Gynecologic Oncology Reports 2 (2012) 51–53

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Case Report

Ovarian recurrence from a Stage 1b1 cervical adenocarcinoma previously treated with radical vaginal trachelectomy: A case report E.C. Brockbank a,⁎, J. Evans b, N. Singh c, J.H. Shepherd a, A.R. Jeyarajah d a

Department of Gynaecological Oncology, Royal Marsden NHS Foundation Trust, London, UK Foundation Year 1, Homerton University Hospital Foundation NHS Trust, London, UK Department of Cellular Pathology, Barts and the London NHS Trust, London, UK d The Gynaecological Oncology Centre, St Bartholomew's Hospital, London, UK b c

a r t i c l e

i n f o

Article history: Received 15 August 2011 Accepted 9 January 2012 Available online 16 January 2012 Keywords: Cervical cancer Recurrence Trachelectomy

We report the first case of an unequivocal ovarian recurrence from a FIGO stage 1b1 cervical adenocarcinoma following previous treatment by radical vaginal trachelectomy and laparoscopic bilateral pelvic lymphadenectomy (RVT & LPLND). A 32 years old woman, para one, was referred to the unit for a second opinion regarding treatment options for a cervical cancer. She initially presented following an abnormal smear (high grade Cervical Glandular Intraepithelial Neoplasia—CGIN) and new onset post-coital bleeding. Her last smear, 7 years previously, was normal. She had no significant past medical or surgical history. Colposcopy at presentation revealed an ulcerated lesion on the anterior lip of the cervix measuring 1 cm × 1.5 cm. This was confirmed to be a grade II mucinous adenocarcinoma on a background of CGIN without vascular invasion. MRI revealed no detectable cervical or parametrial disease nor any pelvic lymphadenopathy. On the basis of these findings, an initial diagnosis of FIGO stage 1b1 disease was made. After careful counselling, in accordance with her wishes for fertility-sparing surgery, she was scheduled for RVT & LPLND, which was carried out, with no complication, as previously described (Shepherd and Milliken, 2008). Final histology confirmed a Stage 1b1 G2 adenocarcinoma with a maximal horizontal diameter of 15 mm and a depth of 3.4 mm, 12 mm from the vaginal resection margin with no parametrial invasion. There was no evidence of lymphovascular space invasion. All

⁎ Corresponding author. Fax: + 44 207 8118104. E-mail address: [email protected] (E.C. Brockbank). 2211-338X/$ – see front matter © 2012 Published by Elsevier Inc. doi:10.1016/j.gynor.2012.01.001

21 lymph nodes were negative for disease. Adjuvant treatment was not indicated. The woman was followed up in accordance with our Centre guidelines with clinic visits, imaging and multidisciplinary team (MDM) review (Shepherd and Milliken, 2008). The first two years of follow-up were uneventful. At 24 months, her routine MRI showed a right ovarian cyst measuring 11 cm × 10 cm, containing a few fine septations but no solid component. Physical examination of the woman soon after the MRI revealed a mobile 10 cm pelvic mass palpable per vagina, with no associated lymphadenopathy. All blood tests, including tumour markers were normal; CA125 b15 IU/mL, CEA b2mcg/L, CA19-9 3.9kunits/L. Tumour markers had not been tested at presentation. At MDM review it was confirmed that the radiological impression was that the lesion was most likely benign, but in view of its de novo nature and size surgical removal was advised. Although the patient was asymptomatic, she agreed to laparoscopy for ovarian cystectomy. Unfortunately, due to unforeseen circumstances, her operation was cancelled, rescheduled and cancelled again at short notice. In view of the delay between the MDM decision and the likely procedure date, a repeat pelvic MRI was obtained at 28 months post RVT. This revealed an enlarging mass, now measuring 18.7 cm× 17.4 cm× 16.6 cm, demonstrating increased complexity but remaining unsuggestive of malignancy. The right ovary, uterus, trachelectomy anastomosis, bladder and rectum all appeared normal. CA125 remained normal, b15 IU/mL. Regrettably, the increase in cyst size meant that a laparoscopic procedure was no longer considered appropriate, and she was listed for laparotomy. She underwent an uncomplicated midline laparotomy and left salpingo-oophorectomy at which a 20 cm benign looking left ovarian cyst was removed. No normal left ovarian tissue was identifiable. The right ovary, bowel, omentum, diaphragm and liver were normal. Macroscopically this was a cyst with a smooth outer surface. Internally the cyst was multiloculated with a few velvety areas on the inner surface but no solid or papillary foci. Histology showed cystic and glandular spaces lined by uniformly atypical mucinous epithelium. The lining cells were tall and columnar with numerous interspersed goblet cells. A single mural nodule of invasive carcinoma with chondroid stroma was present. Immunohistochemistry and HPV testing was used to ascertain the nature of this neoplasam; on immunohistochemistry tumour cells were diffusely and strongly positive for p16, together with positive staining for cytokeratin 7 and carcinoembryonic antigen. Staining for cytokeratin 20 was negative. HPV testing carried

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E.C. Brockbank et al. / Gynecologic Oncology Reports 2 (2012) 51–53

reporting on 674 autopsy specimens put the overall ovarian metastasis rate from advanced adenocarcinoma and squamous cell carcinoma of the cervix at 28.6% and 17.4% respectively, p b 0.02 (Tabata et al., 1987). Also Shimada et al. demonstrated a statistically significant difference between the two in their large radical hysterectomy series, with an ovarian metastasis rate from Ib cervical cancers of 3.72% for adenocarcinoma but only 0.22% for squamous cell primaries (Shimada et al., 2006). Several factors are recognised to be important when calculating the risk of recurrence from early cervical cancer. These include the diameter of the tumour, depth of invasion, tumour grade, tumour stage and evidence of nodal involvement. Following RVT our patient had no recognised adverse prognostic factors. In 2005, Piketty et al. published what is held to be the first ovarian recurrence of a microinvasive cervical adenocarcinoma treated by RVT (Piketty et al., 2005). Metastasis from the previous cervical adenocarcinoma was suggested on the basis of the ovarian tumour immunochemistry; CK7 positive and CK 20 negative tumour cells. While this may indeed represent an ovarian recurrence, their reported histopathology cannot exclude this being a metastatic upper gastrointestinal tract adenocarcinoma. In their paper looking at immunohistochemisty of primary and secondary mucinous ovarian neoplasms, Vang et al. demonstrated that a CK7+/CK20− profile was observed in primary ovarian tumours (74%), as well as metastases from upper gastrointestinal tract (78%), and endocervical adenocarcinomas (88%) (Vang et al., 2006). In their recent case series of 29 endocervical adenocarcinomas with ovarian metastases, Ronnett et al. demonstrated that in all cases of HPV-related cervical cancer studied, the paired ovarian metastasis contained identical HPV subtypes. These HPV-related tumours also strongly expressed p16/INK, while non-HPV related tumours did not (Ronnett et al., 2008). The immunohistochemistry profile of our patient's ovarian tumour and the identification of HPV 18 in the ovarian neoplasm indicate without a doubt that her ovarian tumour originated from the preceding cervical adenocarcinoma. Our case also shares the unusual features seen in this pattern of ovarian metastasis highlighted in the series of Ronnett et al. (2008). While metastatic mucinous ovarian carcinomas are typically bilateral and infiltrative, involvement of the ovaries from invasive endocervical adenocarcinomas typically occurs as unilateral cystic masses with a lack of macroscopic, and therefore radiological, features

out on paraffin embedded tissue confirmed the presence of HPV 18 DNA. The fallopian tube was normal. On the basis of these findings the diagnosis of isolated ovarian metastasis from the previous cervical adenocarcinoma was made. She subsequently had a negative whole body FGD-PET scan. She had a course of ovarian stimulation and egg retrieval prior to commencing pelvic radiotherapy and concomitant chemotherapy; 50.4 Gray in 28 fractions via 15 MV photon fields to the 100% isodose. She received five cycles of concurrent cisplatin with no significant toxicities. Following this she received three cycles of carboplatin and paclitaxel. Due to malaise and parasthesia the woman opted not to receive the planned final fourth cycle of adjuvant chemotherapy. Post treatment imaging showed no evidence of local or regional recurrence. At most recent follow-up, 8 months after completion of chemoradiotherapy, she was well with no symptoms or signs on examination suggestive of further recurrence. Discussion First described by Dargent in 1994 and subsequently refined by Shepherd et al., RVT has emerged as a fertility-sparing operation suitable for selected patients with stage I cervical cancer. A recent article reviewing 790 radical vaginal trachelectomy cases showed that 302 pregnancies have yielded 190 live births (Shepherd and Milliken, 2008). A review of the published literature suggests that out of 829 cases reported as part of trachelectomy case series, there have been 27 recurrences (3.25%) resulting in 15 deaths (1.8% of all cases, 55.5% of all recurrences). The mean reported time to recurrence is 30.6 months (range 3 to 93 months). Time to recurrence data are reported for 26 of the 27 recurrences (see Table 1). This compares favourably with reported survival rates for IB1 cervical cancer treated with radical hysterectomy; Benedet et al. report a 5-year survival of 80.7% in the 2470 women with stage 1b1 carcinoma of the cervix treated from 1993 to 1995 (Benedet et al., 2001). Ovarian metastasis of cervical cancer has been well documented within the literature. The effect of histological cervical type is however uncertain. Sutton et al. in their study of 990 patients with stage Ib cervical cancer report an ovarian recurrence rate of 1.7% for adenocarcinoma and 0.5% for squamous cell carcinoma; this difference is statistically non-significant (Sutton et al., 1992). Conversely, a post mortem study

Table 1 Radical trachelectomy outcomes, literature review. Reference

Number

% AC

Recurrence

Deaths

Mean F/U (months)

Sites (time to recurrence, where given)

Milliken and Shepherd

158

n/a

4

4

45

Beiner et al.

137

49

5

3

51

Marchiole et al.

118

21

7

5

95

Plante et al.

125

37

6

2

93

Hertel et al. Roman et al. Jin Li et al. Sonoda et al. Querlou Svane Maneo et al. Chen et al. Hellberg Total

100 69 64 43 29 24 21 16 8 893

31 13 37 n/a n/a 57 n/a n/a Av 35%

4 2 0 1 1 0 0 0 0 30 (3.4%)

2 0 0 0 0 0 0 0 0 16 (1.8%)

29 31 23 21 n/a n/a 69 28 n/a Av 44

Paraaortic region (90/12); left pelvic side wall (51/12); left paracervical tissue (26/12); vaginal vault (7/12) Para-aortic and supra-clavicular regions (70/12); pelvic wall (54/12); -aortic region (44/12); upper abdomen (15/12); lung (10/12) Lateropelvic (93/12); lateropelvic and lung (21/12); liver, lung, lumbo-aortic nodes (20/12); bilateral suparenal glands and lombo-aortic nodes (19/12); parametrial and lumbo-aortic nodes (18/12); lumbo-aortic nodes (11/12); parametrial (and lung (7/12) Parametrium (72/12), parametrium (9/12), parametrium (18/12), residual cervix (36/12), mesocolon (15/12), widely metastatic (‘rapid’) Cervix (34/12); pelvic side wall (11/12); uterus (7/12); corpus (3/12)

AC = Adenocarcinoma. n/a = Not available. F/U = Follow up.

E.C. Brockbank et al. / Gynecologic Oncology Reports 2 (2012) 51–53

suggestive of malignancy and with histological similarities with primary ovarian borderline tumours. Such metastases are reported to present prior to, concurrently with or up to 7 years after the endocervical neoplasm. In the Ronnett series, 17 of 19 patients who underwent lymphadenectomy had no lymph nodal metastasis, and of the 18 cases with available follow-up, 14 patients were alive with no evidence of disease (10–83 months' follow-up period) and two others were alive with disease. Due to these unusual pathological features and apparently favourable clinical outcome, the possibility that this represents an example of an independent ovarian neoplasm as a result of a ‘field effect’ of oncogenic HPV has also been suggested (Reichert, 2005a) though refuted (Reichert, 2005b). This case identifies the importance of follow up for women previously treated for an early cervical cancer. We recognise that imaging will never have 100% sensitivity for detecting malignant disease and that the most effective imaging modality for use in follow up is unclear. Additionally, this case highlights the view that any new pelvic abnormality must be managed in light of the possibility that it is a recurrence of previously appropriately treated cervical cancer. Conflict of interest statement There are no disclosures of interest.

Contribution to authorship The case report was written by ECB and JE with contributions from NS, JHS and ARJ. ECB, JHS and ARJ were directly involved in the clinical management of the case. Details of ethics approval Ethics approval was not sought for our case report. Our patient gave written consent for her case to be presented and published in a peer-reviewed journal.

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Funding Funding was not required for our case report. Acknowledgements There are no acknowledgements to be made. References Benedet, J.L., Odicino, F., Maisonneuve, P., Beller, U., Creasman, W.T., Heintz, A.P., et al., 2001. Carcinoma of the cervix uteri. J. Epidemiol. Biostat. 6, 7–43. Piketty, M., Barranger, E., Najat, M., François, P., Daraï, E., 2005. Ovarian recurrence after radical trachelectomy for adenocarcinoma of the cervix. Am. J. Obstet. Gynecol. 193, 1382–1383. Reichert, R.A., 2005a. Synchronous and metachronous endocervical and ovarian neoplasms: a different interpretation of HPV data. Am. J. Surg. Pathol. 29, 1686–1687. Reichert, R.A., 2005b. Synchronous and metachronous endocervical and ovarian neoplasms: a different interpretation of HPV data—authors reply. Am. J. Surg. Pathol. 29, 1687–1689. Ronnett, B.M., Yemelyanova, A.V., Vang, R., Gilks, C.B., Miller, D., Gravitt, P.E., et al., 2008. Endocervical adenocarcinomas with ovarian metastases: analysis of 29 cases with emphasis on minimally invasive cervical tumors and the ability of the metastases to simulate primary ovarian neoplasms. Am. J. Surg. Pathol. 32, 1835–1853. Shepherd, J.H., Milliken, D.A., 2008. Conservative surgery for carcinoma of the cervix. Clin. Oncol. 20, 395–400. Shimada, M., Kigawa, J., Nishimura, R., Yamaguchi, S., Kuzuya, K., Nakanishi, T., et al., 2006. Ovarian metastasis in carcinoma of the uterine cervix. Gynecol. Oncol. 101, 234–237. Sutton, G.P., Bundy, B.N., Delgado, G., Sevin, B.U., Creasman, W.T., Major, F.J., et al., 1992. Ovarian metastases in stage IB carcinoma of the cervix: a Gynecologic Oncology Group study. Am. J. Obstet. Gynecol. 166, 50–53. Tabata, M., Ichinoe, K., Sakuragi, N., Shiina, Y., Yamaguchi, T., Mabuchi, Y., 1987. Incidence of ovarian metastasis in patients with cancer of the uterine cervix. Gynecol. Oncol. 28, 255–261. Vang, R., Gown, A.M., Barry, T.S., Wheeler, D.T., Yemelyanova, A., Seidman, J.D., et al., 2006. Cytokeratins 7 and 20 in primary and secondary mucinous tumors of the ovary: analysis of coordinate immunohistochemical expression profiles and staining distribution in 179 cases. Am. J. Surg. Pathol. 30, 1130–1139.