas, the glands extended deeply into the cervical wall in a rather irregular fashion with depths of up to 0.9 and 1 cm from the mucosal surface in cases 2 and 3, respectively (Figs. 5 and 6). Even in these areas, however, no distinct nuclear abnormality, architectural distortion, mitosis, or typical desmoplastic reaction was observed, and some clusters showing lobular arrangement were noted (Fig. 6). There was periglandular stromal edema, and some disrupted glands showed extravasation of mucin eliciting florid stromal reaction with infiltration of foamy macrophages and mononuclear cells. Most nabothian cysts were lined by hyperplastic columnar cells with or without intestinal metaplasia and surrounded by clusters of smaller glands in some areas (Fig. 7). In all three cases, extensive sampling was carried out with serial
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FIG. 5. Case 2. (A) Deeply located and rather irregularly arranged glands with pyloric gland metaplasia. (B) High-power magnification showing small glands with back-to-back appearance. Nuclei are basally located, and there are no discernible nuclear abnormalities.
slices from the cervix, but no features suggesting adenoma malignum were observed. The uterine corpus was unremarkable in every case. Histochemically the epithelium with intestinal metaplasia was predominantly positive for alcian blue staining, whereas the epithelium devoid of intestinal metaplasia forming clusters was negative for alcian blue and positive for PAS. Normal endocervical glandular epithelium was predominantly alcian blue positive. Immunohistochemically, staining with monoclonal antibody against CEA (BioGenix, San Ramon, CA; dilution 1:1) was generally negative, except in very limited areas with intestinal metaplasia in case 3, where only faint staining was obtained focally. Mucin in the clustered and some irregularly arranged glands was positive for MGGMC-1 staining (Kanto Kagaku, Tokyo, Japan; dilution, 1:20) (Figs. 4C and 7B). On the other hand, many scattered glands with or without intestinal metaplasia, dilated or normal preexisting endocervical glands surrounded by clustered glands, and nabothian cysts showed no immunoreactivity. DISCUSSION To the best of our knowledge, the existence of pyloric gland metaplasia in the uterine cervix has not been well recognized and described in the English literature to date. We have described three examples of florid endocervical gland hyperplasia with morphologic and phenotypic resemblance to pyloric glands of the stomach. This glandular lesion is characterized by (i) clusters of densely packed smaller glands with lobular architecture, surrounding dilated and/or hyperplastic endocervical glands and nabothian cysts; (ii) small glands lined by columnar epithelium with pale eosinophilic cytoplasm; (iii) concomitant intestinal metaplasia; (iv) some irregularly arranged glands deep in the cervical wall; (v) absence of nuclear abnormality and mitotic figures; and (vi) strongly PAS-positive
intracytoplasmic neutral mucin of the smaller glands, which shows immunoreactivity for M-GGMC-1 that normally reacts with mucin of the pyloric gland [3]. Recently, Ishii et al. [2] briefly mentioned gastric metaplasia found in a series of adenoma malignum. They noted that the metaplastic gland was characterized by intracytoplasmic neutral mucin and immunoreactivity for M-GGMC-1, showing lobular architecture resembling pyloric glands. This lesion seems to be basically the same lesion we are describing. Although we feel it is appropriate to call this condition pyloric gland metaplasia and use the term in this article, there might be room for discussing whether this is a metaplastic process or a kind of ectopic tissue. This lesion can be easily distinguished from other welldescribed pseudoneoplastic glandular lesions, i.e., tunnel cluster, deep-seated nabothian cysts, glandular hyperplasia, diffuse laminar endocervical glandular hyperplasia, mesonephric duct hyperplasia, adenomyoma of endocervical type, intestinal, tubal, and endometrioid metaplasias [1], and florid deep glands of the uterine cervix [4], based on the characteristic lobular arrangement of acinar and/or small glands as mentioned above. A tunnel cluster shows aggregates of glands imparting a certain architectural resemblance to pyloric gland metaplasia, although each gland in a tunnel cluster is usually widely dilated and filled with mucin, showing a flat lining epithelium. Therefore, being familiar with the concept of pyloric metaplasia, one would be able to recognize this epithelial change based on low-power microscopic features. Clinically, the patients in cases 2 and 3 were suspected to have adenoma malignum because of watery vaginal discharge and MRI studies suggesting the existence of florid glandular proliferation with cystic appearance, although case 2 had concomitant invasive squamous cell carcinoma treated with irradiation. Doi et al. [5] demonstrated that adenoma malignum was depicted on MR images as a multicystic mass with solid
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FIG. 6. Case 3. Florid endocervical glandular hyperplasia. (A) Low-power magnification showing endocervical glandular proliferation. (B) Occasional glands with intestinal metaplasia. Generally, no distinct nuclear atypia can be seen. (C) Rather irregularly arranged glands with some architectural abnormalities. (D) Careful observation revealed lobular arrangements of small glands. No typical desmoplastic reaction or nuclear atypia are recognizable.
FIG. 7. Deep-seated nabothian cyst in case 3. (A) The cyst, lined by hyperplastic columnar epithelium with or without intestinal metaplasia, is in an area surrounded by clusters of smaller glands with direct connection to the cystic cavity. (B) Surrounding smaller glands showing immunoreactivity for M-GGMC-1. Areas with intestinal metaplasia tend to be negative.
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portions located in the deep cervical stroma. However, in fact, as was the case in the present study, it might be difficult to make a definite distinction between adenoma malignum and deep-seated nabothian cysts with confidence [6]. Although watery or mucoid discharge is considered to be a characteristic manifestation of adenoma malignum [7, 8], our cases indicate that this manifestation per se is not specific. The cases under discussion showed a spectrum of histopathological features. When glandular proliferation shows lobular architecture and is confined to the superficial portion of the cervical wall, as seen in case 1, it is easy to recognize the lesion as benign. On the other hand, scattered glands without lobular arrangement, as seen in cases 2 and 3, combined with the above-mentioned clinical features, would make adenoma malignum a serious diagnostic consideration. Clues for making a correct diagnosis seem to be association with typical pyloric gland metaplasia, basally located nuclei without notable atypia, and absence of mitotic figures, architectural distortion, and characteristic desmoplasia. Although adenoma malignum is a highly differentiated adenocarcinoma by definition, occasional neoplastic glands should show recognizable nuclear abnormality and/or desmoplastic reaction [7]. Stromal edema around the glands or extravasation of mucin eliciting stromal reaction with active fibroblasts, as seen in our cases, might be misinterpreted as true desmoplasia and thus should be examined carefully. Originally, immunopositivity for CEA was considered to be a supportive finding for adenoma malignum [9, 10]. However, negative staining for CEA would not necessarily be helpful in determining a benign diagnosis because adenoma malignum can be very focally positive [7, 11]. Interestingly, pyloric gland metaplasia was predominantly located in the upper portion of the endocervical canal close to the internal ostium, in association with deep-seated nabothian cysts. Although the reason is uncertain, pyloric gland metaplasia might occur preferentially in this location. In our cases, nabothian cysts also were located away from the transformation zone, lined by hyperplastic epithelium with or without intestinal metaplasia, and surrounded by clusters of glands with pyloric gland metaplasia. Occasional direct connections between nabothian cysts and clustered glands were noted. In areas, irregularly dilated endocervical glands were also surrounded by lobules of glands. In general, nabothian cysts are lined by cuboidal or flat epithelium and have been considered to result from occlusion of endocervical glands in association with squamous metaplasia or chronic cervicitis [12]. However, these findings suggest the possibility that nabothian cysts in association with pyloric glands metaplasia arise as a result of active secretion of metaplastic epithelium, which might be manifested as a watery vaginal discharge, as seen in cases 2 and 3. As mentioned previously, Ishii et al. [2] found gastric metaplasia resembling pyloric glands in 9 of 10 cases of adenoma malignum and discussed the histogenesis of adenoma malignum. Based on histochemical and immunohistochemical stud-
ies employing M-GGMC-1, the same antibody we used, they concluded that gastric metaplasia and adenoma magnum have a common phenotype and speculated that gastric metaplasia could be a precursor or early stage of adenoma malignum. In the present authors’ opinion, considering their incidence, and judging from the figures presented in the report, some examples of adenoma malignum studied by Ishii et al. might have represented just pyloric gland metaplasia in association with endocervical glandular hyperplasia, rather than true adenoma malignum. Their cases were retrieved from their own file over a period of 3 years from 1994 to 1996. Although they did not note the total number of cases reviewed, the number of adenoma malignum cases and the frequency of associated gastric metaplasia seem too high. The estimated incidence of adenoma malignum in all primary adenocarcinoma arising in the uterine cervix ranges from 1 to 3% of adenocarcinoma arising in the uterine cervix [8, 13]. Although their speculation regarding the significance of gastric metaplasia in the uterine cervix is attractive, conclusions on the histogenesis of adenoma malignum and its relationship with pyloric gland metaplasia await further studies demonstrating genetic alteration associated with these epithelial changes. In summary, we have described a hitherto undescribed florid endocervical glandular proliferation with pyloric gland metaplasia, which can be confused with adenoma malignum both clinically and histopathologically. What should be emphasized is the morphological spectrum of the lesion, particularly the rather irregularly arranged glands deep in the cervical wall. Awareness of this lesion would prevent misinterpretation. The relationship between this glandular lesion and adenoma malignum, which share common histochemical and immunohistochemical profiles, remains to be investigated with molecular studies.
REFERENCES 1. Young RH, Clement PB: Pseudoneoplastic glandular lesions of the uterine cervix. Semin Diagn Pathol 8:234 –249, 1991 2. Ishii K, Hosaka N, Toki T, Momose M, Hidaka E, Tsuchiya S, Katsuyama T: A new view of the so-called adenoma malignum of the uterine cervix. Virch Arch 432:315–322, 1998 3. Ota H, Nakayama J, Momose M, Kurihara M, Ishihara K, Hotta K, Katsuyama T: New monoclonal antibodies against gastric gland mucous cell-type mucins: A comparative immunohistochemical study. Histochem Cell Biol 110:113–119, 1998 4. Daya D, Young RH: Florid deep glands of the uterine cervix. Another mimic of adenoma malignum. Am J Clin Pathol 103:614 – 617, 1995 5. Doi T, Yamashita Y, Yasunaga T, Tujiyoshi K, Tsunawaki A, Takahashi M, Katabuchi H, Tanaka N, Okamura H: Adenoma malignum: MR imaging and pathologic study. Radiology 204:39 – 42, 1997 6. Umesaki N, Nakai Y, Honda K, Kawamura N, Kanaoka Y, Nishimura S, Ishiko O, Ogita S: Power Doppler findings of adenoma malignum of uterine cervix. Gynecol Obstet Invest 45:213–216, 1998 7. Gilks CB, Young RH, Aguirre P, DeLellis RA, Scully RE: Adenoma
CASE REPORT malignum (minimal deviation adenocarcinoma) of the uterine cervix. A clinicopathological and immunohistochemical analysis of 26 cases. Am J Surg Pathol 13:717–729, 1989 8. Hirai Y, Takeshima N, Haga A, Arai Y, Akiyama F, Hasumi K: A clinicocytopathologic study of adenoma malignum of the uterine cervix. Gynecol Oncol 70:219 –223, 1998 9. Michael H, Grawe L, Kraus FT: Minimal deviation endocervical adenocarcinoma: Clinical and histologic features, immunohistochemical staining for carcinoembryonic antigen, and differentiation from confusing benign lesions. Int J Gynecol Pathol 3:261–276, 1984 10. Steeper TA, Wick MR: Minimal deviation adenocarcinoma of the uterine
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cervix (“adenoma malignum”). An immunohistochemical comparison with microglandular endocervical hyperplasia and conventional endocervical adenocarcinoma. Cancer 58:1131–1138, 1986 11. Bulmer JN, Griffin NR, Bates C, Kingston RE, Wells M: Minimal deviation adenocarcinoma (adenoma malignum) of the endocervix: A histochemical and immunohistochemical study of two cases. Gynecol Oncol 36:139 –146, 1990 12. Silverberg S, Gompel C: Pathology in Gynecology and Obstetrics. Philadelphia, PA, 1994, Lippincott, 4th ed 13. Kaminski PF, Norris HJ: Minimal deviation carcinoma (adenoma malignum) of the cervix. Int J Gynecol Pathol 2:141–152, 1983
CASE REPORT Florid Endocervical Glandular Hyperplasia with Intestinal and Pyloric Gland Metaplasia: Worrisome Benign Mimic of “Adenoma Malignum” Yoshiki Mikami, M.D.,* ,1 Sakae Hata, C.T.,* Keiichi Fujiwara, M.D.,† Yoshinari Imajo, M.D.,‡ Ichiro Kohno, M.D.,† and Toshiaki Manabe, M.D.* *Department of Pathology, †Department of Obstetrics and Gynecology, and ‡Department of Radiology, Kawasaki Medical School Hospital, 577 Matsushima, Kurashiki, Okayama 701-01, Japan Received January 27, 1999
encountered a hitherto undescribed pseudoneoplastic glandular proliferation distinguishable from these lesions, which is characterized by densely packed glands showing morphologic and immunophenotypic resemblance to pyloric glands of the stomach. Recently, Ishii et al. [2] also mentioned the existence of gastric metaplasia of the cervix, resembling the pyloric gland, in their article on adenoma malignum. We herein describe clinical, morphologic, histochemical, and immunophenotypic features of three examples of gastric metaplasia with discussion of its diagnostic problems.
We describe three cases of florid endocervical glandular hyperplasia with intestinal and pyloric gland metaplasia, which can be a benign mimic of adenoma malignum. In two cases, adenoma malignum was seriously considered preoperatively because of watery vaginal discharge and the results of imaging studies. The three cases shared common histopathological features, i.e., (i) proliferating endocervical glands surrounded by clusters of smaller glands, resembling the pyloric glands of the stomach; (ii) occasional intestinal metaplasia; (iii) bland nuclear features; and (iv) predominantly PAS-positive neutral mucin in the glandular epithelium. In two cases, glands were densely and irregularly arranged in some areas. Immunohistochemistry disclosed that the intracytoplasmic mucin of the metaplastic epithelium was positive for M-GGMC-1 (HIK1083), which reacts with mucin of pyloric glands. Monoclonal CEA was negative in all cases. This pseudoneoplastic benign condition should be recognized by both gynecologists and pathologists, although it might be difficult to establish a definite diagnosis preoperatively even with deep cone biopsy. © 1999 Academic Press Key Words: pyloric gland metaplasia; uterine cervix; adenoma malignum; pathology.
CASE PRESENTATION Case 1
INTRODUCTION
A 55-year-old, gravida 3, para 2, Japanese woman, who had been healthy except for having well-controlled hyperlipidemia, was referred to our hospital because atypical glandular cells were found on Pap smear at the time of annual check-up. At the presentation, her uterus was small and her cervix was unsatisfactory for colposcopic findings. Transvaginal ultrasonography showed one cervical cyst measuring 1.2 cm in diameter, suggesting a deep nabothian cyst. A cervical smear using a cotton swab and an endocervical brushing smear again disclosed atypical glandular cells. Vaginal smears were positive for human papillomavirus type 18. Magnetic resonance imaging (MRI) suggested the presence of deep nabothian cysts, but gadolinium enhancement failed to reveal any other abnormalities. Microscopic examination of a cervical specimen obtained by a loop electric excision procedure disclosed glandular dysplasia. Under the suspicion of coexisting adenocarcinoma, abdominal total hysterectomy with bilateral salpingo-oophorectomy was performed. No grossly identifiable abnormalities were found during the surgery. She has been uneventful for 36 months following surgery without any additional therapy.
Adenoma malignum of the uterine cervix, alternatively called minimal deviation adenocarcinoma, can be a histopathologic diagnostic problem, although clinical manifestations of mucoid vaginal discharge or irregular bleeding and existence of florid glandular proliferations extending deep into the cervical wall are suggestive of this very-well-differentiated form of adenocarcinoma. There are benign glandular lesions that can be misinterpreted as adenoma malignum. Such lesions include endocervical glandular hyperplasia, deep-seated nabothian cysts, and florid mesonephric duct hyperplasia [1]. We have 1
To whom correspondence and reprint requests should be addressed. Fax: 181-86-462-1199. E-mail: [email protected]. 0090-8258/99 $30.00 Copyright © 1999 by Academic Press All rights of reproduction in any form reserved.
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Case 3
FIG. 1. An MRI image from case 2. A sagittal T2-weighted image showing enlargement of the cervical contour and widening of the endocervical canal, which contains a multicystic high-signal-intensity mass anteriorly and a solid slightly high-signal-intensity mass posteriorly.
Case 2 A 48-year-old, gravida 5, para 3, Japanese woman visited a local clinic because of increased vaginal discharge. Her past history and family history were not contributory. Since invasive squamous cell carcinoma of the uterine cervix was found, she was referred to our hospital for further treatment. MRI findings revealed a tumor occupying the cervical wall, extending deeply into both parametria. In addition, a sagittal T2weighted image showed enlargement of the cervical contour and widening of the endocervical canal between the internal and the external ostia of the uterus. The endocervical canal contained a multicystic high-signal-intensity mass anteriorly and a solid slightly high-signal-intensity mass posteriorly (Fig. 1). The multicystic mass was demarcated from the stromal ring, but the solid mass located in the posterior cervical lip was later proved to be invasive squamous cell carcinoma by microscopic examination of a biopsy specimen. Based on the diagnosis of stage IIB cervical cancer, two courses of neoadjuvant intra-arterial chemotherapy using carboplatin and mitomycin C were given, followed by standard pelvic and intracavitary irradiation. A partial response was obtained with chemotherapy. After radiotherapy, the tumor was shrunken, but multicystic glandular lesions were still recognizable. Since residual squamous cell carcinoma was strongly suspected, and watery discharge and image studies made concomitant adenoma malignum a serious diagnostic consideration, a total abdominal hysterectomy was performed. Thereafter she has been well for 8 months without evidence of recurrent disease.
A 49-year-old, gravida 3, para 2, Japanese woman consulted a local gynecologist because of profuse watery vaginal discharge and was found to have multiple cystic lesions in the uterine cervix by ultrasonography. Since adenoma malignum was suspected, she was referred to our hospital. At presentation, she had a massive watery discharge from the enlarged cervix. Otherwise, she had no significant physical findings. She had a previous history of acute glomerulonephritis at the age of 11, surgery for a right tubal pregnancy at 27, and acute cholecystitis at 38. Her family history was unremarkable. A colposcopic examination showed that the vaginal canal was filled with a massive amount of a clear, translucent mucus substance that discharged from the external ostium of the cervix. The cervix was mildly enlarged. A cervical smear showed atypical mucus cells, although a subsequent biopsy failed to reveal any abnormalities. Her MRI showed multiple cysts, mostly with low T1, high T2, and high FLAIR (fluid attenuated inversion recovery) fluid content. The T2-weighted images parallel to the uterine long axis disclosed multiple irregular cystic lesions with high signal intensity, varying in size from several millimeters to several centimeters (Fig. 2). These lesions showed mainly an endophytic growth pattern, but partly an encroaching pattern on the cervical stroma. Widening of the internal ostium and endocervical canal could also be observed. There were several cysts showing slightly higher T1, high T2, and high FLAIR content.
FIG. 2. An MRI image from case 3. A sagittal T2-weighted image parallel to the uterine long axis revealing multiple irregular cystic lesions with high signal intensity, varying in size from several millimeters to several centimeters. These lesions show predominantly an endophytic growth pattern, but partly an encroaching pattern on the cervical stroma.
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FIG. 3. Gross features in cases 1 and 3. (A) Case 1 shows slight elevation of the posterior wall with some translucent cystic areas (status: postconization). (B and C) In case 3, a dome-shaped elevation of the posterior wall measuring 3 cm in its largest dimension was located predominantly at the internal ostium away from the transition zone. The horizontal section shows nabothian cysts up to 1.8 cm in diameter with tiny dilated glands scattered at the superficial portion of the wall.
Gadolinium-enhanced T1-weighted imaging could not be taken because the patient was allergic to contrast materials. Deep nabothian cysts were considered most likely but adenoma malignum could not be ruled out with confidence. Therefore, laparoscopy-assisted vaginal simple hysterectomy with right salpingo-oophorectomy was performed. The patient has been followed after surgery for 24 months with no evidence of recurrent disease. Gross Findings In cases 1 and 3, the resected uterus showed dome-shaped elevations, each measuring 2 and 3 cm in diameter, predom-
inantly on the posterior portion of the internal ostium of the cervical wall (Figs. 3A and 3B). The mucosal surface was smooth, although several translucent cystic areas were seen on the surface. In case 3, the cut surface of the cervical wall also showed thickening of the posterior wall, with macroscopically recognizable cystic cavities up to 1.8 cm in diameter (Fig. 3C). Small cystic areas less than 1 mm in diameter were also observed between these large cystic cavities. Case 2 showed no discernible elevation of the mucosal surface, although multicystic lesions could be observed predominantly at the portion of the internal ostium.
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FIG. 4. Case 1. Endocervical glandular hyperplasia with pyloric gland metaplasia. (A) Low-power magnification showing densely packed glands with some dilated glands. (B) Dilated glands surrounded by clusters of smaller glands showing lobular appearance. (C) Immunohistochemistry showing that the smaller glands forming clusters are positive for M-GGMC-1.
Microscopic Findings Histologically, glandular dysplasia was seen in case 1, residual invasive squamous cell carcinoma with radiation-induced necrosis and bizarre morphology was observed in case 2, and high-grade squamous intraepithelial lesions were seen in case 3. In addition, all three cases showed a glandular lesion in the cervix (Figs. 4 –7), which was characterized by a mixture of nabothian cysts and florid glandular proliferation with or without intestinal metaplasia, although the degree of proliferation was remarkable and the pattern was rather irregular in some areas in cases 2 and 3 (Figs. 5 and 6). These glandular lesions, predominantly located in the portion of the internal ostium distant from the transition zone, were either separated from or partly adjacent to the above-mentioned neoplastic lesions. Proliferating glands lined by columnar cells with pale eosinophilic cytoplasm, which were tightly arranged in clusters with a back-to-back appearance, resembling pyloric glands of the stomach (Figs. 4 and 5), were commonly seen. As illustrated
for case 1, clusters of smaller glands surrounded mildly or moderately dilated ducts (Fig. 4), some of which were connected to the mucosal surface. In general, nuclei were located basally and showed neither discernible nuclear atypia nor mitotic figures (Fig. 5). In some areas, the glands extended deeply into the cervical wall in a rather irregular fashion with depths of up to 0.9 and 1 cm from the mucosal surface in cases 2 and 3, respectively (Figs. 5 and 6). Even in these areas, however, no distinct nuclear abnormality, architectural distortion, mitosis, or typical desmoplastic reaction was observed, and some clusters showing lobular arrangement were noted (Fig. 6). There was periglandular stromal edema, and some disrupted glands showed extravasation of mucin eliciting florid stromal reaction with infiltration of foamy macrophages and mononuclear cells. Most nabothian cysts were lined by hyperplastic columnar cells with or without intestinal metaplasia and surrounded by clusters of smaller glands in some areas (Fig. 7). In all three cases, extensive sampling was carried out with serial
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FIG. 5. Case 2. (A) Deeply located and rather irregularly arranged glands with pyloric gland metaplasia. (B) High-power magnification showing small glands with back-to-back appearance. Nuclei are basally located, and there are no discernible nuclear abnormalities.
slices from the cervix, but no features suggesting adenoma malignum were observed. The uterine corpus was unremarkable in every case. Histochemically the epithelium with intestinal metaplasia was predominantly positive for alcian blue staining, whereas the epithelium devoid of intestinal metaplasia forming clusters was negative for alcian blue and positive for PAS. Normal endocervical glandular epithelium was predominantly alcian blue positive. Immunohistochemically, staining with monoclonal antibody against CEA (BioGenix, San Ramon, CA; dilution 1:1) was generally negative, except in very limited areas with intestinal metaplasia in case 3, where only faint staining was obtained focally. Mucin in the clustered and some irregularly arranged glands was positive for MGGMC-1 staining (Kanto Kagaku, Tokyo, Japan; dilution, 1:20) (Figs. 4C and 7B). On the other hand, many scattered glands with or without intestinal metaplasia, dilated or normal preexisting endocervical glands surrounded by clustered glands, and nabothian cysts showed no immunoreactivity. DISCUSSION To the best of our knowledge, the existence of pyloric gland metaplasia in the uterine cervix has not been well recognized and described in the English literature to date. We have described three examples of florid endocervical gland hyperplasia with morphologic and phenotypic resemblance to pyloric glands of the stomach. This glandular lesion is characterized by (i) clusters of densely packed smaller glands with lobular architecture, surrounding dilated and/or hyperplastic endocervical glands and nabothian cysts; (ii) small glands lined by columnar epithelium with pale eosinophilic cytoplasm; (iii) concomitant intestinal metaplasia; (iv) some irregularly arranged glands deep in the cervical wall; (v) absence of nuclear abnormality and mitotic figures; and (vi) strongly PAS-positive
intracytoplasmic neutral mucin of the smaller glands, which shows immunoreactivity for M-GGMC-1 that normally reacts with mucin of the pyloric gland [3]. Recently, Ishii et al. [2] briefly mentioned gastric metaplasia found in a series of adenoma malignum. They noted that the metaplastic gland was characterized by intracytoplasmic neutral mucin and immunoreactivity for M-GGMC-1, showing lobular architecture resembling pyloric glands. This lesion seems to be basically the same lesion we are describing. Although we feel it is appropriate to call this condition pyloric gland metaplasia and use the term in this article, there might be room for discussing whether this is a metaplastic process or a kind of ectopic tissue. This lesion can be easily distinguished from other welldescribed pseudoneoplastic glandular lesions, i.e., tunnel cluster, deep-seated nabothian cysts, glandular hyperplasia, diffuse laminar endocervical glandular hyperplasia, mesonephric duct hyperplasia, adenomyoma of endocervical type, intestinal, tubal, and endometrioid metaplasias [1], and florid deep glands of the uterine cervix [4], based on the characteristic lobular arrangement of acinar and/or small glands as mentioned above. A tunnel cluster shows aggregates of glands imparting a certain architectural resemblance to pyloric gland metaplasia, although each gland in a tunnel cluster is usually widely dilated and filled with mucin, showing a flat lining epithelium. Therefore, being familiar with the concept of pyloric metaplasia, one would be able to recognize this epithelial change based on low-power microscopic features. Clinically, the patients in cases 2 and 3 were suspected to have adenoma malignum because of watery vaginal discharge and MRI studies suggesting the existence of florid glandular proliferation with cystic appearance, although case 2 had concomitant invasive squamous cell carcinoma treated with irradiation. Doi et al. [5] demonstrated that adenoma malignum was depicted on MR images as a multicystic mass with solid
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FIG. 6. Case 3. Florid endocervical glandular hyperplasia. (A) Low-power magnification showing endocervical glandular proliferation. (B) Occasional glands with intestinal metaplasia. Generally, no distinct nuclear atypia can be seen. (C) Rather irregularly arranged glands with some architectural abnormalities. (D) Careful observation revealed lobular arrangements of small glands. No typical desmoplastic reaction or nuclear atypia are recognizable.
FIG. 7. Deep-seated nabothian cyst in case 3. (A) The cyst, lined by hyperplastic columnar epithelium with or without intestinal metaplasia, is in an area surrounded by clusters of smaller glands with direct connection to the cystic cavity. (B) Surrounding smaller glands showing immunoreactivity for M-GGMC-1. Areas with intestinal metaplasia tend to be negative.
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portions located in the deep cervical stroma. However, in fact, as was the case in the present study, it might be difficult to make a definite distinction between adenoma malignum and deep-seated nabothian cysts with confidence [6]. Although watery or mucoid discharge is considered to be a characteristic manifestation of adenoma malignum [7, 8], our cases indicate that this manifestation per se is not specific. The cases under discussion showed a spectrum of histopathological features. When glandular proliferation shows lobular architecture and is confined to the superficial portion of the cervical wall, as seen in case 1, it is easy to recognize the lesion as benign. On the other hand, scattered glands without lobular arrangement, as seen in cases 2 and 3, combined with the above-mentioned clinical features, would make adenoma malignum a serious diagnostic consideration. Clues for making a correct diagnosis seem to be association with typical pyloric gland metaplasia, basally located nuclei without notable atypia, and absence of mitotic figures, architectural distortion, and characteristic desmoplasia. Although adenoma malignum is a highly differentiated adenocarcinoma by definition, occasional neoplastic glands should show recognizable nuclear abnormality and/or desmoplastic reaction [7]. Stromal edema around the glands or extravasation of mucin eliciting stromal reaction with active fibroblasts, as seen in our cases, might be misinterpreted as true desmoplasia and thus should be examined carefully. Originally, immunopositivity for CEA was considered to be a supportive finding for adenoma malignum [9, 10]. However, negative staining for CEA would not necessarily be helpful in determining a benign diagnosis because adenoma malignum can be very focally positive [7, 11]. Interestingly, pyloric gland metaplasia was predominantly located in the upper portion of the endocervical canal close to the internal ostium, in association with deep-seated nabothian cysts. Although the reason is uncertain, pyloric gland metaplasia might occur preferentially in this location. In our cases, nabothian cysts also were located away from the transformation zone, lined by hyperplastic epithelium with or without intestinal metaplasia, and surrounded by clusters of glands with pyloric gland metaplasia. Occasional direct connections between nabothian cysts and clustered glands were noted. In areas, irregularly dilated endocervical glands were also surrounded by lobules of glands. In general, nabothian cysts are lined by cuboidal or flat epithelium and have been considered to result from occlusion of endocervical glands in association with squamous metaplasia or chronic cervicitis [12]. However, these findings suggest the possibility that nabothian cysts in association with pyloric glands metaplasia arise as a result of active secretion of metaplastic epithelium, which might be manifested as a watery vaginal discharge, as seen in cases 2 and 3. As mentioned previously, Ishii et al. [2] found gastric metaplasia resembling pyloric glands in 9 of 10 cases of adenoma malignum and discussed the histogenesis of adenoma malignum. Based on histochemical and immunohistochemical stud-
ies employing M-GGMC-1, the same antibody we used, they concluded that gastric metaplasia and adenoma magnum have a common phenotype and speculated that gastric metaplasia could be a precursor or early stage of adenoma malignum. In the present authors’ opinion, considering their incidence, and judging from the figures presented in the report, some examples of adenoma malignum studied by Ishii et al. might have represented just pyloric gland metaplasia in association with endocervical glandular hyperplasia, rather than true adenoma malignum. Their cases were retrieved from their own file over a period of 3 years from 1994 to 1996. Although they did not note the total number of cases reviewed, the number of adenoma malignum cases and the frequency of associated gastric metaplasia seem too high. The estimated incidence of adenoma malignum in all primary adenocarcinoma arising in the uterine cervix ranges from 1 to 3% of adenocarcinoma arising in the uterine cervix [8, 13]. Although their speculation regarding the significance of gastric metaplasia in the uterine cervix is attractive, conclusions on the histogenesis of adenoma malignum and its relationship with pyloric gland metaplasia await further studies demonstrating genetic alteration associated with these epithelial changes. In summary, we have described a hitherto undescribed florid endocervical glandular proliferation with pyloric gland metaplasia, which can be confused with adenoma malignum both clinically and histopathologically. What should be emphasized is the morphological spectrum of the lesion, particularly the rather irregularly arranged glands deep in the cervical wall. Awareness of this lesion would prevent misinterpretation. The relationship between this glandular lesion and adenoma malignum, which share common histochemical and immunohistochemical profiles, remains to be investigated with molecular studies.
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CASE REPORT malignum (minimal deviation adenocarcinoma) of the uterine cervix. A clinicopathological and immunohistochemical analysis of 26 cases. Am J Surg Pathol 13:717–729, 1989 8. Hirai Y, Takeshima N, Haga A, Arai Y, Akiyama F, Hasumi K: A clinicocytopathologic study of adenoma malignum of the uterine cervix. Gynecol Oncol 70:219 –223, 1998 9. Michael H, Grawe L, Kraus FT: Minimal deviation endocervical adenocarcinoma: Clinical and histologic features, immunohistochemical staining for carcinoembryonic antigen, and differentiation from confusing benign lesions. Int J Gynecol Pathol 3:261–276, 1984 10. Steeper TA, Wick MR: Minimal deviation adenocarcinoma of the uterine
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