Sonographic characteristics of squamous cell ... - Wiley Online Library

Ultrasound Obstet Gynecol 2010; 36: 512–516 Published online 3 September 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.7638

Sonographic characteristics of squamous cell cancer and adenocarcinoma of the uterine cervix ¨ ˚ ACK‡, E. EPSTEIN*, A. DI LEGGE†, A. MASB P. G. LINDQVIST§, P. KANNISTO* and A. C. TESTA† Institute of Clinical Sciences Lund, Departments of *Obstetrics and Gynecology and ‡Pathology, Lund University Hospital, Lund and §Clintec, Department of Obstetrics and Gynecology, Karolinska University Hospital, Huddinge, Stockholm, Sweden and †Gynecologic Oncology Unit, Catholic University of Sacred Heart, Rome, Italy

K E Y W O R D S: adenocarcinoma; cervical cancer; Doppler ultrasound; sonomorphology; squamous cell cancer; transvaginal sonography; transvaginal ultrasound

ABSTRACT Objective The objective of this study was to describe the sonographic characteristics of squamous cell cancer (SCC) and adenocarcinoma (AC) of the cervix using transvaginal ultrasound. Methods Women with early stage cervical cancer undergoing transvaginal ultrasound examination before surgery were prospectively included. The sonographic characteristics were assessed with regard to tumor morphology, vascularization, size, extension and location. Histological assessment of tumor subtype, size, growth pattern, extension and location was performed. Both sonographic and histological assessments were carried out according to a standardized protocol. Results Fifty-five women were recruited. Ten were excluded because no tumor was seen on ultrasound examination and five were excluded because radical surgery was aborted as a result of positive lymph nodes, detected using the sentinel node technique. Among the remaining 40 women, 20 had AC and 20 had SCC. At pathological examination, 34 women had tumors confined to the cervix, three had parametrial invasion and three had vaginal invasion. Hypoechogenicity was associated with SCC in 73% (11/15) of the women, while isoechogenicity indicated AC in 68% (13/19) of the women (P = 0.03). Mixed echogenicity (n = 4) showed a non-significant association with larger tumor volume (P = 0.23). Hyperechogenicity was found in two women, both of whom had the less malignant villoglandular AC. Color Doppler signals were found in all cases of AC and in 90% (18/20) of cases of SCC, compared with most normal cervical tissue in which virtually no detectable vascularization was found.

Conclusion We found that the sonographic appearance of SCC and AC differs. This knowledge should be useful in the clinical evaluation of cervical tumors. Copyright  2010 ISUOG. Published by John Wiley & Sons, Ltd.

INTRODUCTION Cervical cancer ranks second worldwide among female malignancies1 . The mortality of patients with cervical cancer decreased after the introduction of cervical cancer screening programs, with participating women showing a 10-fold lower risk of cervical cancer and a 20-fold lower mortality risk2 . The overall 5-year survival rate has been reported to be 73%, but the prognosis of the subgroup with locally advanced cervical cancer still remains unsatisfactory3 . Invasive cervical cancer is classified into squamous cell cancer (SCC), adenocarcinoma (AC) and other rare epithelial tumors such as adenosquamous carcinoma, small cell carcinoma and neuroendocrine carcinoma4 . The most common type of cervical cancer is SCC, previously reported to account for 85% of the cases. SCC can be categorized depending on invasiveness and grade of differentiation. The incidence of AC has shown an increase over the last three to four decades5,6 . AC is predominantly mucinous, but there are several other types (including endometrioid, serous, clear cell, villoglandular). Villoglandular AC is often well differentiated, with a limited risk of spread beyond the uterus7 . FIGO8 recommends a clinical staging system, even though the accuracy is suboptimal when compared with surgical and pathological data. Although ultrasound examination is not included in the FIGO clinical staging system, ultrasound examination is gaining interest because

Correspondence to: Dr E. Epstein, Institute of Clinical Sciences, Department of Obstetrics and Gynecology, University of Lund, Lund University Hospital, 221 85 Lund, Sweden (e-mail: [email protected]) Accepted: 3 March 2010

Copyright  2010 ISUOG. Published by John Wiley & Sons, Ltd.

ORIGINAL PAPER

Cervical cancer it has been reported to have a diagnostic accuracy similar to that of magnetic resonance imaging (MRI) on local extension of the disease9 – 13 . Ultrasound examination is less time consuming, requires no preparation of the patient, is cheaper and is more widely available than is MRI. The sonographic appearance of cervical tumors in relation to histology has not previously been described. The aim of the study was to prospectively describe the sonographic characteristics of SCC and AC of the cervix by using transvaginal ultrasound examination.

METHODS This study was a two-center collaboration between the ultrasound unit at the Department of Obstetrics and Gynecology, Lund University Hospital, Sweden and the Gynecologic Oncology Unit, Catholic University of Sacred Heart, Rome, Italy. Ethical approval was obtained from the Ethics Committees of Lund University (LU-41207) and Catholic University of Sacred Heart, Rome. Consecutive women (from January 2007 until May 2009) with early-stage cervical cancer, planned for surgery, with a tumor detectable on transvaginal ultrasound examination were included in the study. All women were examined within 1 week of surgery. Patients with early-stage tumors (IB1 and IIA with a tumor size of < 4 cm) were treated surgically (with radical hysterectomy and pelvic lymphadenectomy), as were selected patients with clearly exophytic tumors with a size of just over 4 cm. In Lund University Hospital, all procedures for treating early invasive cervical cancers involved the use of laparoscopic robotic surgery. All patients were staged according to FIGO criteria and underwent a physical examination, tumor biopsy and gynecological examination under anesthesia, and chest X-ray and abdominal-pelvic MRI. In Lund University Hospital, the sentinel node technique is routinely used to detect lymph-node metastasis peroperatively. Frozen sections are made on sentinel nodes during the operation. If positive lymph nodes are detected, pelvic lymphadenectomy is performed, but radical surgery is aborted in favor of neoadjuvant therapy. All examinations were performed by the same ultrasound examiners (E.E. in Lund University Hospital and A.C.T. in Catholic University of Sacred Heart, Rome). Both examiners had more than 10 years of experience in advanced gynecological ultrasound techniques. The transvaginal ultrasound (TVS) technique used was decided upon at a consensus reading session undertaken by the two authors performing the examinations (E.E. and A.C.T.) before starting the study. At the time of the examination the ultrasound examiners were unaware of the histotype of the tumor. Criteria for defining the extent of the neoplasm, as well as for deciding whether there was parametrial involvement, were established. Sonographic findings suggestive of parametrial invasion are extension of the cervical tumor beyond the cervical stroma with the presence of hypoechoic irregular tissue infiltrating the pericervical tissue13,14 . The women were examined


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in the lithotomy position with an empty bladder. The ultrasound equipment used in Lund University Hospital was a GE Voluson E8 Ultrasound System with an RIC5-9 transducer or a Philips IU22 Ultrasound System with a 3D9-3v transducer. The ultrasound equipment used in Catholic University of Sacred Heart, Rome was an ESAOTE Technos MPX with a 5–9 MHz transducer until January 2008 and a GE Voluson E8 Ultrasound System with an RIC5-9 transducer after January 2008. A predefined examination protocol was filled out for each patient, including information on tumor size, echogenicity, vascularization, location, extension and the presence of hematometra. Tumor size was measured in three orthogonal diameters (craniocaudal, transverse and anteroposterior). The craniocaudal extension was measured in a longitudinal projection from the outermost margin of the tumor (facing the vagina) to the highest (most cranial) extension of the tumor, and the anteroposterior extension was measured perpendicular to this measurement. The transverse extension was measured in the transverse projection from the outermost lateral aspects of the tumor. The mean tumor diameter was calculated from the formula, dmean = (d1 + d2 + d3 )/3, and the tumor volume was calculated from the formula of a sphere, Tvol = (dmean /2)3 × π × 4/3. Tumor echogenicity was classified as hypoechoic, isoechoic, hyperechoic or mixed compared with the surrounding cervical tissue. All women underwent color Doppler ultrasound examination. The vascularization was classified subjectively using a ‘color score’: absent (color score = 0), scarce (color score = 1), moderate (color score = 2) or strong (color score = 3). Tumor location was described as below the vaginal fornix, above the vaginal fornix or both. Tumor extension to the isthmus region, to the uterus or to the parametria was assessed. The presence of hematometra was also noted (yes/no). A dynamic examination technique was used, as previously described by Testa and coworkers15 to assess and determine the margins of the tumor. In both centers a dedicated pathologist, with substantial experience, assessed the pathological specimens, and provided the results on a predetermined paper-form. The variables assessed were: maximal tumor diameter, tumor extension (to the isthmus region – if growth was seen at the point of the internal cervical os, to the uterine body or to the parametria), growth pattern (endophytic or exophytic), or histological subtype (adenocarcinoma/other epithelial tumor or squamous cell cancer). The chi-square test or Fisher’s exact test were used for categorical data and the Mann–Whitney test was used in non-normally distributed data. To determine the agreement between ultrasound and histology for assessment of tumor extension, Cohen’s kappa was used. All calculations were performed using SPSS software (Statistical Package for Social Sciences (SPSS), version

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10.0.1; SPSS Inc., Chicago, IL, USA), and P < 0.05 was considered significant.

Table 2 Ultrasound characteristics of adenocarcinoma (AC) and squamous cell cancer (SCC) of the cervix

RESULTS

Characteristic

Fifty-five women selected for primary surgery were included. Ten women were excluded because no tumor was found on ultrasound examination; in all cases, histology showed either no remaining tumor or only a micro invasive tumor. In addition, five women from Lund were excluded because they did not undergo radical hysterectomy (as a result of the presence of positive lymph nodes, detected using the sentinel node technique and frozen sectioning at the beginning of surgery). Among the remaining 40 women, 20 were included from Lund University Hospital and 20 were included from Catholic University of Sacred Heart, Rome. The histological characteristics are presented in Table 1. Twenty women had AC and 20 women had SCC. In the AC group, one adenosquamous carcinoma, one clear cell tumor and two villoglandular tumors were found. According to the histological examination of the surgical specimens there was no significant difference in the size, growth pattern (endo/exophytic) or presence of isthmus or uterine invasion between the different tumor types. Parametrial invasion was found in three of the 20 (15%) women with SCC, but in none (0%) of the women with AC. Table 2 presents the sonographic characteristics of AC and SCC. There were no significant differences in tumor volume, maximal tumor diameter, anteroposterior diameter or transverse tumor diameter, or in the presence of hematometra, between SSC and AC. The

Tumor volume (mL) 7 (0.3–92) 14 (0.3–56) 0.13§ Maximal tumor diameter 28 (9–62) 34 (11–66) 0.17§ (mm) Craniocaudal tumor diameter 18 (8–62) 31 (8–66) 0.07§ (mm) Anteroposterior tumor 24 (8–48) 28 (6–40) 0.34§ diameter (mm) Transverse tumor diameter 24 (9–58) 33 (4–50) 0.48§ (mm) Location Only below fornix 7 (35) 6 (30) 0.78¶ Both below and above 11 (55) 12 (60) fornix Only above fornix 2 (10) 2 (10) Hematometra seen 2 (10) 2 (10) 1.0¶ Echogenicity* Hyperechoic 0 (0) 2 (10) 0.03¶ Isoechoic 6 (30) 13 (65) Hypoechoic 11 (55) 4 (20) Mixed 3 (15) 1 (5) Color score† 0 2 (10)‡ 0 (0) 0.89¶ 1 3 (15) 4 (20) 2 9 (45) 13 (65) 3 6 (30) 3 (15)

Table 1 Histological characteristics of adenocarcinoma (AC) and squamous cell cancer (SCC) of the cervix

Characteristic Maximal tumor diameter (mm) Tumor stage IA IB IIA IIB Growth pattern Endophytic Exophytic Missing data Involvement of internal cervical os Involvement of uterine body Lymph node metastasis* Parametrial involvement

SCC (n = 20)

AC (n = 20)

P

29 (3–70)

30 (3–80)

0.86†

1 14 2 3

0 19 1 0

11 8 1 6

11 7 2 4

0.84‡

2

3

1.00§

2 3

1 0

1.00§ 0.23‡

0.47‡

Data presented as n or median (range). *In Lund University Hospital, five women with positive sentinel nodes were excluded because they did not undergo radical hysterectomy. †Mann–Whitney test. ‡Chi-square test. §Fisher’s exact test.


SCC (n = 20)

AC (n = 20)

P

Data presented as median (range) or n (%). *Echogenicity compared with surrounding cervical tissue. †Color score is a subjective estimation of the vascularity within the tumor. The normal cervical tissue is usually very sparsely vascularized. ‡Both unvascularized tumors were hypoechoic. §Mann–Whitney test. ¶Fisher’s exact test.

median craniocaudal extension of the tumors was greater for AC (31 mm) than for SCC (18 mm) but the difference was not statistically different (P = 0.07). Isoechoic tumors were most commonly AC (68%, 13/19) whereas hypoechoic tumors were most often SCC (73%, 11/15), P = 0.03. The median volume of the tumors showing mixed echogenicity was 23 (range 1–38) mL compared with 7 (range 0.8–92) mL for isoechoic tumors and 8 (range 0.3–36) mL for hypoechoic tumors (P = 0.23). In the four women with uncommon tumors, the two exophytic villoglandular ACs were hyperechoic with strong blood flow, the adenosquamous carcinoma was hypoechoic with moderate blood flow and the clear cell tumor was hypoechoic with strong blood flow. All AC and 90% (18/20) SCC were vascularized tumors, compared with the surrounding cervical tissue which usually had very scarce vascularization. The color score was not significantly different between tumor types (P = 0.89) (Table 2), but showed a nonsignificant association with tumor volume (P = 0.09), namely the larger the tumor, the more vascularized it was. Figure 1a shows an isoechoic AC, and Figure 2a shows a hypoechoic SCC. Figures 1b and 2b show the corresponding color/power Doppler findings.


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Figure 2 Hypoechoic tumor shown on gray-scale ultrasound imaging (a) and with power Doppler (b).

Figure 1 Isoechoic tumor shown on gray-scale (a) and color Doppler (b) ultrasound imaging.

Agreement between ultrasound assessment of invasion and pathology was good (sensitivity, 90%; specificity, 87%; agreement, 88%; Cohen’s kappa, 0.70) with regard to isthmus invasion, very good (sensitivity, 80%; specificity, 100%; agreement, 98%; Cohen’s kappa, 0.88) with regard to uterine invasion, and poor (sensitivity, 66%; specificity, 86%; agreement, 85%; Cohen’s kappa, 0.33) with regard to parametrial invasion.

DISCUSSION This study showed sonomorphological differences between SCC and AC of the cervix. The finding of a hypoechoic tumor was associated with SCC in 73% of the cases, whereas isoechogenicity indicated AC in 68% of the cases. A novel and clinically important observation is the isoechogenicity of AC, which makes such tumors difficult to assess. Moreover, it is not uncommon for cervical AC to be unrecognizable at the vaginal inspection


or to be missed at cytological examination. However, all isoechoic tumors had a detectable color score, as opposed to the surrounding cervical tissue, where virtually no color was detected. We found that color Doppler is a very valuable sonographic technique in the assessment of cervical tumors, because the vast majority (95%) of such tumors are vascularized, which will make it easier to detect them and to determine their borders. Another sonographic tool that may be used to assess isoechoic cervical tumors is a dynamic examination technique, as recently reported by Testa et al.15 . In fact, by pushing the probe against the cervix the isoechoic tissue will appear as a rigid, undeformable lesion. The strengths of the study were its prospective design and the structured ultrasound assessment by experts using high-end ultrasound systems. The main weakness of the study was its small sample size. Because of a substantial morphologic overlap between AC and SCC it is too early to establish whether the morphology assessment can be used for predictive purposes. It is important to emphasize that this is a descriptive study and that future studies should be designed to assess the predictive performance and the clinical value of the morphological assessment of cervical tumors. Hyperechogenicity was only seen in two cases, both of which were villoglandular AC with exophytic growth. This is of interest because these tumors are reported to


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have an excellent prognosis7 . Based on a small sample size of 13 patients with villoglandular AC, Young and coworkers suggested that these tumors may be managed using a procedure less radical than hysterectomy, provided that the tumor is superficial, has been completely excised, does not exhibit vascular space invasion and close followup examination is possible7 . Mixed echogenicity was found in four women and seemed to be related to a larger tumor volume. When specifically looking at these cases we found inflammatory changes in all women, with the addition of necrosis in one case. We found no difference in color score between tumor types, but a non-significant association with tumor volume – the larger the tumor the more vascularized it was. It has previously been described that tumor vascularization is related to cervical tumor size, tumor stage and risk of lymph-node metastasis16,17 . Before the start of the study we hypothesized that the craniocaudal extension of AC would be greater than that of SCC (in similar FIGO staging tumors) because of a presumed predominant longitudinal growth in AC. This was, in fact, the case, as the median craniocaudal extension of AC was 13 mm larger than that of SCC. However, there were no cases of parametrial involvement in women with AC, by contrast to three cases in women with SCC, and uterine/isthmus involvement did not seem to be different between the two groups. Another interesting observation was the high incidence of AC in our study. The incidence has been reported to be around 15%. We know that the incidence of AC has been rising over the last three to four decades, perhaps because of improved ability of the screening programs to detect SCC. In Lund University Hospital and Catholic University of Sacred Heart, Rome the incidence of AC during the last 2–3 years was 29% and 24%, respectively, for all stages, and 40% and 60%, respectively, for women with early disease triaged for surgery. We found a very good (Cohen’s kappa = 0.88) or good (Cohen’s kappa = 0.70) agreement with regard to uterine and isthmus invasion, but only a poor agreement (Cohen’s kappa = 0.33) for parametrial invasion. Parametrial invasion was correctly identified by ultrasound examination in two out of three cases, but in the third case the pathology showed only microinvasion. These findings must, however, be interpreted with caution because of the very few (n = 3) women with parametrial invasion in this series. This study was not aimed or designed to evaluate tumor extension by comparing the results of ultrasound examination and histology. In a recently published study, Testa and coworkers also found a poor agreement between ultrasound examination and MRI results with regard to parametrial invasion13 . To the best of our knowledge the appearance of SCC and AC on ultrasound examination has not previously been described. Our study shows that the appearance of AC and SCC might be different when examined using ultrasound. Cervical tumors are quite often difficult to detect using grayscale ultrasound. We suggest that color


Doppler should routinely be used in the assessment of cervical tumors. We believe that it is important to understand the sonographic features of different types of cervical tumors. This knowledge can help in the detection and assessment of tumors, in particular, of isoechoic AC and small-size tumors.

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