Risk factors for poor prognosis in microinvasive adenocarcinoma of the uterine cervix (IA1 and IA2): A pooled analysis

Gynecologic Oncology 121 (2011) 135–142

Contents lists available at ScienceDirect

Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y g y n o

Risk factors for poor prognosis in microinvasive adenocarcinoma of the uterine cervix (IA1 and IA2): A pooled analysis☆ June Hou a, Gary L. Goldberg a,b, Clifford R. Qualls d, Dennis Y.S. Kuo a, Aliza Forman c, Harriet O. Smith a,e,⁎ a

Department of Obstetrics and Gynecology and Women's Health, 1695 Eastchester Road, Bronx, NY 10461, USA Department of Obstetrics & Gynecology and Women's Health, Director of the Division of Gynecologic Oncology, Albert Einstein College of Medicine, Albert Einstein Cancer Center Montefiore Medical Center, USA c Albert Einstein College of Medicine, 1495 Eastchester Road, Bronx NY, 10461, USA d Department of Mathematics and Statistics, University of New Mexico Health Sciences Center, 1 University of New Mexico, MSC 09 5240, Albuquerque, NM 87131-0001, USA e Department of Obstetrics and Gynecology and Women's Health, Division of Gynecologic Oncology, Albert Einstein College of Medicine and Montefiore Medical Center, 1695 Eastchester Road, Suite 601, Bronx, NY 10461, USA b

a r t i c l e

i n f o

Article history: Received 21 October 2010 Available online 30 December 2010 Keywords: Microinvasive adenocarcinoma Cervical carcinoma Histology Adenocarcinoma in situ

a b s t r a c t Objective. To identify adverse risk factors for FIGO IA1 and IA2 cervical adenocarcinoma. Methods. PubMed was used to identify all microinvasive adenocarcinoma cases. Case specific data pooled for 35 “high risk” microinvasive adenocarcinoma (MIAC), defined as cases with lymph node or lymphovascular space involvement, positive surgical margins, or recurrence was compared with 478 “low risk” cases abstracted from the SEER database (1988–1997). Statistical methods included non-paired t and Fisher's Exact tests. Results. Survival for 1A1 and 1A2 MIAC is 99% and 98%, respectively. Significantly more 1A2 patients underwent aggressive radical surgery and received postoperative treatment. Parametrial involvement was rare (1/373 cases). Significantly more “high-risk” cases were of endometrioid histology (6/34 vs. 14/478, p=0.001), whereas adenocarcinoma (p=0.046) and mucinous (p=0.021) tumors were observed in the “low-risk” group. Among the “high-risk” cases with at least 5 years follow-up, 1.4% has recurred or died. Conclusions. Endometrioid histology may be associated with late recurrence and worse survival in stage 1A1 and 1A2 MIAC. © 2010 Elsevier Inc. All rights reserved.

Introduction Adenocarcinoma of the uterine cervix (ADC) represents a diverse group of invasive glandular tumors, usually retaining a resemblance to mullerian mucinous epithelium [1]. Women with adenocarcinoma share many epidemiological features in common with squamous cell carcinoma of the cervix (SCC), including lower socioeconomic status, early age of first coitus, multiple sexual partners, and a causal relationship with human papilloma virus infection [2]. Unlike SCC, ADCs can be linked to obesity, exogenous estrogen, [3] and oral contraceptives, [4,5], and do not appear to be associated with cigarette smoking [6]. Microinvasive adenocarcinoma (MIAC) often arise in glandular crypts distant from the squamocolumnar junction, and determining presence of invasion and its depth is more difficult [7,8]. In 2009, the

☆ Supported by the DHHS/PHS/NIH/NCRR/GCRC Grant # 5 M01 RR00997, Clinical and Translational Science Center, University of New Mexico Health Sciences Center. ⁎ Corresponding author. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine and Montefiore Medical Center, 1695 Eastchester Road, Suite 601, Bronx, NY 10461, USA. Fax: +1 718 405 8087. E-mail address: hasmith@montefiore.org (H.O. Smith). 0090-8258/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2010.11.036

FIGO staging system was modified to state that the definitions of IA1 and IA2 microinvasive cervical cancer apply to both glandular and squamous lesions [9–11]. This important change in the definition should facilitate comparisons of outcome by treatment strategy, histologic subtype, and stage. There has been a steady population-based increase in the rates of preinvasive and invasive ADC, especially in younger women, where these lesions now account for 27% of all invasive cervical carcinomas [12]. This raises concern that conventional cervical cytology may be less reliable for detecting glandular lesions [13,14]. Fertility is a strong concern in this group, and practitioners are being called upon to assist patients in making informed decisions about the treatment options and the potential risks [18–21]. Most surgeons consider radical hysterectomy as the treatment of choice for MIAC. Nevertheless, there is a growing body of literature indicating that under certain circumstances these patients can be managed by conization, trachelectomy, or simple hysterectomy with/without lymphadenectomy [15–28]. Case series and meta-analyses have identified lymph node involvement, depth and width of stromal invasion, and the presence of lymphovascular space involvement (LVI) as “high risk” factors associated with higher rates of recurrence. Less is known about the impact of age at diagnosis, histologic subtype, and tumor grade on the biological aggressiveness of MIAC.

136

J. Hou et al. / Gynecologic Oncology 121 (2011) 135–142

We have previously published incidence and survival data for patients diagnosed with MIAC using the Surveillance, Epidemiology and End Results (SEER) Public Use database for all cases diagnosed between 1988 and 1997 [29,30]. The purpose of our current study is to determine the impact of the potential risk factors on the survival for MIAC, pooling “high risk” cases from all previously published reports and comparing them to the “low risk” MIAC cases in SEER, defined as those without lymph node positivity or who did not die from cervical cancer. Materials and methods PubMed (1952–January 2010) was utilized to identify all previously reported cases in the English language literature. Citations were crossreferenced against the type of treatment received. If a selected study contained results from previously published data, where feasible, only the most recent data was included. Additional details about specific surgical treatment and depth of invasion provided to us by Dr. A.G. Östör that were not included in the original citations are used in the tables [18,31–38]; these data have been included in prior reports [24,29]. In 2010, Professor Benjamin Piura, M.D. provided us with follow-up data for the 3 patients with MIAC in his original series, and these cases also are included [39]. Before MIAC was clearly defined, investigators used different definitions for early invasive disease including tumor volume, which was usually also stratified by depths of invasion. In some series, the depth (but not width) of invasion was reported, and cases with horizontal tumor measurements greater than 7 mm were included. Given these limitations, we elected to report the number of cases in each category plus/minus the maximum (minimum) number represented by that variable, when an exact number was not available. Our inclusion criteria are consistent with the previous reported methodologies, and include cases fitting the FIGO definition, depth of invasion b5 mm, and tumor volume b500 mm3. Casespecific data from “high risk” cases, defined as having lymph node positivity, LVI or recurrence, was tabulated by stage. Due to a lack of reported case-specific data in published reports, we used the SEER Database to abstract age, histologic subtype and grade for the 486 cases of MIAC FIGO IA1 and IA2 registered between 1988 and 1997 using the previously described methods, [29,30] and updating the survival time using SEER*Stat 6.2.4. The 35 patients with “high-risk” characteristics pooled from published reports and SEER was compared to 478 cases in SEER with IA1 and IA2 MIAC without these features (Supplementary 1). Fisher's exact test (StatXact-8 for Windows, 2007, CYTEL Software Corporation, Cambridge, MA), and non-paired student t tests were used. Two sided p values (b0.05) were considered statistically significant. Results Update on MIAC cases from SEER A total of 486 cases from SEER with MIAC, (202 IA1 and 284 IA2) registered between 1988 and 1997 [29,30]. The number of cases by FIGO stage and histology is depicted in Fig. 1. Adenocarcinoma not otherwise specified was the most common histological subtype, and accounted for 353 cases (72.6%): 31.1% IA1 and 41.6% IA2. By tumor grade (Fig. 2), 133 (27.4%) were well differentiated: 23.5% were moderately differentiated, 8.6% were poorly or undifferentiated. Grade was frequently not assigned (40.5%). There were three cases with at least one positive regional lymph node, and 7 women who died from cervical cancer. The case-specific data for these seven patients was unchanged from earlier reports [29,30]. Literature analysis We identified 42 case reports and series that included cases that met some or all of the criteria for IA1 and IA2 MIAC. At least six of these series included previously published cases [21,22,26,29,30,40]. Summary data by FIGO stage are provided in Tables 1 and 2. It was not always possible to abstract case-specific data by stage, histology, and type of therapy given,

except for the “high risk” cases, defined as those patients who recurred or died, had positive nodal involvement or LVI. These cases are described in detail in Tables 3 and 4. Our best estimate for the number of reported IA1 MIAC is between 814 and 862 cases (mean: 838). Of these, 102–138 (12–17.2%, mean: 14.6%) were managed primarily by conization, 159–205 (mean: 22.6%) by simple hysterectomy (SH) with or without regional lymphadenectomy, 343–389 (43.9%) by radical hysterectomy (RH), and 14–19 (2.0%) by a variety of other surgical procedures that included trachelectomy, abdominal or vaginal, and parametrectomy, usually after hysterectomy or conization as the initial procedure. In addition to surgery, 16 (1.9%) also received radiation therapy (RT). The duration of follow-up was extremely variable, from as little as one month to 29 years. There were 13 confirmed recurrences. One additional case, that of an HPV-negative metastatic mucinous adenocarcinoma diagnosed 82 months after RH with lymphadenectomy for IA1 mucinous adenocarcinoma may also have had a late recurrence or primary metastatic ovarian cancer [41]. Depending upon the inclusion of this case, the rate of recurrence for IA1 MIAC is 1.5 to 1.7%. At publication, 4/13 (or 14, if the previously mentioned cases is included) cases were undergoing or had completed salvage radiation ± chemotherapy, and 8 (0.9%) had died from cervical cancer. Thus, the overall survival rate for IA1 MIAC was 99%, and not different from published survival rates for IA1 SCC [42,43]. However, as shown in Table 1, patients with stage IA1 MIAC received far more aggressive therapy than patients with IA1 SCC [42,43]. LVI was identified in only 8 (2.1%) of 357–408 IA1 MIAC cases where RH, trachelectomy, or parametrectomy was performed. Although no one with LVI was reported to have positive nodes, 2/8 (25%) recurred. Of the 383–385 1A1 cases undergoing lymph node dissection, 4–5 (1.2%) were identified with one or more positive regional nodes [44]. Further details about these cases are provided in Table 3. Only 3 IA1 MIAC cases have been reported to have more than one lymph node involvement [29,44,45], and only one with bilateral pelvic nodal involvement [45]. The other two cases, one with three positive nodes, were SEER cases (Table 3) [29,30]. Among the five patients with regional nodal involvement, 2 (40%) died from cervical cancer and 2 (40%) had less than 1 year of follow-up. Data for all stage IA2 MIAC is summarized in Table 2. There were 487–493 cases (mean: 490), and the survival rate was 98%. Although comparable to IA1 MIAC, these patients received more aggressive therapy. The number (%) managed by conization, SH, RH, or other procedures, was 49 (10.0%), 142–162 (30.9%), 265–276 (55.1%), and 15 (3.1%), respectively. Compared with IA1 MIAC, significantly more 1A2 patients had one or more positive regional nodes (p = 0.002), but the rate of recurrence was not significantly higher (p = 0.15). Radiation was employed more often for IA2 than IA1 MIAC (5.7% vs. 1.9–2.0%, p b 0.001). More IA2 MIAC also underwent radical surgeries (IA2, 55.1% vs. IA1, 43.9%, p = 0.03). With respect to fertility-sparing surgery, of 102–138 managed by cone/LEEP/LLETZ, recurrence has been observed in only four 1A1 cases (3.4%) [27,29,44,46]. Of importance, 3/4 (75%) had either residual glandular and squamous dysplasia, close margin, or persistently abnormal cervical cytology; [27,44,46] no data was available with respect to margins for the fourth [29]. One case recurred in the 45 1A2 cases managed by local excision (2.2%) [75]. The status of the parametrium was specifically addressed in 373 reports (IA1 and IA2, b5 mm invasion). Of these, parametrial involvement has been specifically identified in only one, a patient with stage IB1 adenocarcinoma diagnosed at one year after conization for adenocarcinoma in situ (Table 3) [4]. Analysis of ‘high risk’ cases There were 35 “high risk” cases (18 IA1 and 17 IA2) identified from the literature/SEER with sufficient data for analysis (Tables 3 and 4). Compared with the SEER “low-risk” group, there were no differences

J. Hou et al. / Gynecologic Oncology 121 (2011) 135–142

137

Fig. 1. Histologic subtypes of MIAC IA1 and 1A2 (SEER 1988–1997). Count (number, %) per histological subtype. ADC NOS, Adenocarcinoma not otherwise specified [8140], ENDO, Endometrioid [8380]; AS, Adenosquamous Carcinoma [8650]; PAP, Papillary Carcinoma [8260], MUC, Mucin [8480] and Mucin Producing [8481] Adenocarcinomas, VIL, Villoglandular adenocarcinoma [8262]; CC, Clear Cell Adenocarcinoma [8310], and OTHER, Mixed Adenocarcinoma [8323]; Mucoepidermoid [8430], and Signed Ring [8490].

in the distribution by stage or age at diagnosis (p N 0.30). Although IA2 “high-risk” cases were on average 7.4 years older than 1A1, this difference was not statistically significant (IA1: 39.7 years ± 12.0 vs. IA2: 47.1 years ± 15.6, p = 0.56). Histological subtype was not recorded for the four ‘high risk’ cases, and these were pooled into the “other” category (11.8%). The remaining cases included 19 (55.9%) adenocarcinoma, 2 (5.9%) adenosquamous, 6 (17.6%) endometrioid, 3 (8.8%) mucinous, and 4 (11.8%) were others. In contrast, the SEER “low-risk” group included 349 (73.0%) adenocarcinoma, 71 (14.9%) adenosquamous, 14 (2.9%) endometrioid, and 13 (2.7%) mucinous or mucin secreting cases. The difference between “high” and “low risk” groups by histological subtype was statistically significant (p b 0.001). In post hoc analyses,

significantly more “high-risk” cases were of endometrioid histology (p = 0.001), whereas significantly more “low-risk” cases were adenocarcinoma (p = 0.046) and mucinous (p = 0.021) tumors, with no differences for the other cell types (all p N 0.20). Tumor grade was not recorded for 197 (41.2%) of the SEER “lowrisk” cases and 11 (31.4%) of the “high-risk” cases. Among the “high risk” cases, 7 (29.2%) had well differentiated tumors and 17 (70.8%) had tumors that were grade 2 or higher, a difference that was not statistically significant (p = 0.09). At the time of publication, 28 (80%) of the “high risk” cases had recurred. We combined all adverse events (recurrence, dead [DOD], and alive with disease [AWD]) and looked at its association with risk factors of interest. The association between tumor grade 2 or higher

Fig. 2. Tumor Grade of MIAC IA1 and IA2 (SEER 1988–1997). Absolute count (number and %) by Tumor Grade. Gr 1, well differentiated; Gr 2, moderately differentiated; Gr 3, poorly differentiated; Gr 4, undifferentiated; and UK, grade unknown.

138

J. Hou et al. / Gynecologic Oncology 121 (2011) 135–142

Table 1 Stage IA1 Adenocarcinoma (≤ 3 mm invasion, tumor volume b 500 mm3). Author

Sachs [32] a Nakajima [38] Berek [18] b Simon [65] c, Teshima [25] b Andersen [66] b Fu [20] Matsukuma [40] b Rollason [67] d Burghardt [33] Angel [68] e Matthews [48] Jones [31] Kaspar [69] Van den Broek [27] Kennedy [44] Wolf [17] b,f Kaku [26] Östör [21] Kurian [28] c Nicklin [36] Schorge [70] Covens [49] b Elliott [46] Nagarsheth [45] Schorge [71] Lee [72] Östör [22] b Utsugi [50] Kasamatsu [47] g Smith [29,30] b Erzen [51] b Balega [73] h Hirai [74] Poynor [75] Ceballos [41] Bisseling [63] Yahata [76] Singh [16] Total IA1

Year

1975 1983 1985 1986 1985 1989 1987 1989 1989 1989 1992 1993 1993 1993 1995 1995 1996 1997 1997 1999 1999 1999 1999 2000 2000 2000 2000 2000 2001 2002 2002 2002 2004 2003 2006 2006 2007 2008 2008

Cases(n)

1 14 6 6 11 8 3 8 2 3 9 24 8 22 1 1 2 21 43 8 26 21 47 19 1 6 38 22 65 24 200 9 17 22 21 29 29 16 1 814–862

Type of surgical therapy

Number of cases per parameter

† Follow-up (year)

Cone

SH

RH

Other

XRT

LVI

LND

+ LN

Recurred

DOD

0 0 0 0 0 1 3 1 0 0 0 0 1 0 0 1 0 1 12 1 1 1 0 Uk 0 5 22 Uk Uk 0 31 12 0 0 2 1 16 4 1 102–138

1 0 0 0 0 7 0 4 1 0 1 0 0 2 1 0 2 20 21 7 11 4 0 Uk 1 1 16 Uk Uk 3 82 Uk 0 0 4 4 9 0 0 159–205

0 7 6 0 22 0 0 3 1 3 7 0 7 20 0 0 0 0 10 0 15 16 47 Uk 0 0 0 4 Uk 21 76 Uk 17 22 14 22 4 3 0 343–389

0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 Uk 0 0 0 8 Uk 0 11 Uk 0 0 0 2 0 Uk 0 14–19

Uk Uk Uk 0 0 0 3 0 0 0 0 0 1 0 0 0 0 0 0 0 0 1 0 Uk 1 0 0 0 Uk 0 12 Uk 0 0 0 1 0 Uk 0 16.0

Uk Uk Uk 0 0 Uk 0 0 0 0 0 0 0 0 0 Uk Uk 16 4 0 0 0 1 0 0 0 Uk 0 Uk 1 Uk Uk 0 0 0 0 2 0 0 8

0 7 6 Uk 11 0 0 3 1 Uk 8 24 6 22 1 0 0 0 22 Uk 16 16 47 At least 2 1 0 0 0 Uk 21 70 Uk 17 22 14 24 10 3 0 383–385

0 0 0 0 0 0 0 0 0 0 0 Uk 0 0 0 1? Uk 0 0 0 0 0 0 1 1 0 Uk N/A Uk 0 2 Uk 0 0 0 0 0 0 0 4–5

0 0 0 0 1 0 3–6 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 1 2 0 0 Uk

0 0 0 0 0 0.5–8

Uk 5 1.5–11 1–10 1–10

0 0 0 0 0 0 0 1 0 0 2–19.3 0 0 0 0 0 2 0 0 2.16

2.2–6.7 0.25–2 5 0.08–10.6 0.6–18 4.3 1–10 2 1.42 0.58–11

1 1 3 0 0 1 0 1? 0 0 1 13–14

0 1 3 0 0 0 0 1? 0 0 1 8–9

5.3 8.3 (0.75–29.0) 0.5–9.9 3.59 ± 16.2 3.59 ± 16.2 † 2.5 (0.5–10.3) At least 3 2.5 (0.25–18) 6.0 2–13 4 0.08–29

0.25–12 2–7 0.25–9.7 2.5–14.3 4.17 10 0.03 0.5–1.7

SH: simple hysterectomy (abdominal or vaginal ±LND); RH: radical hysterectomy ± LND; Cone: (cone, LEEP, and LLETZ); LND: lymph node dissection; Uk: unknown; and DOD, dead of disease. †Median survival used if range not available. a English translation provided courtesy of Dr. Ostor. b Cases were not further stratified by type of surgery. c Defined early invasive as b5 mm of invasion. d Described 4 cases each of “microinvasive ADC” and “occult ADC”, 3 with tumor volumes less than 520 mm. e Authors did not attempt to define “microinvasive” disease. f Series (30 cases) included 6 previously reported by Matsukuma, [40]. g Included the 301 SEER cases reported by Webb et al. h Did not report outcome of 2 cases with MIAC treated by laser/cone.

(p = 0.08), lymph node positivity (p = 0.16), and histology (p = 0.16) was not statistically significant. Stratified by stage, 14/18 (77.8%) of the IA1 “high-risk” cases had recurred, compared to 13/17 (76.4%) of 1A2 cases. Fifteen 1A1 patients (83.5%) experienced an adverse event (recurrence, DOD, and AWD) compared to 14 (82.4%) of 1A2 patients. Long-term follow-up was available for 29 “high risk” cases. Of these, 6 (20.7%) experienced a death/recurrence 5 or more years after diagnosis (3/ 18 (16.7%) IA1 and 3/17 (17.6%) IA2). No cases of primary or metastatic ovarian involvement at the time of initial treatment were reported.

1A2: 2.8%). There is a statistically significant trend to employ radical surgeries and adjuvant RT more often for patients with 1A2 disease. Recurrence after fertility-sparing surgery is uncommon (1A1: 3.4% and 1A2: 2.2%). Looking at the association of risk factors of interest and “high risk” patients: grade 2 or higher trended towards significance (p = 0.09), and endometrioid cell type was significantly associated with “high risk” cases. Within the “high risk” cases, recurrence rates between 1A1 and 1A2 MIAC were similar. Of interest, 20.7% recurred 5 or more years after diagnosis. Discussion

Summary The survival rates for MIAC 1A1 and 1A2 from the published literature were 99% and 98%, respectively. Despite of significantly more 1A2 patients having positive regional lymph nodes, the recurrence rates were not significantly different (1A1: 1.6% and

Survival rates for microinvasive adenocarcinoma are excellent. For 1A1 and 1A2, the risk of nodal involvement, LVI, and recurrence were low, but significantly more IA2 cases underwent radical surgeries, and were given RT postoperatively. These factors may account for the lack of differences in survival rates by stage. LVI was identified in 8 1A1

J. Hou et al. / Gynecologic Oncology 121 (2011) 135–142

139

Table 2 IA2 microinvasive disease (N 3 mm and ≤ 5 mm of invasion or tumor volumes b 500 mm3). Author

a

Sachs [32] Nakajima [38] Teshima [25] b Andersen [66] d Burghardt [33] e Matthews [48] f Jones [77] g Kaspar [69] h Wolf [17] Piura [39] b,c,i Kaku [26] Östör [21] Kurian [28] c,j Nicklin [36] k Covens [49] l Elliott [46] m Lee [72] n Smith [29,30] Kasamatsu [47] o Erzen [51] Hirai [74] b,c,p Balega [73] Poynor [75] Ceballos [41] Bisseling [63] Total IA2 a

b,c

Year

1975 1983 1985 1989 1989 1991 1993 1993 1996 1996 1997 1997 1999 1999 1999 2000 2000 2002 2002 2002 2003 2004 2006 2006 2007

N

1 9 11 1 5 12 3 3 1 3 8 34 2 4 21 29 2 286 4 8 6 31 12 3 9 487–493

Type of surgical therapy

Number of cases per parameter

Deaths

† Follow-up (year)

Cone

SH

RH

Other

XRT

LVI

LND

+ LN

Recurred

0 0 0 0 1 0 0 3 0 0 8 4 0 0 0 0 0 29 0 8 0 0 1 0 2 45

0 0 0 1 0 0 0 Uk 1 2 1 14 2 0 0 Uk 2 116 0 Uk 0 0 0 0 3 142–162

1 4 11 0 4 12 3 Uk 0 1 1 16 0 4 21 Uk 0 134 4 Uk 6 31 10 3 5 265–276

0 0 0 0 0 0 0 3 0 0 8 0 0 0 0 Uk 0 7 0 Uk 0 0 1 0 7 15

0 0 Uk 0 0 Uk 0 2 1 0 0 1 0 0 0 Uk 2 25 0 Uk 0 0 0

0 0 0 Uk 0 Uk 0 3 0 0 1 3 0 0 2 Uk 2 Uk 0 Uk 0 4 1 0 2 15

1 0 11 0 Uk 12 Uk Uk 0 2 1 26 0 0 21 Uk 0 Uk 4 Uk 6 31 12 3 7 132–141

0 0 0 0 0 Uk 0 1–10 Uk 0 2–19.3 0 Uk 0 2 Uk 0 1 0 Uk 0 0 0 0 0 5

0 0 0 0 0 3 0

0 0 0 0.5–8 0 Uk 0

Uk 5 1/4–14

0 0

0 0

0.58–11 10

2 0 0 2 1 0 4 0 Uk 1 0 0 0 0 17

0 0 0 1 1 2.16 4 0 Uk 0 0 0 0 0 7

1/4–12 2–7 1/4–9.7 4.1 10

0 28

5 0.6–18 4.3

0.08–9.9 8.3(0.75–29.0) 3.59 ± 16.2 3 † 2.5 (0.5–10.3) 3 4.5 (0.42–13) 6.0 0.08–18

SH, abdominal or vaginal hysterectomy ± LND; RH, radical hysterectomy; Cone (cold knife conization, LEEP, and LLETZ); other, primary surgery other than SH, RH, or Cone; LND, Lymph node dissection; + LN = one or more lymph nodes positive for metastatic tumor; Deaths = Cervical-cancer related deaths; †Median, and if median is not reported, mean follow-up in years; and Uk, unknown. a English translation provided courtesy of Dr. Östör. b Cases not further stratified by type of surgery. c Defined early invasive as less than 5 mm invasion. d Included cases with tumor volumes less than 520 mm3; one case who underwent conization refused further treatment and was NED at 5 years. e This was an analysis of surgically treated cases of Stage I ADC; there were 3 recurrences among 12 patients with 3.1–5 mm of invasion. There was no attempt to define a group with “microinvasive” disease; further stratification by lymph node status and LVI by depth of invasion was not provided. Included tumor volumes over 100 mm3. f Among 12 early invasive adenocarcinomas, 8 were diagnosed by biopsy, and 4 by cone; 8 had b3 mm of invasion, 2 had 3 mm of invasion, and 1 each had 4 and 5 mm of invasion. g Two cases, with stromal invasion of 2.6 (630 mm3) and 3.8 mm (880 mm3) recurred — the later had spread to the pelvic nodes at surgery. h In a series of 55 cases of AIS, 8 patients were found to have invasive ADC in hysterectomy specimens, and 2 of 10 who did not undergo hysterectomy developed ADC; depth of invasion was recorded in only 3 cases (included in the tables). i Included 6 previously reported cases [37]. j We counted minimally invasive with tumor volumes ≤ 100 mm3 as IA1. k 22 patients had tumor volumes N 600 mm3; only one had a depth of stromal invasion b3 mm (Table 1). While there had been no deaths at publication, the one who recurred 66 months with liver and pelvic metastases has probably died. l Described 58 Stage IA glandular epithelial tumors not further characterized as IA1 or IA2 and arbitrarily, half were included in each table. m 40 patients with MIAC ≤5 mm invasion (average 2.3 mm), including 10 with minimal stromal invasion; 8 underwent hysterectomy (type not further specified) and 32 underwent conization. n Included the 301 SEER cases reported by Webb et al. [9]. o Described 12 patients (not further stratified by stage) who were surgically managed by conization. p Cases were not stratified as IA1 vs. IA2.

patients (2.1%), and although none of them had nodal involvement, 2/8 (25%) recurred. Therefore, LVI may be a significant risk factor for recurrence irrespective of nodal status. These results are in keeping with those of Matthews and colleagues, who reported 56% of LVI + patients recurred. In their multivariate analysis, only nodal positivity remained significant, with LVI approaching significance [48]. Unfortunately, there was insufficient case-specific data given to include these patients in our analysis. The extremely low rate of parametrial involvement (1/373 cases) suggests that parametrectomy has little if any influence on survival. However, we cannot deny the possibility that parametrectomy lowered recurrence rates, or that failure to identify parametrial disease was the result of insufficient tissue sampling. Other factors have been evaluated as predictors for poor prognosis [21,33]. Covens used tumor volume 500 mm3 as the “cut off” for defining microinvasive disease and found that this increased the specificity of predicting pelvic nodal involvement, LVI, and recurrence without compromising sensitivity. Two out of his 22 cases had positive lymph nodes. Neither had LVI in the primary tumor, nor did they recur [49].

In the series by Kaspar, lymphatic involvement and recurrence was observed in 2/25 cases with tumor volumes N500 mm3 (depths of stroma invasion: 1.5 and 3.8 mm). Usagi identified recurrence in 1/65 MIAC cases. This lesion was 3 mm in depth by 3 mm in longitudinal axis. He surmised that the recurrence risk is greater when the depth of invasion exceeded the depth of the normal cervical epithelium [50]. Stage and screening history were the only significant independent predictors of outcome identified by Erzen. Over half of his patients had no visible lesions on colposcopy. However, the probability of having symptoms increased with advancing stage of disease [51]. We compared 35 patients with IA1 and IA2 MIAC with “high risk” criteria (LVI, nodal involvement, and/or recurrence) to 478 cases without these features derived from the SEER database. Endometrioid histology was observed significantly more frequently in patients with “high-risk” disease. It should be noted that when stratified by stage, endometrioid histology was not significantly associated with recurrence. This may be due to the limited number of positive events within each subgroup. More “high-risk” cases had tumors that were grade 2 or higher, a difference that only trended towards significance

140

J. Hou et al. / Gynecologic Oncology 121 (2011) 135–142

Table 3 Clinicopathological features of patients with “high risk” (recurrence, + LVI, or lymph node positivity) 1A1 MIAC (N = 18). Age

Histology

Gr

Surgery

Margins

Invasion (mm) D/W (V)

Param inv

LVI

No. LN

+ LN

Treatment (B/A)

Recur

DFI/OS (year)

FS

Teshima [25] Vanden Broek [27]

47 21

Endocervical ADC

2 2–3

Neg AIS, CIS

3.0/Uk 2.0/5.0

0 Uk

0 Uk

30 Uk

0 Uk

Exent (A) Chemo (A)

Vagina Episiotomy

3.25/4 0.3/0.4

NED AWD

Kennedy [44]

28

ADC

1

AIS

Uk

1

Uk

Uk

2

1/1.42

NED

27 41 26

Endocervical ADC ADC

2 Uk Uk

Uk Uk Uk

2.5(844) 1.8/Uk b 1 mm/Uk

0 Uk Uk

1 0 Uk

0 Uk 1

0 1 0

ChemoRT (A) XRT (A) Uk Uk

Cervix

Covens [49] Elliott [46] Elliott [46]

Pelvis Pelvis CNS

1.08/Uk 5.0/6.0 7/8

NED DOD DOD

Nagarsheth [45] Smith [29,30] Smith [29,30] Smith [29,30] Smith [29,30] Utsugi [50] b Kasamatsu [47] Kasamatsu [47] Kasamatsu [47] Hirai c Cabellos d Singh [16]

62 43 37 27 49 52 47 Uk Uk 52 46 30

Endometrioid ADC AS AS Endometrioid Endocervical Endocervical Endometrioid Endocervcial Endocervical ADC Endometrioid

2–3 3 2 3 3 1 2 2 2 1 Uk 1

RH LEEP; SH (recur) LLETZ; RH (recur) RH RH Cone; SH (recur) SH SH RH Cone Hysterectomy Hysterectomy RH RH RH RH RH Cone, RH (recur)

Neg Uk Uk Uk Uk AIS Neg Neg Neg Uk Uk b1 mm

2.5/4.0 Uk Uk Uk Uk 3.0/3.0 3.0/7.0 3.0/7.0 3.0/9.0 3.0/3.0 ≤ 3/7 b 3 mm/Uk

Uk Uk Uk Uk Uk Uk 0 0 0 Uk Uk Uk

0 Uk Uk Uk Uk 0 0 1 1 1 0 1

18 0 17 0 21 0 30 Uk Uk 22 Uk 24

2 Uk 3 Uk 1 0 0 0 0 0 0 0

ChemoRT XRT XRT XRT XRT Uk 0 0 0 XRT (A) Uk 0

0 Uk Uk Uk 0 Vagina Pelvis 0 0 Vagina Ovary Uterus, systemic

0.03/Uk Uk/2.1 Uk/1.0 Uk/1.75 9.3/Uk 3.9/8.9 2.25/10 6.08 12.4 3.75/8.0 6.83/6.83 2/2.75

Uk DOD DOD DOD NED NED DOD NED NED NED DOD DOD

a

b

a

P, Parity; AIS, adenocarcinoma in situ; AGC, abnormal glandular cytology; ADC, adenocarcinoma; AS, adenosquamous carcinoma; NOS, not otherwise specified; Gr, grade (1 well differentiated, 2 moderately differentiated, and 3 poorly/undifferentiated); SCC, squamous cell carcinoma; SH, simple hysterectomy ±LND; RH, radical hysterectomy; Ovary, whether or not ovaries were removed; D, Depth of stromal invasion; W, Width of stromal invasion, V, tumor volume (if width not reported); Chemo, chemotherapy; XRT, radiation therapy; (B, before recurrence; and A, after recurrence); Uk, status unknown, data not reported, or procedure was not performed; FS, last known survival status; DOD, dead of cervical cancer; NED, no evidence of disease; and AWE, alive with disease. a ADC in situ managed by LLETZ, followed with serial cytology; 1 year later cytology c/w AGC, suspect AIS; repeat LLETZ revealed multifocal AIS and ADC. At RH, microscopic involvement of parametrial tissue and 2 positive obturator nodes were found. b Disease-free 81 months after salvage therapy, but recurred and died 120 months after initial treatment. c One patient died of metastatic adenocarcinoma thought to be of ovarian origin based upon the pattern of spread 82 months after diagnosis. Immunostaining of the cervical and ovarian tumors were negative for HPV DNA; there were minor differences in the immunostaining profiles of both tumors; the origin of the ovarian tumor could not be determined with certainty. d Cervical and endometrial tumors both had HPVDNA positive for type 16; the only symptom at recurrence was infertility, for which she underwent D&C; cytological screening for recurrence was negative; initial pathology was.difficult to interpret; depth of invasion b 3 mm; large area of AIS; narrow cone margin (b 1 mm).

(p = 0.09). Late recurrences (N5 years after diagnosis) were observed in 6/28 (21.4%) cases. The high rate is unique to adenocarcinoma biology, and emphasizes the importance of long-term follow-up in patients who undergo fertility-sparing treatments. The risk of ovarian

metastases in our series is extremely low, suggesting that ovarian preservation may be safely considered in microinvasive disease. With increasing stage, recent data suggests that the risk is higher for ADC than SCC and irrespective of histology [52–62].

Table 4 Clinicopathological features of patients with “high risk” (recurrence, + LVI, or lymph node positiveity) 1A2 MIAC (N = 16).

Kaspar [69] Kaspar [69] Kaspar [69] Östör [21] Östör [21] a Covens [49] a Covens [49] a Covens [49] a Covens [49] Elliott [46] Smith [29,30] Smith [29,30] Smith [29,30] Smith [29,30] Hirai [74] Poynor [75] Kaku [75]

Age

Histology

Gr

Surgery

Margins

Invasion (mm) D/W (V)

Param Inv

LVI

No. LN

+ LN

Treatment (B/A)

Recur

DFI/OS (Years)

FS

Uk Uk Uk 65 52 27 34 48 43 42 39 36 59 82 38 Uk UK

Uk Uk Uk ADC NOS Mesonephric Endometrioid Mucinous Endometrioid Endometrioid ADC ADC NOS ADC NOS ADC NOS Mucinous Endocervical Endocervical UK

Uk Uk Uk Uk Uk 2 2 1 1 Uk 2 3 3 3 1 Uk UK

RH RH RH SH SH RH RH RH RH SH RH SH RH Cone RH Cone RH/SH

Uk Uk Uk Uk Uk Uk Uk Uk Uk Uk Uk Uk Uk Uk Uk 1.5 mm (AIS) Uk

1.5 (N 500) 3.8 (N 500) 2.6 (N 500) 3.2/21 (670) 5/10 (450) 5.0(3480) 3.7 (672) 3.6 (1196) 4.9 (2624) 5/Uk Uk Uk Uk Uk 4.0/2.0 3.3/8.5 3–3.9 mm (137)

Uk Uk Uk 0 0 0 0 Uk Uk Uk Uk Uk Uk Uk 0 0 UK

Uk Uk Uk 0 Uk 1 1 Uk Uk Uk Uk Uk Uk Uk 0 1 0

Uk Uk Uk 0 Uk Uk Uk Uk Uk Uk 11 Uk 24 0 16 Uk 0

Y Y 0 0 0 0 0 1 1 Uk 1 Uk Uk Uk 0 0(1) 0

Uk Uk Uk XRT No Chemo (A) XRT (A) Uk XRT Uk Uk XRT Uk XRT Uk RH (A) XRT

Uk Yes Yes Vagina Vagina Pelvis/Liver Pelvis No No Vagina Uk Uk Uk Uk Vagina No Vagina

Uk Uk Uk 4/9 9/Uk 5.5 4.17 4.08 4.08 3.0/6.0 Uk/6.2 Uk/4.33 Uk/6.42 Uk/0.42 1.5/12.75 OS 2.5 13.5/19.2

NED Uk Uk DOC NED AWD NED NED NED NED DOD DOD DOD DOD NED NED NED

P, Parity; SX, symptoms; AIS, adenocarcinoma in situ; AGC, abnormal glandular cytology; ADC, adenocarcinoma; AS, adenosquamous carcinoma; NOS, not otherwise specified; Gr, tumor grade (1 well differentiated, 2 moderately differentiated, and 3 poorly/undifferentiated); SCC, squamous cell carcinoma; SH, simple hysterectomy with or without lymphadenectomy; RH, radical hysterectomy; Ovary, whether or not ovaries were removed; OI, ovarian involvement; D, Depth of stromal invasion; W, Width of stromal invasion, V, tumor volume (if width not reported); Chemo, chemotherapy; XRT, radiation therapy; (B, chemotherapy or radiation therapy before recurrence; A, after recurrence); Uk status unknown, data not reported, or procedure was not performed; FS, last known survival status; DOD, dead of cervical cancer; DOC, dead from other causes, NED, no evidence of disease; and AWE, alive with disease; Systemic, recurred with peritoneal and/or distant metastases. Other series with insufficient information to describe recurrences include Matthews and Erzen [44,48,70]. a While depth of invasion correlated fairly well with tumor volume, both recurrences were in patients with N 500 mm3 of invasion.

J. Hou et al. / Gynecologic Oncology 121 (2011) 135–142

There are limitations to this study, many previously addressed [29,30]. We used SEER data, which accounts for 34% of all published cases, to identify a patient cohort with MIAC without LVI, lymph node positivity, or recurrence. Since SEER does not include this variable, some patients with LVI could have been included in the low risk group [29,30]. Because the SEER data is continuously updated, one would expect the final data to be very similar. The ideal comparison would include all “low-risk” MIAC cases identified by the literature review, instead of using only the SEER cohort. Unfortunately, cases-specific information was not usually given for the low-risk cases. Some cases included in the “high risk” group do not meet the criteria for MIAC, and some were excluded because of insufficient data. The definitions for FIGO staging over time have changed, and some studies were published before there was an appreciation that MIAC could be defined. The total number of MIAC cases we report differs from the most recent review of this topic [63], but otherwise, our summary observations are similar. We credit the higher number of cases reported by Bisseling to the inclusion of replicate cases. For example, the 486 SEER cases published in 2002 [29] contained the 310 cases originally reported by Webb and colleagues [30]. Also, Östör's analysis of the 436 patients was drawn from 26 published reports, and included data obtained by professional correspondence [22,29] not found in the original reports [31,36,38] because MIAC is relatively uncommon, including the same cases in several reports can skew cumulative analyses. Data evaluating fertility-sparing surgery including conization for patients with MIAC is limited. Nonetheless, our series and others provide evidence that these procedures do not significantly elevate recurrence risk, provided that there are clear margins and close follow-up with adequate visualization of the endocervix. Kasamatsu noted that in 9/21 patients with IA1 disease who did not undergo conization, the endocervical tumor margins were situated over 1.5 cm from the external cervical os [47]. Failure to identify disease high in the endocervical canal despite close follow-up and surveillance occasionally can be lethal [16,44]. Following conization, if there is any question about the ability to evaluate for residual disease, imaging modalities to evaluate the endocervix and lower uterine segment, aggressive endocervical sampling, or repeat conization should be considered [64]. Our data suggest that endometrioid histology is a novel risk factor that also warrants more careful evaluation, especially when conservative management is being considered. Conflict of interest statement The authors declare that there are no conflicts of interest.

Appendix A. Supplementary data Supplementary data to this article can be found online at doi:10.1016/j.ygyno.2010.11.036. References [1] Hopkins MP, Roberts JA, Schmidt RW. Cervical adenocarcinoma in situ. Obstet Gynecol 1988;71:842–4. [2] Moreno V, Bosch FX, Munoz N, Meijer CJ, Shah KV, Walboomers JM, et al. Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case–control study. Lancet 2002;359: 1085–92. [3] Lacey Jr JV, Brinton LA, Barnes WA, Gravitt PE, Greenberg MD, Hadjimichael OC, et al. Use of hormone replacement therapy and adenocarcinomas and squamous cell carcinomas of the uterine cervix. Gynecol Oncol 2000;77:149–54. [4] Brinton LA, Tashima KT, Lehman HF, Levine RS, Mallin K, Savitz DA, et al. Epidemiology of cervical cancer by cell type. Cancer Res 1987;47:1706–11. [5] Lacey Jr JV, Swanson CA, Brinton LA, Altekruse SF, Barnes WA, Gravitt PE, et al. Obesity as a potential risk factor for adenocarcinomas and squamous cell carcinomas of the uterine cervix. Cancer 2003;98:814–21. [6] Appleby P, Beral V, Berrington de Gonzalez A, Colin D, Franceschi S, Goodill A, Green J, Peto J, Plummer M, Sweetland S. Carcinoma of the cervix and tobacco smoking: collaborative reanalysis of individual data on 13,541 women with carcinoma of the cervix and 23,017 women without carcinoma of the cervix from 23 epidemiological studies. Int J Cancer 2006;118:1481–95.

141

[7] Zaino RJ. Symposium part I: adenocarcinoma in situ, glandular dysplasia, and early invasive adenocarcinoma of the uterine cervix. Int J Gynecol Pathol 2002;21: 314–26. [8] Shipman SD, Bristow RE. Adenocarcinoma in situ and early invasive adenocarcinoma of the uterine cervix. Curr Opin Oncol 2001;13:394–8. [9] Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 2009;105:103–4. [10] Pecorelli S. Corrigendum to “Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium”: [International Journal of Gynecology and Obstetrics (2009) 105: 103–104]. International Journal of Gynecology & Obstetrics 108: 176-176 [11] Mutch DG. The new FIGO staging system for cancers of the vulva, cervix, endometrium and sarcomas. Gynecol Oncol 2009;115:325–8. [12] Smith HO, Padilla LA. Adenocarcinoma in situ of the cervix: sensitivity of detection by cervical smear: will cytologic screening for adenocarcinoma in situ reduce incidence rates for adenocarcinoma. Cancer 2002;96:319–22. [13] Case AS, Rocconi RP, Straughn Jr JM, Wang W, Roark K, Waltman EE, et al. Cervical intraepithelial neoplasia in adolescent women: incidence and treatment outcomes. Obstet Gynecol 2006;108:1369–74. [14] Herzog TJ, Monk BJ. Reducing the burden of glandular carcinomas of the uterine cervix. Am J Obstet Gynecol 2007;197:566–71. [15] Cohn DE, Morrison CD, Zanagnolo VL, Goist MM, Copeland LJ. Invasive cervical adenocarcinoma immediately following a cone biopsy for adenocarcinoma in situ with negative margins. Gynecol Oncol 2005;98:158–60. [16] Singh P, Scurry J, Proietto A. Lethal endometrial recurrence after cone biopsy for microinvasive cervical adenocarcinoma. J Obstet Gynaecol Res 2008;34:413–7. [17] Wolf JK, Levenback 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. [18] Berek JS, Hacker NF, Fu YS, Sokale JR, Leuchter RC, Lagasse LD. Adenocarcinoma of the uterine cervix: histologic variables associated with lymph node metastasis and survival. Obstet Gynecol 1985;65:46–52. [19] Qizilbash AH. In-situ and microinvasive adenocarcinoma of the uterine cervix. A clinical, cytologic and histologic study of 14 cases. Am J Clin Pathol 1975;64:155–70. [20] Fu YS, Berek JS, Hilborne LH. Diagnostic problems of in situ and invasive adenocarcinomas of the uterine cervix. Appl Pathol 1987;5:47–56. [21] Ostor A, Rome R, Quinn M. Microinvasive adenocarcinoma of the cervix: a clinicopathologic study of 77 women. Obstet Gynecol 1997;89:88–93. [22] Ostor AG. Early invasive adenocarcinoma of the uterine cervix. Int J Gynecol Pathol 2000;19:29–38. [23] Ostor AG, Duncan A, Quinn M, Rome R. Adenocarcinoma in situ of the uterine cervix: an experience with 100 cases. Gynecol Oncol 2000;79:207–10. [24] Ostor AG, Rome RM. Micro-invasive squamous cell carcinoma of the cervix: a clinico-pathologic study of 200 cases with long-term follow-up. Int J Gynecol Cancer 1994;4:257–64. [25] Teshima S, Shimosato Y, Kishi K, Kasamatsu T, Ohmi K, Uei Y. Early stage adenocarcinoma of the uterine cervix. Histopathologic analysis with consideration of histogenesis. Cancer 1985;56:167–72. [26] Kaku T, Kamura T, Sakai K, Amada S, Kobayashi H, Shigematsu T, et al. Early adenocarcinoma of the uterine cervix. Gynecol Oncol 1997;65:281–5. [27] Van den Broek NR, Lopes AD, Ansink A, Monaghan JM. “Microinvasive” adenocarcinoma of the cervix implanting in an episiotomy scar. Gynecol Oncol 1995;59:297–9. [28] Kurian K, al-Nafussi A. Relation of cervical glandular intraepithelial neoplasia to microinvasive and invasive adenocarcinoma of the uterine cervix: a study of 121 cases. J Clin Pathol 1999;52:112–7. [29] Smith HO, Qualls CR, Romero AA, Webb JC, Dorin MH, Padilla LA, et al. Is there a difference in survival for IA1 and IA2 adenocarcinoma of the uterine cervix? Gynecol Oncol 2002;85:229–41. [30] Webb JC, Key CR, Qualls CR, Smith HO. Population-based study of microinvasive adenocarcinoma of the uterine cervix. Obstet Gynecol 2001;97:701–6. [31] Jones WB, Mercer GO, Lewis Jr JL, Rubin SC, Hoskins WJ. Early invasive carcinoma of the cervix. Gynecol Oncol 1993;51:26–32. [32] Sachs H, Ikeda J, Brachetti AK. Microinvasive adenocarcinoma and adenocarcinoma in situ of the cervix uteri. Med Welt 1975;26:1181–3. [33] Burghardt E. Pathology of preclinical invasive carcinoma of cervix. (Microinvasive and occult invasive carcinoma). In: Fu Y, Reagan JW, Bennington JL, editors. Pathology of the Uterine Cervix, Vagina, and Vulva. Philadelphia: Saunders; 1989. p. 447–9. [34] Schumacher TN, Kantesaria DV, Serreze DV, Roopenian DC, Ploegh HL. Transporters from H-2b, H-2d, H-2s, H-2k, and H-2g7 (NOD/Lt) haplotype translocate similar sets of peptides. Proc Natl Acad Sci USA 1994;91:13004–8. [35] Krimmenau R. Adenocarcinoma in situ, beginning adenocarcinomatous invasion and microcarcinoma adenomatosum. Geburtshilfe Frauenheilkd 1966;26:1297–305. [36] Nicklin JL, Perrin LC, Crandon AJ, Ward BG. Microinvasive adenocarcinoma of the cervix. Aust N Z J Obstet Gynaecol 1999;39:411–3. [37] Werner R, Waidecker F. Adenocarcinoma in situ and microinvasive adenocarcinoma of the cervix uteri (author's transl). Österr Z Onkol 1975;2:154–7. [38] Nakajima H. Clinicopathological study on early adenocarcinoma. Nagasaki Med J 1983;58:218–33. [39] Piura B, Dgani R, Yanai-Inbar I, Cohen Y, Glezerman M. Adenocarcinoma of the uterine cervix: a study of 37 cases. J Surg Oncol 1996;61:249–55. [40] Matsukuma K, Tsukamoto N, Kaku T, Matsumura M, Toki N, Toh N, et al. Early adenocarcinoma of the uterine cervix — its histologic and immunohistologic study. Gynecol Oncol 1989;35:38–43. [41] Ceballos KM, Shaw D, Daya D. Microinvasive cervical adenocarcinoma (FIGO stage 1A tumors): results of surgical staging and outcome analysis. Am J Surg Pathol 2006;30:370–4.

142

J. Hou et al. / Gynecologic Oncology 121 (2011) 135–142

[42] Sevin BU, Lu Y, Bloch DA, Nadji M, Koechli OR, Averette HE. Surgically defined prognostic parameters in patients with early cervical carcinoma. A multivariate survival tree analysis. Cancer 1996;78:1438–46. [43] Benedet JL, Anderson GH. Stage IA carcinoma of the cervix revisited. Obstet Gynecol 1996;87:1052–9. [44] Kennedy AW, el Tabbakh GH, Biscotti CV, Wirth S. Invasive adenocarcinoma of the cervix following LLETZ (large loop excision of the transformation zone) for adenocarcinoma in situ. Gynecol Oncol 1995;58:274–7. [45] Nagarsheth NP, Maxwell GL, Bentley RC, Rodriguez G. Bilateral pelvic lymph node metastases in a case of FIGO stage IA(1) adenocarcinoma of the cervix. Gynecol Oncol 2000;77:467–70. [46] Elliott P, Coppleson M, Russell P, Liouros P, Carter J, MacLeod C, et al. Early invasive (FIGO stage IA) carcinoma of the cervix: a clinico-pathologic study of 476 cases. Int J Gynecol Cancer 2000;10:42–52. [47] Kasamatsu T, Okada S, Tsuda H, Shiromizu K, Yamada T, Tsunematsu R, et al. Early invasive adenocarcinoma of the uterine cervix: criteria for nonradical surgical treatment. Gynecol Oncol 2002;85:327–32. [48] Matthews CM, Burke TW, Tornos C, Eifel PJ, Atkinson EN, Stringer CA, et al. Stage I cervical adenocarcinoma: prognostic evaluation of surgically treated patients. Gynecol Oncol 1993;49:19–23. [49] 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. [50] Utsugi K, Shimizu Y, Akiyama F, Hasumi K. Is the invasion depth in millimeters valid to determine the prognosis of early invasive cervical adenocarcinoma? A case of recurrent FIGO stage IA1 cervical adenocarcinoma. Gynecol Oncol 2001;82: 205–7. [51] Erzen M, Mozina A, Bertole J, Syrjanen K. Factors predicting disease outcome in early stage adenocarcinoma of the uterine cervix. Eur J Obstet Gynecol Reprod Biol 2002;101:185–91. [52] Abdulhathi MB, Al-Salam S, Kassis A, Ghazal-Aswad S. Unusual presentation of cervical cancer as advanced ovarian cancer. Arch Gynecol Obstet 2007;276: 387–90. [53] Brown JV, Fu YS, Berek JS. Ovarian metastases are rare in stage I adenocarcinoma of the cervix. Obstet Gynecol 1990;76:623–6. [54] Delotte J, Ferron G, Kuei TL, Mery E, Gladieff L, Querleu D. Laparoscopic management of an isolated ovarian metastasis on a transposed ovary in a patient treated for stage IB1 adenocarcinoma of the cervix. J Minim Invasive Gynecol 2009;16:106–8. [55] Khunamornpong S, Suprasert P, Chiangmai WN, Siriaunkgul S. Metastatic tumors to the ovaries: a study of 170 cases in northern Thailand. Int J Gynecol Cancer 2006;16(Suppl 1):132–8. [56] Mann WJ, Chumas J, Amalfitano T, Westermann C, Patsner B. Ovarian metastases from stage IB adenocarcinoma of the cervix. Cancer 1987;60:1123–6. [57] Nakanishi T, Wakai K, Ishikawa H, Nawa A, Suzuki Y, Nakamura S, et al. A comparison of ovarian metastasis between squamous cell carcinoma and adenocarcinoma of the uterine cervix. Gynecol Oncol 2001;82:504–9. [58] Natsume N, Aoki Y, Kase H, Kashima K, Sugaya S, Tanaka K. Ovarian metastasis in stage IB and II cervical adenocarcinoma. Gynecol Oncol 1999;74:255–8. [59] Ronnett BM, Yemelyanova AV, Vang R, Gilks CB, Miller D, Gravitt PE, et al. Endocervical adenocarcinomas with ovarian metastases: analysis of 29 cases

[60]

[61] [62]

[63]

[64]

[65] [66] [67]

[68] [69]

[70] [71]

[72] [73]

[74]

[75]

[76]

[77]

with emphasis on minimally invasive cervical tumors and the ability of the metastases to simulate primary ovarian neoplasms. Am J Surg Pathol 2008;32: 1835–53. Sutton GP, Bundy BN, Delgado G, Sevin BU, Creasman WT, Major FJ, et al. Ovarian metastases in stage IB carcinoma of the cervix: a Gynecologic Oncology Group study. Am J Obstet Gynecol 1992;166:50–3. Yada-Hashimoto N, Yamamoto T, Kamiura S, Seino H, Ohira H, Sawai K, et al. Metastatic ovarian tumors: a review of 64 cases. Gynecol Oncol 2003;89:314–7. Young RH, Gersell DJ, Roth LM, Scully RE. Ovarian metastases from cervical carcinomas other than pure adenocarcinomas. A report of 12 cases. Cancer 1993;71:407–18. Bisseling KC, Bekkers RL, Rome RM, Quinn MA. Treatment of microinvasive adenocarcinoma of the uterine cervix: a retrospective study and review of the literature. Gynecol Oncol 2007;107:424–30. Salani R, Puri I, Bristow RE. Adenocarcinoma in situ of the uterine cervix: a metaanalysis of 1278 patients evaluating the predictive value of conization margin status. Am J Obstet Gynecol 2009;200(182):e1–5. Simon NL, Gore H, Shingleton HM, Soong SJ, Orr Jr JW, Hatch KD. Study of superficially invasive carcinoma of the cervix. Obstet Gynecol 1986;68:19–24. Andersen ES, Arffmann E. Adenocarcinoma in situ of the uterine cervix: a clinicopathologic study of 36 cases. Gynecol Oncol 1989;35:1–7. Rollason TP, Cullimore J, Bradgate MG. A suggested columnar cell morphological equivalent of squamous carcinoma in situ with early stromal invasion. Int J Gynecol Pathol 1989;8:230–6. Angel C, DuBeshter B, Lin JY. Clinical presentation and management of stage I cervical adenocarcinoma: a 25 year experience. Gynecol Oncol 1992;44:71–8. Kaspar HG, Dinh TV, Doherty MG, Hannigan EV, Kumar D. Clinical implications of tumor volume measurement in stage I adenocarcinoma of the cervix. Obstet Gynecol 1993;81:296–300. Schorge JO, Lee KR, Flynn CE, Goodman A, Sheets EE. Stage IA1 cervical adenocarcinoma: definition and treatment. Obstet Gynecol 1999;93:219–22. Schorge JO, Lee KR, Sheets EE. Prospective management of stage IA(1) cervical adenocarcinoma by conization alone to preserve fertility: a preliminary report. Gynecol Oncol 2000;78:217–20. Lee KR, Flynn CE. Early invasive adenocarcinoma of the cervix. Cancer 2000;89: 1048–55. Balega J, Michael H, Hurteau J, Moore DH, Santiesteban J, Sutton GP, et al. The risk of nodal metastasis in early adenocarcinoma of the uterine cervix. Int J Gynecol Cancer 2004;14:104–9. Hirai Y, Takeshima N, Tate S, Akiyama F, Furuta R, Hasumi K. Early invasive cervical adenocarcinoma: its potential for nodal metastasis or recurrence. BJOG 2003;110: 241–6. Poynor EA, Marshall D, Sonoda Y, Slomovitz BM, Barakat RR, Soslow RA. Clinicopathologic features of early adenocarcinoma of the cervix initially managed with cervical conization. Gynecol Oncol 2006;103:960–5. Yahata T, Numata M, Kashima K, Sekine M, Fujita K, Yamamoto T, et al. Conservative treatment of stage IA1 adenocarcinoma of the cervix during pregnancy. Gynecol Oncol 2008;109:49–52. Jones MW, Silverberg SG, Kurman RJ. Well-differentiated villoglandular adenocarcinoma of the uterine cervix: a clinicopathological study of 24 cases. Int J Gynecol Pathol 1993;12:1–7.