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Obstetrics & Gynecology 2001;98:726-731
© 2001 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Fertility Sparing Treatment for In Situ and Early Invasive Adenocarcinoma of the Cervix

Michael T. McHale, MD, Thuan D. Le, MD, Robert A. Burger, MD, Mai Gu, MD, PhD, Joanne L. Rutgers, MD and Bradley J. Monk, MD

From the University of California, Irvine, Medical Center, Chao Family Comprehensive Cancer Center, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, and Department of Pathology, Orange, California; and Long Beach Memorial Medical Center, Department of Pathology, Long Beach, California.

Address reprint requests to: Bradley J. Monk, MD, University of California, Irvine Medical Center, Medical Center, 101 The City Drive South, Building 23, Room 107, Orange, CA 92868; E-mail: bjmonk{at}uci.edu.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: To explore the outcome and long-term follow-up of fertility sparing surgery for cervical adenocarcinoma in situ and early invasive adenocarcinoma.

METHODS: Between 1985 and 1996, all women with adenocarcinoma in situ (AIS) and stage I adenocarcinoma were identified. Data were abstracted from clinical records and pathology reviewed.

RESULTS: One hundred thirty three women with stage I adenocarcinoma of the cervix were treated. Twenty subjects met the criteria for International Federation of Gynecology and Obstetrics stage IA1 lesions. Fourteen subjects were treated with radical hysterectomy, whereas two were treated with simple hysterectomy. Because of the desire to preserve fertility, four women with adenocarcinoma were treated with cervical conization alone, and three women have gone on to deliver viable infants. Forty-two women with adenocarcinoma in situ were identified, of whom 20 were treated with fertility sparing surgery (conization). Five women treated with conization had positive margins recurring in two, and one developed an invasive adenocarcinoma 5 years after conization. None of the women with adenocarcinoma treated with cervical conization have developed recurrent disease after a median follow-up of 48 months. Cone margin status was predictive of residual disease at hysterectomy.

CONCLUSION: Women with adenocarcinoma in situ and negative margins may be treated with conservative, fertility sparing surgery. Education is essential regarding the risks of residual/recurrent disease because subjects can develop lethal recurrent disease. The fertility sparing management of invasive stage IA1 adenocarcinoma of the uterine cervix may also be entertained among women who desire future fertility and have negative margins of resection.

Hepler et al first described the concept of preinvasive glandular disease of the cervix in 1952.1 Adenocarcinoma in situ is now a well-described pathologic entity, which is thought to be a precursor of adenocarcinoma of the cervix.2,3 Unlike squamous intraepithelial lesions, the detection, diagnosis, and management of adenocarcinoma in situ can be both challenging and controversial because glandular dysplasia is frequently thought to be multifocal and is generally located high in the endocervical canal. For these reasons, the management for adenocarcinoma in situ has historically been hysterectomy. However, because this intraepithelial neoplasia affects women of reproductive age who often desire future fertility, hysterectomy may not be an acceptable option. Thus, a clinician is frequently faced with the dilemma of fertility sparing management (ie, conization) for uterine preservation versus hysterectomy in the treatment of cervical adenocarcinoma in situ. Although there has been a trend for conservative management consisting of conization alone, the supporting studies have been small, and the safety of uterine preservation not well defined.4–7

The treatment for early invasive adenocarcinoma of the cervix has been radical surgery or radiation. Recently, clinicians have explored less radical therapy for such early cancers.8,9 This has been an extension of the extensive experience with fertility sparing surgery for early squamous cancers.10

Mestwerdt first introduced the concept of microinvasive carcinoma of the cervix in 1947.11 Since its introduction, most clinicians assumed that this term applied only to minimally invasive squamous lesions and not those arising from glandular epithelium. Many have argued that the architectural complexity of endocervical glands including deep invagination as well as branching and tunnel formation made accurate measurement of the depth of invasion in adenocarcinomas problematic. Thus, the definition of early invasive adenocarcinoma remained controversial until 1997 when the International Federation of Gynecology and Obstetrics (FIGO) defined stage IA1 cervical cancer of either squamous or glandular type to be invasive to a depth of less than 3 mm beneath the basement membrane and less than 7 mm of lateral spread.12 Since the publication of this definition, there has been a paucity of data regarding the fertility sparing treatment of microinvasive or early invasive adenocarcinoma of the cervix. Because lymphatic and parametrial spread is rarely associated with stage IA1 adenocarcinomas of the cervix, Schorge et al recently published the results of five women with stage IA1 adenocarcinoma of the cervix treated with only cervical conization.9 However, none of their subjects have been followed for more than 2 years. The purpose of this investigation was to explore the outcome of uterine preservation and long-term follow-up for early invasive cervical adenocarcinoma and adenocarcinoma in situ among women desiring future fertility in our practice.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Between 1985–1996, cases of cervical adenocarcinoma in situ and stage I adenocarcinoma were identified by searching the tumor registries at the University of California, Irvine Medical Center, and Long Beach Memorial Medical Center after obtaining approval from the Institutional Review Boards (Figure 1Go). Medical records and office charts were abstracted for Papanicolaou smear history, cervical and cone biopsy results, treatment, disease status, and length of follow-up. All pathologic specimens were reviewed by a gynecologic pathologist and/or presented at a Multidisciplinary Gynecologic Oncology Tumor Board. Stage IA1 tumors were defined as buds of malignant cells arising from a gland with adenocarcinoma in situ in which stromal invasion was less than or equal to 3 mm and horizontal spread less than 7 mm (Figure 2Go).12 The actual tumor depth was measured from the surface epithelium showing adenocarcinoma in situ to the deepest point of invasion. Horizontal spread included the maximal length of invasion on the entire slide.



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  		Figure 1. Adenocarcinoma in situ (AIS) and invasive adenocarcinoma of the cervix included in the current study.

McHale. Fertility Sparing Treatment. Obstet Gynecol 2001.

 


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  		Figure 2. Early invasive adenocarcinoma of the cervix. The arrow indicates a focus of invasion.

McHale. Fertility Sparing Treatment. Obstet Gynecol 2001.

 
Postfertility sparing treatment included Papanicolaou smear and endocervical curettage at 4-month intervals. Colposcopy was performed when clinically indicated.

Proportions were compared with Fisher’s exact test using NCSS 97 statistical software (NCSS, Kaysville, UT).


   RESULTS
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
One hundred thirty three women with stage I adenocarcinoma of the uterine cervix treated between 1985 and 1996 were identified. Twenty of these women met the criteria for FIGO stage IA1 early invasive adenocarcinoma. Our standard therapy for these subjects has evolved during the last 15 years. Initially, subjects with IA1 cancers were treated with radical hysterectomy and pelvic lymphadenectomy. More recently, simple hysterectomy without lymphadenectomy has been used. Rarely, women who strongly desired future fertility and refused extirpative surgery were treated with cervical conization. Thus, 14 subjects with stage IA1 tumors were treated with radical hysterectomy and pelvic lymphadenectomy, whereas two had simple hysterectomy and four cervical conization alone. The mean age for this group of women desiring fertility was 30.75 years. Three were white and one Hispanic. All four of these women had a depth of invasion less than 1.5 mm, and three eventually had negative cone biopsy margins (one woman initially had a positive margin, and consequently, a repeat cone was completed). One woman with stage IA1 cancer treated with conization alone had adenocarcinoma in situ at the cone biopsy margin. As demonstrated in Table 1Go, none of these subjects have recurred with individual follow-up of 25, 36, 61, and 108 months. Three have had successful pregnancies after their treatment including the one woman with positive margins for adenocarcinoma in situ. All women with early invasive adenocarcinoma treated with either hysterectomy or radical hysterectomy and pelvic lymphadenectomy had a preoperative cold knife conization. Interestingly, 13 of these 16 women had a positive cone biopsy margin of which ten (77%) had residual disease in their hysterectomy specimen. Importantly, four had residual cancer, and the remaining six had adenocarcinoma in situ. Of those with a negative cone biopsy margin, none had residual disease in their hysterectomy specimen. None of the subjects included in this group have recurred with a median follow-up of 48 months. There was no evidence of disease outside of the cervix (ie, lymph nodes) in any of the women treated with hysterectomy and pelvic lymphadenectomy.


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  		Table 1. Treatment and Outcome of 20 Women With Early Invasive Adenocarcinoma of the Uterine Cervix
 
Forty-two subjects were identified with adenocarcinoma in situ, 20 of whom were treated with fertility sparing surgery, whereas the remaining 22 had a simple hysterectomy. The mean age for the 20 women desiring fertility sparing treatment was 31.65 years, whereas the mean age of the women treated with hysterectomy was 41.86. Seventeen of the 20 conservatively treated women were white, and the remaining, two Asians and one Hispanic. Five of the twenty women treated with conization alone had positive margins. Two of these women eventually recurred by developing adenocarcinoma in situ. Unfortunately, a third woman with a positive margin developed an invasive adenocarcinoma 5 years after the initial diagnosis of adenocarcinoma in situ. She was treated with radical hysterectomy and pelvic lymphadenectomy for her adenocarcinoma and eventually died of distant metastases. Of note, there were no recurrences in the subjects with negative cone biopsy margins. Median follow-up for this group was 42 months.

Margin status and the presence of residual disease were evaluated in the 22 subjects who were treated with a cone biopsy followed by hysterectomy (Table 2Go). There were 14 positive, six negative, and two indeterminate cone biopsy margins. Ten (71%) of the women with positive margins had identifiable residual disease in the hysterectomy specimen. In comparison, one (16.6%) of those with a negative cone margin had residual disease in the hysterectomy specimen (P = .024). Both women with indeterminate cone margins had documented residual disease.


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  		Table 2. Incidence of Residual Disease at the Time of Hysterectomy After Cervical Cone for Adenocarcinoma In Situ According to Cone Margin Status
 

   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The appropriate treatment of cervical adenocarcinoma in situ has been controversial because some authors have reported multifocal adenocarcinoma in situ high in the cervical canal having been missed even on cervical conization. Thus, hysterectomy has been advocated as the definitive treatment by most authorities. Indeed, the risk of residual adenocarcinoma in hysterectomy specimens seems to be highly dependent upon cone biopsy margin status. In the current study, ten of the 14 (71%) subjects treated with cervical conization had residual disease in the hysterectomy specimen when the margins were compromised. This decreased to 17% when the margins were negative. This is in line with other studies reported in the literature. As demonstrated in Table 2Go, when combining cumulative data on 227 subjects from the current report plus five studies in the published literature, 65 of 113 subjects with positive margins (58%, 95% confidence interval = 48%, 67%) had pathologic evidence of residual disease, versus only 22 of 114 with negative margins (19%, 95% confidence interval = 12%, 27%, {chi}2 P < .001). Importantly, all of these studies were in that treatment, and outcomes and margin status were addressed retrospectively.

Because many women with adenocarcinoma in situ are young and desire fertility preservation, clinicians are frequently faced with the dilemma of treating cervical adenocarcinoma in situ with cervical conization alone. In a recent report by Östör et al, 56 subjects underwent definitive therapy with cold knife conization alone after the diagnosis of adenocarcinoma in situ.13 Follow-up of the subjects treated with cone ranged from 1 to 16 years with a mean of 8 years and revealed no recurrences of adenocarcinoma in situ or adenocarcinoma. However, as in the current series, invasive adenocarcinoma after cone biopsy alone for adenocarcinoma in situ was reported (Table 3Go). In addition to the current case, seven other women have developed invasive adenocarcinoma after cone biopsy alone for adenocarcinoma in situ.4,14–18 Three of these seven women had positive margins at the time of cervical conization.


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  		Table 3. Incidence of Invasive Adenocarcinoma After Fertility Sparing Surgery for Adenocarcinoma In Situ According to Cervical Cone Margin Status
 
The risk of developing invasive adenocarcinoma after fertility sparing surgery has not yet been defined, but this concern makes hysterectomy the continuing gold standard of the treatment of adenocarcinoma in situ. Importantly, in none of the case series reported above was the incidence of invasive adenocarcinoma after fertility sparing surgery for adenocarcinoma in situ greater than 25%. Because margin status seems to increase the risk of recurrence and is definitely associated with an increased risk of residual disease in hysterectomy specimens, fertility sparing surgery should only be offered to those women with negative cone margins. When margins are compromised and future fertility desired, a second cone should be performed if the subject accepts the risks associated with fertility sparing surgery. Moreover, a second cone is recommended before definitive hysterectomy if the original cone margins are involved with disease so that the extent of disease can be completely assessed. This will prevent performing a simple hysterectomy for an occult lesion greater than stage IA1 when a radical hysterectomy and pelvic lymphadenectomy is indicated.

Over the past 40 years, the relative proportion and absolute incidence of adenocarcinoma compared with squamous cell carcinoma of the uterine cervix has been changing in the United State and in Western Europe. A recent review of the Surveillance, Epidemiology, and End Results (SEER) database by Smith et al at the University of New Mexico demonstrated an age-adjusted increase in incident rates of adenocarcinoma by 29% from 1973–1977 to 1993–1996.19 The portion of adenocarcinoma increased 107% relative to all cervical cancers.

Several recent case series and an extensive review of the published literature have shown that early invasive adenocarcinoma of the cervix has an excellent prognosis.9,20–23 Recent reports have demonstrated the absence of lymphatic metastasis and parametrial disease among women with stage IA1 adenocarcinoma treated with radical hysterectomy and pelvic lymphedectomy.8 Moreover, there are emerging data that early invasive adenocarcinoma behaves in a similar fashion to squamous cancers. Together, these data have suggested that fertility sparing surgery such as cervical conization may be adequate treatment for selected women with early invasive glandular lesions. However, similar to adenocarcinoma in situ, cone biopsy margin status may be important in selecting women for fertility sparing surgery. In the recent report by Schorge et al, a woman with adenocarcinoma in situ who was not diagnosed with invasive adenocarcinoma after two cervical conization procedures was only diagnosed with invasive adenocarcinoma after having a third cervical conization. In addition, a recent report from Nagarsheth et al described a 62-year-old woman with a FIGO stage IA1 adenocarcinoma of the cervix found to have bilateral microscopic pelvic lymph node metastases at the time of hysterectomy and pelvic lymphadectomy.24 To date, this is the only documented case of lymph node metastasis in a woman with stage IA1 cervical adenocarcinoma. In addition to depth of invasion, tumor volume may be important in predicting the presence of metastatic disease. Covens et al, at the Princess Margaret Hospital in Toronto, Canada, reported no lymphatic metastasis among 46 women with cervical adenocarcinoma whose tumor volumes were less than 600 mm.25 Importantly, one woman with a depth of invasion of less than 2 mm had a tumor volume greater than 600 mm3.

Although cervical conization cannot be advocated as a standard treatment for early invasive cervical carcinoma, some well-informed women willing to accept the additional risks may be candidates for a fertility sparing surgery. However, this approach must be cautiously considered because experience with this conservative therapy is limited. Moreover, similar to the adenocarcinoma in situ experience, margin status is expected to be an important predictor of recurrence, although no recurrences have been reported to date after fertility sparing treatment of stage IA1 cervical adenocarcinoma.


   Footnotes
 
PII S0029-7844(01)01544-7

Received February 8, 2001. Received in revised form June 18, 2001. Accepted June 28, 2001.


   REFERENCES
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Hepler TK, Dockerty MB, Randall LM. Primary adenocarcinoma of the cervix. Am J Obstet Gynecol 1952;63: 800–8.

2. Betsill WL, Clark AH. Early endocervical glandular neoplasia I. Histomorphology and cytomorphology. Acta Cytol 1986;30:115–26.[Medline]

3. Christopherson WM, Nealon N, Gray LA. Noninvasive precursor lesions of adenocarcinoma and mixed adenosquamous carcinoma of the cervix uteri. Cancer 1979;44: 975–83.[Medline]

4. Wolf JK, Levenbeck C, Malpica A, Morris M, Burke T. Mitchell MF. Adenocarcinoma in situ of the cervix: Significance of cone biopsy margins. Obstet Gynecol 1996;88: 82–6.[Abstract]

5. Hopkins MP, Roberts JA, Schmidt RW. Cervical adenocarcinoma in situ. Obstet Gynecol 1988;71:842–4.[Abstract]

6. Im DD, Duska LR, Rosenshein NB. Adequacy of conization margins in adenocarcinoma in situ of the cervix as a predictor of residual disease. Gynecol Oncol 1995;59: 179–82.[Medline]

7. Widrich T, Kennedy AW, Myers TM, Hart WR, Wirth S. Adenocarcinoma in situ of the uterine cervix: Management and outcome. Gynecol Oncol 1996;61:304–8.[Medline]

8. Schorge JO, Lee KR, Flynn CE, Goodman AK, Sheets EE. Stage IA1 cervical adenocarcinoma: Definition and treatment. Obstet Gynecol 1999;93:219–22.[Abstract/Free Full Text]

9. Schorge JO, Lee KR, Sheets EE. Prospective management of Stage IA1 cervical adenocarcinoma by conization alone to preserve fertility; a preliminary report. Gynecol Oncol 2000;78:217–20.[Medline]

10. Morris M, Mitchell MF, Silva EG, Copeland LJ, Gershenson D. Cervical conization as definitive therapy for early invasive squamous carcinoma of the cervix. Gynecol Oncol 1993;51:193–6.[Medline]

11. Mestwerdt G. Die fruhdiagnose des kollumkarzinoms. Zentralbl Gynakol 1947;69:198–202.

12. Pecorelli S, Benedet JL, Creasman WT, Shepherd JH. FIGO staging of gynecologic cancer. Int J Gynaecol Obstet 1999;64:5–10.[Medline]

13. Östör A, Duncan A, Quinn M, Rome R. Adenocarcinoma in situ of the uterine cervix: An experience with 100 cases. Gynecol Oncol 2000;79:207–10.[Medline]

14. Poynor EA, Barakat RR, Hoskins WJ. Management and follow-up of patients with adenocarcinoma in situ of the uterine cervix. Gynecol Oncol 1995;57:158–64.[Medline]

15. Kennedy AW, El Tabbakh GH, Biscotti CV, Wirth S. Invasive adenocarcinoma of the cervix following LLETZ for adenocarcinoma in situ. Gynecol Oncol 1995;58: 274–7.[Medline]

16. Azodi M, Chambers SK, Rutherford TJ, Kohorn EI, Schwartz PE, Chambers JT. Adenocarcinoma in situ of the cervix: Management and outcome. Gynecol Oncol 1999; 73:348–53.[Medline]

17. Brown JV, Peters WA, Corwin DJ. Invasive carcinoma after cone biopsy for cervical intraepithelial neoplasia. Gynecol Oncol 1991;40:25–8.[Medline]

18. Hocking GR, Hayman JA, Ostor AG. Adenocarcinoma in situ of the uterine cervix progressing to invasive adenocarcinoma. Aust N Z J Obstet Gynaecol 1996;36:218–20.[Medline]

19. Smith HO, Tiffany MF, Quall CR, Key CR. The rising incidence of adenocarcinoma relative to squamous cell carcinoma of the uterine cervix in the United States—a 24 year population based study. Gynecol Oncol 2000;78: 97–105.[Medline]

20. Östör A, Rome R, Quinn M. Microinvasive adenocarcinoma of the cervix: A clinicopathologic study of 77 women. Obstet Gynecol 1997;89:88–93.[Abstract]

21. Kaku T, Kamura T, Sakai K, Amada S, Kobayashi H, Shigematsu T, Nakano H. Early adenocarcinoma of the uterine cervix. Gynecol Oncol 1997;65:281–85.[Medline]

22. Nicklin JL, Perrin LC, Crandon AJ, Ward BG. Microinvasive adenocarcinoma of the cervix. Aust N Z J Obstet Gynecol 1999;39:411–3.[Medline]

23. Östör AG. Early invasive adenocarcinoma of the uterine cervix. Int J Gynecol Pathol 1999;19:29–38.

24. Nagarsheth NP, Maxwell GL, Bentley RC, Rodriguez G. Bilateral pelvic lymph node metastases in a case of FIGO stage IA1 adenocarcinoma of the cervix. Gynecol Oncol 2000;77:467–70.[Medline]

25. Covens A, Kirby J, Shaw P, Chapman W, Franseen E. Prognostic factors for relapse and pelvic lymph node metastases in early stage I adenocarcinoma of the cervix. Gynecol Oncol 1999;74:423–7.[Medline]




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