Mesonephric adenocarcinoma of the uterine cervix and literature review

Abstract

Mesonephric adenocarcinoma is a rare type of cervical cancer that derives from mesonephric remnants in the uterine cervix. To the best of our knowledge, this is the 34th case of mesonephric adenocarcinoma in adult women documented in the literature. We present an asymptomatic 64-year-old postmenopausal woman presenting with a suspicious-looking cervix as an incidental finding and diagnosed with a stage IB mesonephric adenocarcinoma of the cervix. This case was managed with radical hysterectomy, bilateral salpingoophorectomy and pelvic lymphadenectomy. The rarity of such cases imposes challenges on the management in terms of diagnosis, prognosis and therapeutic options.

Background

Mesonephric carcinomas are a distinct subtype of epithelial tumours of the uterine cervix which derive from the remnants of the paired mesonephric (Wolff's) ducts.¹

Mesonephric remnants can be present in 22% of uterine cervices in adults.²

The incidence of such neoplasms is difficult to determine due to rarity, previous misclassification of clear cell carcinomas and yolk sac tumours as mesonephric carcinomas and potential underreporting due to misclassification of mesonephric carcinoma as mullerian tumours or mesonephric hyperplasia.³

The evidence regarding the clinical course, prognosis and optimal treatment is limited.

Case presentation

An asymptomatic 64-year-old patient was referred to colposcopy services, by her general practitioner with the indication of a suspicious-looking cervix during routine cervical smear. Her previous obstetric history included that of four vaginal births and the gynaecological that of menopause since the age of 50. Her medical history included hypothyroidism on thyroxin, asthma, osteoporosis and smoking. She also had a history of breast cancer treated with mastectomy and chemoradiation 8 years before.

Colposcopy gave the impression of invasive disease and directed cervical punch biopsies revealed closely packed dilated mucin-filled glands with an attenuated epithelial lining which was focally positive for cytokeratin 7 (CK7). CK20, gross cystic disease fluid protein (GCDFP), thyroid transcription factor-1 (TTF1) and thyroglobulin were negative. These features were considered as consistent with a cervical mucinous lesion. No malignant features were evident but further evaluation was recommended. The cervical smear was normal.

The case was referred to the gynaecology multidisciplinary team and the suggestion was that of examination under anaesthesia, cystoscopy and cervical cone biopsy. The examination under anaesthesia and cystoscopy revealed an unusually indurated cervix.

The knife cone biopsy measures 22 × 13 and 18 mm in depth, and microscopically showed a diffusely infiltrating tumour composed of groups of dilated glands with minimal atypia. The tumour incompletely was excised and was present at one side of the cervical canal and measuring 20 × 9 × 7 mm. No lympho-vascular invasion was identified and the squamous epithelium and endocervical glands were normal.

Immunochemical staining was positive for cytokeratin (pan cytokeratine) AE1/AE3, epithelial membrane antigen (EMA), E cadherin and vimentin. CD10 was focally positive and with only occasional cells positive for calretinine. The tumour was negative for monoclonal carcino embryonic antigen (mCEA), CK20, TTF1, thyroglobulin and GCDFP (figures 1–3).

Figure 1.

Histology showed closely packed glands, lined by cuboidal epithelium with minimal to mild cytological atypia. Some glands are dilated and are filled with eosinophilic secretions. Mesonephric duct hyperplasia was seen elsewhere in the specimen (H&E).

Figure 2.

Strong positivity for Pan-cytokeratin AE1/3 staining.

Figure 3.

Strong positivity for vimentin staining.

The features were considered to be suggestive of a well-differentiated mesonephric adenocarcinoma of the cervix.

MRI was normal and the staging was that of T 1N0M0.

Radical hysterectomy specimen confirmed an International Federation of Gynecology and Obstetrics (FIGO) IB1 (with a maximum horizontal/depth tumour dimensions of 15/5 mm), well-differentiated adenocarcinoma with negative nodes (n = 19) and clear margins, with no lymphovascular space invasion (LVSI).

Staging with MRI scan took place before a radical hysterectomy, and bilateral salpingoophorectomy along with pelvis lymphadenectomy confirmed an IB1 well-differentiated mesonephric adenocarcinoma with negative pelvic nodes.

Differential diagnosis

Differential diagnosis included the more common well-differentiated villoglandular adenocarcinoma of cervix, adenoma malignum, endometrioid adenocarcinoma, clear cell carcinoma and mesonephric hyperplasia.⁴

Treatment

This case was managed with radical hysterectomy, bilateral salpingoophorectomy and pelvic lymphadenectomy.

Outcome and follow-up

Recovery from surgery was uneventful and the patient has remained disease-free for 6 months.

Discussion

The presenting symptom is most commonly abnormal uterine bleeding. Many cases are diagnosed as an incidental finding on cervical cone or hysterectomy specimen. Examination revealed a cervical mass in many of these cases.

Age range at presentation is between 24 and 73 years with a mean of 50.7.

Unlike the case of the more common squamous epithelial carcinoma, it is rarely presenting with the abnormal cervical smear result, has more advanced age at presentation and its incidence does not appear to decline with age.

The diagnosis has been supported by endometrial curettings, directed/cone cervical biopsies and hysterectomy specimens.

A common finding on endometrial biopsies is endometrioid adenocarcinoma.

The microscopic appearance can be characterised by the predominant pattern. More common patterns are the tubular, which needs to be distinguished from diffuse mesonephric hyperplasia, and the ductal pattern, which needs to be distinguished from endometrioid adenocarcinomas of cervix and its minimal deviation variant. Malignant spindle cell biphasic pattern (malignant mixed mesonephric tumour, MMMT) should be differentiated from primary MMMT of cervix. Focal retiform and sex-cord-like patterns are more common in adnexal tumours deriving from remnants of upper Wolffian duct.⁵

These neoplasms tend to be adjacent to areas of mesonephric glandular hyperplasia.⁶

Mesonephric remnant hyperplasia, even with deep infiltrating and diffuse hyperplastic appearance, is not related to poor prognosis and needs to be distinguished from malignant lesions.⁷ Discriminating features of adenocarcinoma are nuclear atypia, increased mitotic activity (>10/HPFs) (high power field), lymphovascular space invasion and necrotic luminal debris. Ki immunostain may also prove useful in differentiating.³

Immunochemical features of mesonephric adenocarcinoma include positivity for CK7, CAM5.2, EMA and reactivity for CD10, calretinine and vimentin. Carcino embryonic antigen (CEA), CK20, ER and PR are usually negative.⁷ As expected, immunoreactivity for p16 is negative, thus not linking these tumours with high-risk human papillomavirus infection.⁸ Immunoreactivity for PAX2 seems to be absent in mesonephric adenocarcinoma and cervical adenocarcinoma along with its minimal deviation variant, but is diffusely positive in mesonephric hyperplasia.⁹

Owing to the small number of cases with adequate follow-up, prognosis cannot be accurately predicted. The vast majority of patients with cervical adenocarcinoma of mesonephric origin diagnosed at a stage IB and had a mean disease-free interval of 48.6 months. Recurrence rate was 23% (6 of 26 patients), with a mean interval of 40 (7–74) months and stage of disease was IB in three of them, above IB in two of them and unknown in one of these six patients. Two patients (7.6%) died of disease at 28 and 38 months.

Out of the eight patients with MMMTs, five were diagnosed at stage IB and three above IB. Five of these eight patients (62.5%) had a recurrence with a mean disease-free interval of 46 months, whereas 2 of 8 (25%) died of the disease at 7 and 74 months.

Out of 34 patients, 15 had lymphadenectomy and positive lymph nodes were found on 3 of them (2 of 7 patients with MMT and 1 of 27 patients with adenocarcinoma).

It appears that the MMMTs are more aggressive since they were diagnosed at a more advanced stage and had worse outcomes.

All the patients except one were treated with hysterectomy as the primary treatment.

Advanced stage disease of adenocarcinoma seemed to respond to radiotherapy, but for the MMMTs the combination of chemotherapy with radiotherapy appears to be preferable.

A summary of the cases reported in the literature so far is presented in Table 1.^{3 5–7 10–13}

Table 1.

Clinicopathological characteristics of cases^{3, 4, 5, 8, 9, 10, 11, 13}

Cases reported author/year	Age	Presenting symptom	Immunochemistry		Primary treatment	Adjuvant treatment	Stage	Recurrence treatment and outcome in months
			Positive	Negative
Adenocarcinomas
1. This case/2012	64	None	AE1/AE3 EMA E cadherin, vimentin, CK7, CD10 focally, calretinine occasional cells	CEA, CK20, TTF1, GCDFP	RAH/BSO pelvic N	None	IB No LVSI	None at 6
2. Fukunanga/2007	46	Irregular vaginal bleeding/suspicious Cx	CAM5.2 CK7, EMA, p53 chromogranine focal, calretinine occasional cells	CEA, CD10 synaptophysin vimentin oestrogen progesterone	TAH/BSO, pelvis N omentectomy	None	IB	None at 4
3. Stephanie Yap/2006	54	PMB	CK7, CAM5.2 EMA	Chromograin synaptophysin CD10, CEA vimentin, inhibin calretinine, oestrogen	RAH/BSO aortic/pelvic N	RT external beam 5040 cGy + intracav. 1275 cGY	IB, LVSI	None at 37
4. Angeles/20044	47	HMB pelvic mass	AE1/AE3 CK7, CK19, EMA, Ca125 oestrogen progesterone CD10 focal		TAH/BSO	RT caesium implants	IB	None at 12
5. Bagué et al/2004 case 1	41	AUB		α-Inhibin	TAH, BSO, pelvic N app	RT	IB1	None at 137
6. Bagué et al/200410 case 3	24	N/A		α-Inhibin	N/A	N/A	IIA	N/A
7. Bagué et al/200410 case 4	45	PCB	Vimentin focal CD10 focal	α-Inhibin	TAH, USO	None	IB1	None at 37
8. Silver et al/20013 case 1	62	PMB	AE1/3, CK1, EMA, CK7difuse	CK20, ER/PR, mCEA	TAH, BSO	None	IB	None at 18
9. Silver et al/20013 case 2	47	Uterine prolapse	AE1/3, CK1, EMA, CK7difuse	CK20, ER/PR, mCEA	TAH, BSO	None	IB	None at 25
10. Silver et al/20013 case 3	40	CIN in smear	AE1/3, CK1, EMA, CK7difuse	CK20, ER/PR, mCEA	TAH, BSO	None	IB	None at 38
11. Silver et al/20013 case 4	54	PMB	AE1/3, CK1, EMA, CK7difuse	CK20, ER/PR, mCEA	TAH, BSO	None	IB	None at 73
12. Silver et al/20013 case 5	67	PMB	AE1/3, CK1, EMA, CK7difuse	CK20, ER/PR, mCEA	TAH, BSO	None	IB	None at 100
13. Silver et al/20013 case 6	72	AGUS on smear	AE1/3, CK1, EMA, CK7difuse	CK20, ER/PR, mCEA	TAH, BSO, pelvic N	RT	IB, vaginal cuff	Rectovaginal at 20, ChemoT, none at 30
14. Silver et al/20013 case 8	62	PMB, endometrial Ca on curete	AE1/3, CK1, EMA, CK7difuse	CK20, ER/PR, mCEA	TAH, BSO, pelvic N	None	IB	N/A
15. Silver et al/20013 case 9	56	Rt ovarian cystadenoma	AE1/3, CK1, EMA, CK7difuse	CK20, ER/PR, mCEA	TAH, BSO,	None	N/A	None at 89
16. Silver et al/20013 case 10	35	AUB pelvic pain	AE1/3, CK1, EMA, CK7difuse	CK20, ER/PR, mCEA	Pelvic RT		IIB	Pelvis at 26, ChemoT, DOD at 38
17. Clement et al/19955 case 1	46	HMB/fibroid	EMA, vimentin		TAH, BSO, pelvic N	N/A	IB, (+)pelvic N	None at 24
18. Clement  et al/19955 case 2	34	HMB	EMA, vimentin		TAH, BSO	N/A	IB, (+)pelvic N	Abdomen at 12, Chemo, none at 24
19. Clement  et al/19955 case 3	71	AdenoCA on smear, pelvic mass	EMA, vimentin		TAH, BSO, pelvic N	RT	IB + endometrioid adenoCA	Abdomen at 4.5, chemo, DOD at 8.5 (concurrent IIC clear cell ovarian carcinoma)
20. Clement et al/19955 case 4	67	PMB/Cx mass	EMA, vimentin		TAH, BSO, pelvic N	N/A	IB	N/A
21. Stewart et al/199311	37	HMB/suspicious Cx	CK1, vimentin chromogranin serotonine	CEA	RAH, BSO, pelvic N	None	IB1	None at 120
22. Ferry and Scully/19902	55	Pelvic relaxation	N/A	N/A	Hyst, BSO	RT	N/A	None at 60
23. Lang et al 1990 case 2	55	N/A	N/A	N/A	TAH	N/A	IB	N/A
24. Valente and Susin 198712	58	PMB	N/A	N/A	RAH, BSO, pelvic N	None	IB1	Pelvis, RT, DOD at 28
25. Buntine/197913	48	Fibroids	N/A	N/A	TAH, BSO	None	N/A	Vaginal at 84, RT, DOD at 108
26. Mc Gee/1962	36	PCB	N/A	N/A	TAH	None	IB	Pelvis at 72, None, 84
Malignant mixed mesonephric tumours
27. Bagué et al/200410 case 6	54	AUB	Vimentine	α-Inhibin	TAH, BSO, PelvicN omentum	None	IIA MMMT	Bowel, DOD AT 7
28. Bagué et al/200410 case 8	62	N/A	Vimentine	α-Inhibin	TAH, BSO	ChemoRT	IVB	Bone, AWD at 40
29. Bagué et al/200410 case 9	54	N/A	Vimentine calretinine focal	α-Inhibin	TAH, BSO, Pelvic N omentum	None	IB1	None at 13
30. Silver et al/20013 case 7	39	Menorrhagia, Cx fibroid	AE1/3, CK1, EMA, CK7difuse	CK20, ER/PR mCEA	TAH, BSO	RT	IB MMMT	Mediastinum at 67, chemo, DOD 74
31. Silver et al/20013 case 11	43	AUB	AE1/3, CK1, EMA, CK7difuse	CK20, ER/PR mCEA	TAH, BSO, Pelvic N omentum, subphrenic mass	Chemo	IVB MMMT	Bladder/pelvis at 8, RT DOD at 9
32. Clement et al/19955 case 5	37	PCB	EMA, vimentin SMA, CK1 focal		TAH, BSO, Pelvic N	Chemo	IB MMMT	Abdo at 108, surgery and chemo, omental/hepatic/bone 132, chemo, AWD at 156
33. Clement et al/19955 case 6	73	PMB	EMA, vimentin SMA, CK1 focal		TAH, BSO	RT	IB, MMMT	None at 36
34. Clement et al/19955	39	AUB	EMA, vimentin		TAH, BSO	N/A	IB	N/A

AE1, pan cytokeratine; AGUS, abnormal glandular cells of undetermined significance; AUB, abnormal uterine bleeding; AWD, alive with disease; BSO, bilateral salpingoophorectomy; CAM, low molecular weight cytokeratine; CD10; CEA, carcino embryonic antigen; ChemoT, chemotherapy; CIN, cervical intraepithelial neoplasia; CK20, cytokeratin 20; Cx, uterine cervix; DOD, died of disease; EMA, epithelial membrane antigen; ER/PR, estrogen receptor/progesterone receptor; FP; GCDFP, gross cystic disease fluid protein; HMB, heavy menstrual bleeding; IB No; IIA, stage IIA; LVSI, lymphovascular space invasion; mCEA, monoclonal carcinoembryonic antigen; MMMT, malignant mesonephric mixed; N, lymph nodes; N/A, not available; PCB, post coital bleeding; PMB, post menopausal bleeding; RAH, radical abdominal hysterectomy; RT, radiotherapy; TAH, total abdominal hysterectomy; TTF1, thyroid transcription factor-1.

Learning point.

• Though the incidence of such tumour is rare, one should consider the above diagnosis in cervical tumours presenting the characteristics mentioned above.