—  SPECIALTY CONFERENCE  —

Gynecologic Pathology

Case 4 - Mesonephric Adenocarcinoma of the Uterine Cervix

Nilsa C. Ramirez
Ohio State University
Columbus, OH


Click on each slide thumbnail image for an enlarged view
Clinical History
55-year-old woman presented with postmenopausal bleeding and a past history of an abnormal PAP smear. Colposcopy followed by cervical conization revealed a neoplastic process involving the cervix. Clinically she had disease consistent with stage IB1. She underwent radical hysterectomy with bilateral salpingo-oophorectomy and pelvic lymphadenectomy.


Case 4 - Figure 1 - The neoplastic process diffusely infiltrates the myometrium of the lower uterine segment without a significant stromal reaction
Case 4 - Figure 2 - Glands with a tubular architecture arranged in a back to back pattern. Note the presence of intraluminal eosinophilic secretions.


Case 4 - Figure 3 - Perineural invasion is prominent.
Case 4 - Figure 4 - Mitotic activity is focal.

Diagnosis:
Mesonephric adenocarcinoma of the uterine cervix

Pathological findings
The uterine cervix was firm and barrel shaped. A healing ulcer was noted in the area where the prior cone biopsy was removed. The adenocarcinoma was characterized by a proliferation of small glands with a predominant tubular architecture that diffusely infiltrated the vaginal cuff, the cervix, and the lower uterine segment. The neoplastic process involved the vaginal and parametrial surgical margins of resection. There was a focal desmoplastic response. A single layer of columnar cells with low-grade nuclei lined the majority of the glands; cellular stratification was focally noted. Many glands had luminal eosinophilic secretions. Mitotic activity was identified in some areas. Perineural and neural invasion was prominent. Benign appearing hyperplastic mesonephric duct remnants were noted in the background. The immunohistochemical profile of the adenocarcinoma included diffuse positivity for vimentin and EMA, focal positivity for CD10, and negative staining for estrogen receptors, progesterone receptors, and monoclonal CEA.

Discussion
Mesonephric adenocarcinoma (MA), a rare subtype of cervical carcinoma, arises from mesonephric (Wolffian) duct remnants. These remnants can be identified mainly in the lateral walls of up to 22% of uterine cervices [1]. The clinical presentation of cervical MA is similar to other types of cervical carcinoma, with the majority of patients initially complaining of vaginal bleeding [1, 2, 3, 4, 5] . Affected patients range from 34 to 72 years [1, 2, 3, 4] . Although a grossly evident tumor is not uncommon, microscopic lesions may be discovered as incidental findings in hysterectomy specimens, in cervical or endometrial currettings, or in cervical biopsies obtained for the purpose of evaluating an abnormal Pap smear [2, 3, 4] . These adenocarcinomas may involve the cervix in a circumferential fashion, be confined to the lateral or posterolateral aspects of the cervix, or extend to the lower uterine segment [2, 3, 4] . The involvement of the cervical wall is usually transmural and includes mucosal involvement [1, 5] .

Several morphologic patterns can be identified, and even though one may be dominant, a combination of patterns is frequently seen. In one study Clement et. al. [2] described five patterns: ductal, small tubular, retiform, solid, and sex cord-like. The most frequently identified are ductal and tubular [4]. In the tubular pattern, numerous small neoplastic tubules are arranged in a back-to-back fashion, with many containing intraluminal eosinophilic secretions similar to the secretions observed in mesonephric duct remnants. The ductal pattern is characterized by larger glands resembling the glands of endometrioid adenocarcinoma, and may also contain intraluminal eosinophilic secretions. These PAS + intraluminal secretions are also weakly mucicarmine positive [3, 4] . Luminal debris may occasionally be seen in association with the neoplastic tubules [3]. Clement et. al. described cervical MAs associated with a malignant spindle cell (sarcomatoid) component resembling endometrial stromal sarcoma or a non specific stromal sarcoma ("malignant mesonephric mixed tumors") which may rarely be associated with heterologous differentiation [2]. In spite of the infiltrative nature of mesonephric carcinomas, a desmoplastic stromal response is absent in many cases [4]. Lymphovascular space invasion and perineural invasion have been described in association with these tumors [3, 4] . The cytologic features of the neoplastic cells vary from mild to severe, even within the same tumor [3, 5] . Most tumors are characterized by mild nuclear atypicality [3, 5] . Mitotic activity is also variable. According to a series of 11 cases published by Silver et. al. considerable variation in the mitotic index was identified among tumors and within a given tumor [3]. These authors noted the highest mitotic counts in tumor areas with ductal and solid architectural patterns. In their series of 11 cases the maximal mitotic counts ranged from 3 to 50 mitoses per 10 HPFs and the two tumors with the highest mitotic counts were associated with metastatic spread [3].

The immunohistochemical profile of MAs is similar to that of mesonephric remnants [2, 3, 6, 7, 9] and the rete ovarii [3]. In the series reported by Silver et. al. [3] all cases of mesonephric adenocarcinomas were immunopositive for epithelial markers CK1, AE1/AE3, CK7, and EMA. Immunopositivity for the following markers was noted in a percentage of cases: vimentin (70%), calretinin (88%), androgen (33%) and inhibin (focal in 30%). Negative immunostaining was demonstrated with CK20, ER, PR, and mCEA. The sarcomatoid component of the biphasic ("mixed") tumor studied in this particular series was diffusely immunopositive for vimentin, and focally for pan-cytokeratin and CAM 5.2. Other studies have demonstrated immunopositivity for CA125 and focally for CEA [2, 8] . Recently, Ordi et. al. reported immunopositivity for CD10 in mesonephric remnants of the uterine cervix, and in cervical mesonephric adenocarcinomas [9]. In one study HPV DNA was not identified in a case of mesonephric adenocarcinoma tested as part of a larger series of cervical adenocarcinomas [10]. Ki-67 proliferation index appears to be higher in cases of mesonephric carcinoma than in hyperplastic processes [2, 3] .

The differential diagnosis includes mesonephric hyperplasia [1, 11] , and primary endocervical carcinomas of mucinous, endometrioid, clear cell, and serous differentiation [1, 2, 3, 4, 5, 11, 12, 13] . Also in the differential diagnosis are malignant mixed mullerian tumors [2, 3] , uterine tumors resembling sex cord tumors [3, 4] , and endometrial endometrioid adenocarcinomas [14] secondarily involving the cervix. It is not uncommon to identify hyperplastic mesonephric duct remnants in the background of MAs [1, 3, 4, 5, 11] . These benign proliferations may display a diffuse or a lobular pattern. Care should be taken not to confuse this hyperplastic process with an invasive carcinoma, especially when dealing with the diffuse pattern [11]. The presence of architectural features associated with malignancy (solid patterns, back-to-back glandular arrangement), significant cellular atypicality, mitotic activity, and a desmoplastic response favor a malignant process. A grossly identifiable tumor is more commonly seen in association with a malignant process, although cases of mesonephric hyperplasia associated with gross cervical distortion (resembling a tumor) have been described [11]. In cases in which the differential diagnosis includes mucinous endocervical, endometrioid, clear cell or serous carcinoma immunohistochemical stains may assist in the characterization of the process.

MA is usually confined to the cervix at the time of initial diagnosis [2, 3, 4] and late recurrences are not uncommon [2]. Some cases may be associated with an aggressive clinical course, resulting in metastases and death [2, 3] , but most have a prognosis that is better than cervical carcinomas of Mullerian origin.

References

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  2. Clement PB, Young RH, Keh P, Ostor AG, Scully RE: Malignant mesonephric neoplasms of the uterine cervix. A report of eight cases, including four with a malignant spindle cell component. Am J Surg Pathol. 1995 Oct;19(10):1158-71
  3. Silver SA, Devouassoux-Shisheboran M, Mezzetti TP, Tavassoli FA: Mesonephric adenocarcinomas of the uterine cervix: a study of 11 cases with immunohistochemical findings. Am J Surg Pathol. 2001 Mar;25(3):379-87.
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