Misdiagnosis Analysis of Cervical Minimal Deviation Adenocarcinoma: a Report of Three Rare Cases and Literature Review

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1 680 Available online at Misdiagnosis Analysis of Cervical Minimal Deviation Adenocarcinoma: a Report of Three Rare Cases and Literature Review Mingxing Sui 1, Yanling Pei 2, Dong Li 1, Qiaori Li 1, Peining Zhu 3, Tianmin Xu 1, and Manhua Cui 1 1 Department of Gynecology and Obstetrics, the Second Hospital of Jilin University, Changchun, Jilin, 2 Department of Nursing, China-Japan Union Hospital of Jilin University, Changchun, Jilin, and 3 Clinical Medicine College, Jilin University, Changchun, Jilin, P.R. China Abstract. Cervical minimal deviation adenocarcinoma (MDA) is a rare variant of cervical adenocarcinoma that is difficult to diagnose due to the deep location, endogenous growth pattern, deceptively benign appearance of tumor cells, and lack of connection to human papillomavirus (HPV). Cytological evaluation and biopsies offer suboptimal detection and transvaginal sonography or Magnetic Resonance Imaging (MRI) only reveal multiple lesions that mimic multiple benign nabothian cysts. Besides, standard screening, diagnostic tools, and treatments are not established. Thus, MDA tends to be misdiagnosed with other gynecological diseases. In this study, we examine three cases with extensive abdominal metastasis and adhesions, which are not initially associated clinically with HPV and cervical malignancies. All cases were misdiagnosed as nabothian cysts, endometrial adenocarcinoma or ovarian cancer, though finally diagnosed as MDA by postoperative pathology. Delay in diagnosis and treatment can result in irreversible outcomes. Misdiagnoses are analyzed and suggestions for improving early detection are discussed with a brief review of the literature. Key words: minimal deviation adenocarcinoma, gastric-type adenocarcinoma, uterine cervix, diagnosis, treatment. Introduction Minimal deviation adenocarcinoma (MDA) or cervical adenoma malignum (AM) is a subtype of cervical mucinous adenocarcinoma [1,2] and accounts for only 1 to 3% of all cervical adenocarcinomas [3] and 0.15% to 0.45% of all cervical carcinomas reported in the literature [4]. Gastric-type adenocarcinoma (GTA) is a newly defined subtype of cervical mucinous adenocarcinoma in the Classification of Tumors of Female Reproductive Organs (4 th edition, 2014). MDA is described as an extremely well-differentiated form of GTA [5]. Chief clinical manifestations are profuse watery or mucoid vaginal discharge and irregular bleeding. MDA may have endophytic rather than exophytic growth pattern and are, therefore, not obvious with clinical Address correspondence to Manhua Cui; Department of Gynecology and Obstetrics, the Second Hospital of Jilin University, 218 Zi Qiang Road, Changchun, Jilin , P.R. China. cuimanhua55@126.com or Tianmin Xu; Department of Gynecology and Obstetrics, the Second Hospital of Jilin University, 218 Zi Qiang Road, Changchun, Jilin , P.R. China. xutianmin@126. com inspection [6]. Differentiating MDA from normal endocervical glands is difficult due to histologically well-differentiated specimens, particularly those from cytological evaluation and cervical punch biopsies. MDA often appears as multilocular lesions which mimic multiple nabothian cysts, benign tumors [7,8]. Although MDA has a benign histological appearance, it is typically aggressive. In addition, MDAs are so rare that their true nature and clinical course has not been fully clarified. This lack of information delays accurate diagnosis and leads to poor patient prognosis. Here, we examine three rare cases of MDA lacking HPV infection and malignant findings, but with extensive abdominal metastases and adhesions in the abdominopelvic organs. These cases were variously identified as nabothian cyst, endometrial adenocarcinoma, and ovarian cancer. All cases were finally diagnosed as MDA according to postoperative pathology. This is the first and largest report of cervical MDA with extensive abdominal metastases /16/ by the Association of Clinical Scientists, Inc.

2 Table 1. The characteristics of our patients and the diagnosis were summarized. Patient Age Presentation Gynecologic HPV ThinPrep Preoperative Postoperative Treatment Outcome Presen (years) examination infection cytology test diagnosis or diagnosis tation to initial outcome diagnosis (months) 1 55 Vaginal discharge Normal cervix (-) Inflammation(+) Pyometra MDA Surgery Died of cancer 6 Malignant lesions(-) 2 63 Vaginal discharge Hypertrophic (-) Inflammation(+) Nabothian cysts MDA Surgery Died of cancer 20 Lower abdominal colic but smooth cervix Malignant lesions(-) Ovarian tumor Chemotherapy Endometrial (6 courses) adenocarcinoma 3 38 Vaginal discharge Cysts in cervix (-) Inflammation(-) Nabothian cysts MDA Surgery Died of cancer 4 Lower abdominal pain Malignant lesions(-) Ovarian Ovarian Chemotherapy carcinoma mucinous (3 courses) adenocarcinoma MDA: minimal deviation adenocarcinoma Misdiagnosis analysis of cervical MDA 681 that mimic nabothian cysts, endometrial adenocarcinoma or ovarian cancer. We present information to better diagnose MDA and ideally lay the foundation for treating patients with MDA. Case Reports Case 1. A 55-year-old Chinese woman (primigravida, primiparous) presented with one year of abnormal vaginal discharge since menopause. Gynecologic examination revealed normal genitalia and a normally appearing cervix except for minor vaginal discharge. The uterus was slightly enlarged and transvaginal sonography showed a uterine cavity mass measuring 5.6 cm x 2.7 cm. HPV infection was negative. A ThinPrep cytology test revealed moderate inflammation and no intraepithelial or malignant lesions. While hysteroscopy was anticipated as an outpatient procedure, the cervical canals were too difficult to navigate beyond the external cervical orifice. Thus, hysteroscopy examination was performed while the patient was under a combined spinal-epidural anesthesia. Intraoperative findings showed internal cervical adhesions and pyometra with a copious amount of yellowish-white pyogenic fluid. The patient finally underwent internal cervix adhesiolysis and pyometra cleaning. Pathologic examination of the endometrium and pyogenic fluids revealed inflammation without malignant cells. Dilatation and curettage were required after antiinflammatory treatment. Hypogastralgia and abnormal odorous bloody vaginal discharge occurred for two months, instead of improving after treatment. Transvaginal sonography confirmed uterine enlargement similar to the previous presentation and a uterine cavity mass (3.5 cm x 2.0 cm) reappeared. Gynecologic examination revealed a firm and hypertrophic cervix and SCC was normal. To evaluate the discharge source, colposcopy was used and biopsy of the area indicated irregular glands consistent with adenocarcinoma (Figure 1a). The cancer was staged as IB1 according to FIGO classification and total abdominal hysterectomy, bilateral salpingooophorectomy, and pelvic lymphadenectomy were planned. Approximately, 800 ml faint yellow mucous ascites were aspirated from the abdominal cavity and the noted pelvic adhesions were pervasive. The greater omentum was hard and nodular (Figure 2a) which was fixed to the transverse colon and partially adherent to the intestines. Several neoplastic focal tissues on the intestine and mesenteric surface were apparent and the largest exceeded 1 cm. The bladder and rectum were firm, brittle, tightly adherent to the uterus and infiltrated with cancer. Both uterine sides were thick and hard, stabilizing the uterus in the middle of the pelvic cavity. The parametrium of the round ligament and the whole uterus could not be visualized. The surface of the abdominopelvic

3 682 Figure 1. Histological findings of cervix. a Photomicrographs of cervical punch biopsy revealed adenocarcinoma with irregular glands (H&E, 100x); b Numerous cervical mucilaginous glands irregularly sized and shaped, infiltrating cervical wall and invading vessels (H&E, 100x). Figure 2. Surgically resected tissues. a Greater omentum was hard with several nodules; b Right ovary was enlarged (approximate 5 x 4 cm) and cystic; c Lesion specimens on peritoneum, mesentery, and bladder wall; d Enlarged uterus and hard cervix.

4 Misdiagnosis analysis of cervical MDA 683 Figure 3. Pelvic CT of soft tissue mass located in the right side of pelvis with low density lesion necrosis, unclear boundary between the lesion and surrounding intestine. cavity peritoneum was covered with miliary cancer lesions. The sigmoid colon was fixed to the upper side of the left pelvic wall so that the left attachment could not be visualized. The right ovary was enlarged (~5 cm x 4 cm) and cystic (Figure 2b) and it adhered to the right uterine and pelvic walls. Thus, intraoperative diagnosis was modified and the patient underwent total abdominal hysterectomy, oophorocystectomy of the right ovary, greater omentum resection, cytoreductive surgery (Figure 2c), lysis of pelvic adhesions, and enterolysis. However, some cervical and parametrial tissues remained after surgery, as identification of uterine and adjacent tissues was difficult due to cancer infiltration. Grossly, the cervix was hard with no other abnormal macroscopic findings (Figure 2d). In addition, numerous irregularly sized and shaped cervical mucilaginous glands were noted microscopically. Lesions infiltrated the entire cervical wall and invaded the vessels (Figure 1b). Tumor glands invaded the uterine corpus and were involved in the endometrium and deeply invaded the uterine muscle wall. Metastatic lesions were noted on the right ovary, peritoneal area, mesentery, and bladder posterior wall; the greater omental lesions were also noted. Irregular cells were observed in ascites that were consistent with adenocarcinoma. Immunohistochemical staining revealed irregularly shaped mucinous glands positive for p53, in addition to scattered areas positive for Ki67 (30%), localized areas positive for CEA, and glands that were negative for P16. Thus, cervical mucinous adenocarcinoma was the eventual diagnosis. Postsurgical chemoradiotherapy was recommended and denied. The patient survived for six months after surgery (Table 1). Case 2. A 63-year-old Chinese woman (gravida 3, para 2), amenorrheic for 15 years presented with lower abdominal colic of no apparent cause. Anti-inflammatory drugs were ineffective. The patient had moderate watery vaginal discharge for 8 months and experienced nausea, vomiting, and occasional abdominal discomfort. Weight loss over 8 months was 3 kg and no bowel movement for 4 days was reported. A hypertrophic but smooth cervix was confirmed and a right adnexal mass of ~7 cm x 4 cm was palpable with poor mobility, fine limits, and mild tenderness. A left attachment area was thickening with mild tenderness. There was lower abdominal tenderness and muscular tension. Transvaginal sonography showed multiple cervical internal cystic foci resembling a honeycomb, right adnexa with multiple septations sans echo cystic mass (6.7 cm x 4.1 cm) and a left adnexa with multiple septations sans echo cystic mass (2.5 cm x 1.6 cm). HPV infection was negative. ThinPrep cytology revealed moderate inflammation, but no intraepithelial or malignant lesions. CA125 was normal, though CA199 was elevated, and CEA was slightly elevated. Pelvic CT indicated a soft tissue mass on the right side of the pelvis, and some necrosis within the lesion. Boundaries were unclear between the lesion and the surrounding intestine (Figure 3). Ovarian cysts were suspected, therefore, neither ovarian carcinoma nor intestinal malignant carcinoma could be excluded. Electronic colonoscopy revealed no intestinal tumors but proctostenosis caused by external pressure. To exclude endometrial carcinoma, dilation and curettage was performed. Pathologic examination of the endometrium revealed that some glands were scattered in papillary arrangement. Cells were slightly irregular with cytoplasmic mucus (Figure 4a). Thus, it could not be excluded from highly differentiated endometrial adenocarcinoma. Total abdominal hysterectomy and bilateral salpingooophenrectomy were planned but upon opening the abdominal cavity, we noted that the lower one-third of peritoneum was a thick, firm mass with several cystic lesions ( cm diameter). The peritoneum was attached to the bladder and the boundary between the two was not clear. About 100 ml of bloody ascites were in the abdominal cavity and the uterus was fixed with extensive adhesions in the bladder, peritoneum, and intestine. Bilateral fallopian tubes were circuitous and enlarged. A cystic tumor (~5 cm diameter) could be seen on the right ovary and the left ovary was enlarged. Major lesions and multiple miliary nodules were spread across the bilateral accessories, bladder, peritoneum, and intestine. The greater omentum was completely invaded and adnexa uteri carcinoma was suspected. The patient underwent subtotal abdominal hysterectomy due to the severity of the adhesions. Bilateral salpingo-oophenrectomy and cytoreductive surgery were also performed. Fast-frozen pathology samples collected during surgery revealed mucinous adenocarcinoma in the

5 684 Figure 4. Histological findings of endometrial and surgical resections. a Endometrial glands scattered in papillary arrangement. Cells slightly irregular with cytoplasmic mucus (H&E, 100x); b and c Lower and high power image show multiple cystic lesions composed of mucin-secreting columnar cells resembling endocervical glands in surgical resections (H&E, 100x; 200x); d IHC staining of surgical resections revealed CK7-positive staining (CK7, 100x); e IHC staining of surgical resections revealed CK(AE1/AE3)-positive staining (CK(AE1/AE3), 100x); f IHC staining of surgical resections revealed p16-positive and scattered staining (p16, 100x). Figure 5. MRI appearance of postsurgical MDA before and after chemotherapy (a-c and d-f). a Sagittal T1WI-SPAIR show heterogeneous enhanced multiple cystic lesions of low signal intensity after contrast agent; b and c Sagittal T2WI and axial T2WI-SPAIR show multiple cystic lesions of high signal intensity; d Sagittal T1WI-SPAIR are similar to image in a; e Sagittal T2WI appear similar to image in b; f Axial T2WI-SPAIR appear similar to image in c.

6 Misdiagnosis analysis of cervical MDA 685 Figure 6. MRI appearance of ovarian mucous adenocarcinoma and cervical cysts. a Sagittal T1WI shows enhanced septated mass of low signal intensity and unenhanced cervix cysts of low signal intensity after contrast agent; b Sagittal T2WI shows septated mass and cervix cysts of high signal intensity; c Axial T1WI shows mass with septation of low signal intensity; d Axial T2WI shows mass with septation of high signal intensity; e Axial T1WI shows cervix cysts of low signal intensity; f Axial T2WI shows cervix cysts of high signal intensity.

7 686 Figure 7. Surgically resected tissues. a Greater omentum was hard with several nodules; b and c Right ovary was enlarged with septations; d Appendix; e Enlarged and embossed cervix; f Malignant lesions on the surface of uterine serous membrane. peritoneum. The bilateral accessory tissues and intramural uterine muscular wall contained cells similar to those identified in the endometrium after dilation and curettage. These were thought to be derived from cervical MDA. Postoperative pathologic examination confirmed this (Figures 4b & c). Immunohistochemically, most columnar cells were positive for CK7 and CK(AE1/ AE3), and were scattered positive for P16 and Ki67 (10%) (Figures 4d-f). The patient was diagnosed with stage IV-B MDA, according to FIGO classification. Six courses of chemotherapy were performed including two courses of taxol and carboplatin and four courses of docetaxel and carboplatin post-surgery. However, cervical lesions did not diminish as evidenced by MRI (Figure 5). Radiation was suggested, but the patient refused and survived for twenty months after surgery (Table 1). Case 3. A 38-year-old woman (primigravida, primiparous) reported lower abdominal pain for five months after a left adnexectomy for ovarian mucinous cystadenoma presented with a more than 5 kg weight loss over the past 20 days. Gynecologic examination revealed vaginal discharge and cervical several cysts. The uterus was palpable with poor mobility and tenderness. A right adnexal mass ~7 cm x 8 cm was palpable with mild tenderness. Transvaginal sonography revealed cysts in the cervix and the right adnexal mass was mixed echo with several septations. HPV infection was negative. ThinPrep cytology revealed many hyperplastic glandular cells. Tumor markers including CA125, CA199, and CEA were elevated significantly. HE4 and CA153 were normal. MRI revealed a septated mass with low signal intensity on T1- weighted images and high signal intensity T2-weighted images in the pelvis which could be strengthened with an enhanced scan. Cervical cysts appeared as several foci of low signal intensity on T1-weighted images and high signal intensity on T2-weighted images which could not be enhanced (Figure 6). During surgery, the greater omentum was firm (Figure 7a), and the uterus adhered to the surrounding intestine. The right fallopian tube was 6 cm x 8 cm thick and the right ovary was enlarged (Figures 7b & c). Frozen sections of the right ovary revealed ovarian mucinous cystadenoma. Finally, the patient had total abdominal hysterectomy, left adnexectomy, pelvic adhesiolysis, and an appendectomy (Figure 7d) as well as a greater omental resection. Grossly, the cervix was enlarged and embossed (Figure 7e). Malignant lesions appeared on the surface of the uterine serous membrane (Figure 7f). Pathologic examination of the right ovary and fallopian tube revealed a highly differentiated mucous adenocarcinoma (Figure 8a) that was invasive and metastasized to the greater omentum, appendix, and myometrium. Pathologic examination of the cervix revealed MDA. The lesion extended from the surface of the cervical canal into the

8 Misdiagnosis analysis of cervical MDA 687 Figure 8. Histological findings of surgically resected tissues. a Highly differentiated mucous adenocarcinoma of right ovary and fallopian tube (H&E, 100x); b Distorted glands with irregular outlines composed of well-differentiated endocervical glands of cervix(h&e, 200x); c IHC staining of surgical resections revealed Villin-positive staining (Villin, 100x); d IHC staining of surgical resections revealed CK(AE1/AE3)-positive staining (CK(AE1/AE3), 100x); e IHC staining of surgical resections revealed Ki67-positive and scattered staining (Ki67, 100x); f IHC staining of surgical resections revealed P16- positive and localized staining (P16, 100x); g IHC staining of surgical resections revealed P53-positive and localized staining (P53, 100x). deep muscle layer and metastasized into the lower uterine mucosal membrane, the myometrial serous membrane, the greater omentum, and the appendix (Figure 8b). Immunohistochemically, most irregular-shaped mucinous glands were positive for Villin and CK(AE1/ AE3), scattered and positive for Ki67 (20%+). Glands were also locally positive for P16 and P53 (Figures 8cg). The patient received three courses of taxol and lobaplatin post-surgery and survived for only four months (Table 1).

9 688 Discussion In this review, we examined three cases of rare MDA with extensive abdominal metastases, adhesions, and no HPV infection or malignant findings that were initially misdiagnosed as nabothian cyst, endometrial adenocarcinoma or ovarian cancer. MDA symptoms chiefly consist of mucoid or watery discharge and atypical genital bleeding. Two of the reviewed cases had moderate or profuse watery or mucoid vaginal discharge; the remaining case had only modest discharge. The patient with little discharge had pyometra, so this was suspected to be a uterine fluid. Cancer was not initially suspected in these cases as the patients presented with a negative HPV status and lesion-free cytological cervical examination. MDA, however, should have been considered after exclusion of other possible causes of bleeding or discharge. MDA is difficult to diagnose; few findings suggest malignancy with cytological or histological examination and how MDA originates is unclear.[9] Previous studies indicate that MDA is likely unrelated to HPV [10]. None of the three cases presented here were HPVpositive, and ThinPrep cytology was used to screen for cervical cancer. However, MDA lesions are located deep within the endocervix and grow internally, so accurate cytological diagnosis is difficult. Li s group reported that MDA confirmation with cytological evaluation was only 32.7% [11]. Preoperative histological diagnosis, such as with punch biopsy, is no more useful for diagnosing MDA than ThinPrep cytology, because the condition is characterized by well-differentiated endocervical glands deep in the cervix. However, deep cervical biopsy (depth >5 mm), such as using cervical conization, can confirm the presence of invasion and assist with diagnosing MDA [12]. Li s group reported that detecting MDA after a single biopsy was 28.7% and confirmation after all biopsies including cervical conization was 50.7% [11]. Our first subject received preoperative punch biopsy at the second consultation, approximately two months after cytological screening and hysteroscopy, as she presented with cervical firmness and hypertrophy, but otherwise grossly normal findings. Pathology revealed adenocarcinoma, but the severity was not confirmed. All cases were diagnosed with postoperative pathology, with diffusely infiltrative patterns of invasive branching and distended glands lined with uniform columnar mucin and immunohistochemistry. For patients lacking HPV infection and intraepithelial or malignant lesions upon cytological evaluation, but who have intractable vaginal discharge or irregular bleeding, a deep cervical biopsy or assessment of the cervix should be done and MDA should be considered after exclusion of other possible causes. Immunohistochemistry with monoclonal antibody HIK-1083 can improve diagnostic accuracy [13,14] and CEA, Ki67, and p53 staining may also be useful, [15,16] whereas, P16 is typically negative, a surrogate marker for HPV [17,18]. For the three cases here, two were unevenly positive for p53 and all were unevenly positive for Ki67. Two were strongly positive for CK(AE1/ AE3) and had well-differentiated irregular glands with uniform columnar mucin distended deep into the cervix. Unexpectedly, however, P16 was diffusely positive in two patients lacking HPV infection. Additional confirmations are required to determine the relationship among HPV infection, P16 and MDA. MDA is difficult to detect but must be differentiated from other gynecological disease. Few cases of MDA that mimic endometrial or ovarian lesions have been reported [3,19]. For the three cases presented here, one was complicated by pyometra and suspicious endometrial lesions. The second case presented with multiple internal cystic foci in the uterine cervix that were mistaken as benign nabothian cysts and was similar in appearance to ovarian cancer and endometrial adenocarcinoma. The third case was complicated by ovarian mucinous cystadenocarcinoma; despite vaginal discharge and cervical cysts, examination and treatment focused on the ovarian mass. For cases, MDA was the final diagnosis after postoperative pathological examination. Two cases had multiple cervical internal cystic foci that were initially considered as benign nabothian cysts.

10 Misdiagnosis analysis of cervical MDA 689 Nabothian cysts are cystically dilated endocervical glands usually located superficially in the cervix and occasionally extending deep into the cervical stroma [20]. Small-sized and well-defined margins differentiate nabothian cysts from most cervical neoplasms, but MDA is a multicystic mass, as evidenced by MRI and transvaginal sonography [8,21]. Even though MDA often extends from the endocervical glands into deep cervical stroma, nabothian cysts also occasionally extend this deep, so differentiating between MDA and nabothian cysts may require biopsy or cytological findings. However, T2-weighted MRI may help to evaluate MDA dissemination [22,23]. The presence of multiple cystic masses extending deep into the cervical stroma as shown on transvaginal sonography or MRI may appear like a honeycomb. This finding is worthy of attention, especially for patients with normal vaginal and cervical findings, as this may point to a diagnosis of MDA. In spite of negative cytological findings and HPV status, attention to cystic lesions and perhaps biopsy or cervical conization, may assist with early detection of adenocarcinoma. Furthermore, if cystic lesions occur, MDA should also be considered. For cases with vaginal discharge or bleeding, and an endometrial biopsy indicating a well-differentiated adenocarcinoma, cystic lesions in the uterine corpus and cervix may indicate a cervical MDA invasion to the uterine corpus. If endometrial lesions are not present but an abdominal mass is noted, an invasion of MDA to the pelvic cavity may be considered. Surgical treatment is optimal for MDA but there is no standard of care. Currently, MDA treatment resembles that of endocervical adenocarcinomas [24]. For our three cases, none could receive radical surgery due to extensive abdominal metastases. Adjuvant chemotherapy was offered but efficacy was not ideal. Two of our three patients lived less than six months after surgery and the last patient lived only twenty months after surgery. However, some studies have reported a favorable prognosis when MDA was detected early and operated on [11,25]. Early diagnosis followed by appropriate auxiliary examinations is a challenge for gynecologists but the common manifestations of vaginal discharge, bleeding, cervical cysts or hypertrophy may be indicative of MDA. Delay in treatment can result in irretrievable outcome. More studies are needed to confirm these assertions and to improve the early detection of MDA. Acknowledgements This study was supported by grants from National Natural Science Foundation of China (NO and ), Research Fund for the Doctoral Program of Higher Education of China (NO ), Jilin Province Science and Technology Funds (NO , JC and YY), Jilin Province Development and Reform Commission Funds (NO. 2013C026-3). The authors also thank LetPub ( for its linguistic assistance during the preparation of this manuscript. References 1. Gusserow. Ueber Sarcome des Uterus. Arch Gynakol 1870;1: Silverberg SG, Hurt WG. Minimal deviation adenocarcinoma ("adenoma malignum") of the cervix: a reappraisal. Am J Obstet Gynecol 1975;121: Gotoh T, Kikuchi Y, Takano M, Kita T, Ogata S, Aida S, Anzai M. An extremely rare case of adenoma malignum with large cystic tumor which resulted in urinary obstruction. Gynecol Oncol 2002;84: Kaminski PF, Norris HJ. Minimal deviation carcinoma (adenoma malignum) of the cervix. Int J Gynecol Pathol 1983;2: Kurman RJ, Carcangiu ML, Herrington CS, Eds. WHO Classification of Tumours of Female Reproductive Organs, 4th ed, International Agency for Research on Cancer, Lyon, 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: Lim KT, Lee IH, Kim TJ, Kwon YS, Jeong JG, Shin SJ. Adenoma malignum of the uterine cervix: Clinicopathologic analysis of 18 cases. Kaohsiung J Med Sci 2012;28: Yamashita Y, Takahashi M, Katabuchi H, Fukumatsu Y, Miyazaki K, Okamura H. Adenoma malignum: MR appearances mimicking nabothian cysts. AJR Am J Roentgenol 1994;162: Ishii K, Katsuyama T, Ota H, Watanabe T, Matsuyama I, Tsuchiya S, Shiozawa T, Toki T. Cytologic and cytochemical features of adenoma malignum of the uterine cervix. Cancer 1999;87: Xu JY, Hashi A, Kondo T, Yuminamochi T, Nara M, Hashi K, Murata S, Katoh R, Hoshi K. Absence of human papil lomavirus infection in minimal deviation adenocarcinoma and lobular endocervical glandular hyperplasia. Int J Gynecol Pathol 2005;24: Li G, Wei J, Gui S, Xu C. Minimal deviation adenocarcinoma of the uterine cervix. Int J Gynaecol Obstet 2010;110: Itoh K, Toki T, Shiohara S, Oguchi O, Konishi, Fujii S. A comparative analysis of cross sectional imaging techniques in minimal deviation adenocarcinoma of the uterine cervix. BJOG 2000;107:

11 Utsugi K, Hirai Y, Takeshima N, Akiyama F, Sakurai S, Hasumi K. Utility of the Monoclonal Antibody HIK1083 in the Diagnosis of Adenoma Malignum of the Uterine Cervix. Gynecol Oncol 1999;75: Sato S, Ito K, Konno R, Okamoto S, Yajima A. Adenoma malignum. Report of a case with cytologic and colposcopic findings and immunohistochemical staining with antimucin monoclonal antibody HIK Acta Cytol 2000;44: Gong L, Zhang WD, Liu XY, Han XJ, Yao L, Zhu SJ, Lan M, Li YH, Zhang W. Clonal status and clinicopathological observation of cervical minimal deviation adenocarcinoma. Diagn Pathol 2010;5: Peng WX, Kure S, Ishino K, Kurose K, Yoneyama K, Wada R, Naito Z. P16-positive continuous minimal deviation adenocarcinoma and gastric type adenocarcinoma in a patient with Peutz-Jeghers syndrome. Int J Clin Exp Pathol 2015;8: Mccluggage WG. New developments in endocervical glandular lesions. Histopathology 2013;62: Kojima A, Mikami Y, Sudo T, Yamaguchi S, Kusanagi Y, Ito M, Nishimura R. Gastric morphology and immunophenotype predict poor outcome in mucinous adenocarcinoma of the uterine cervix. Am J Surg Pathol 2007;31: Nishii Y, Fukuda T, Imai K, Yamauchi M, Hashiguchi Y, Ichimura T, Yasui T, Sumi T. Minimal deviation mucinous adenocarcinoma of the uterine cervix that proved difficult to differentiate from endometrial cancer: A case report. Oncol Lett 2014;8: Clement PB, Young RH. Deep nabothian cysts of the uterine cervix. A possible source of confusion with minimal-deviation adenocarcinoma (adenoma malignum). Int J Gynecol Pathol 1989;8: Kido A, Mikami Y, Koyama T, Kataoka M, Shitano F, Konishi I, Togashi K. Magnetic resonance appearance of gastric-type adenocarcinoma of the uterine cervix in comparison with that of usual-type endocervical adenocarcinoma: a pitfall of newly described unusual subtype of endocervical adenocarcinoma. Int J Gynecol Cancer 2014;24: Takatsu A, Shiozawa T, Miyamoto T, Kurosawa K, Kashima H, Yamada T, Kaku T, Mikami Y, Kiyokawa T, Tsuda H, Ishii K, Togashi K, Koyama T, Fujinaga Y, Kadoya M, Hashi A, Susumu N, Konishi I. Preoperative differential diagnosis of minimal deviation adenocarcinoma and lobular endocervical glandular hyperplasia of the uterine cervix: a multicenter study of clinicopathology and magnetic resonance imaging findings. Int J Gynecol Cancer 2011;21: Oguri H, Maeda N, Izumiya C, Kusume T, Yamamoto Y, Fukaya T. MRI of endocervical glandular disorders: three cases of a deep nabothian cyst and three cases of a minimal-deviation adenocarcinoma. Magn Reson Imaging 2004;22: Ki EY, Byun SW, Park JS, Lee SJ, Hur SY. Adenoma malignum of the uterine cervix: report of four cases. World J Surg Oncol 2013;11: 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: