Grayscale ultrasound feature typing of metastatic ovarian tumors, particularly signet-ring cell carcinoma
Introduction
The ovary is a relatively frequent site of metastases. About 5–20% of ovarian masses are metastases from other malignant tumors, such as gastrointestinal tumors, breast cancer, and gynecological tumors (1-3). Primary ovarian cancer must be distinguished from metastatic ovarian tumor (MOT), because this clinical information is crucial in devising appropriate treatment strategies and establishing prognosis (4-6). Ultrasound (US) is advantageous because of its accessibility as a first-line imaging examination that is painless and relatively inexpensive compared with computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET). Few studies have specifically compared the characteristics of metastatic ovarian malignancies of different origins (7-13). Such studies have reported that metastases in the ovaries are either predominantly or completely solid, but have failed to note specific sonographic features that characterize metastatic lesions.
As observed in routine clinical examination, most cases of solid metastases in the ovary are signet-ring cell carcinoma (SRCC), a special type of mucinous carcinoma characterized by a purely solid mass or a solid mass with one to several round or oval cysts. These observations prompted us to conduct a thorough investigation of the prevalence of this feature in a series of MOTs. We present the following article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-21-1149/rc).
Methods
Patients
This was a retrospective cross-sectional single-center study. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The Independent Ethics Committee of Shanghai Cancer Center, Fudan University (Shanghai, China) approved this study, and individual consent for this retrospective analysis was waived. Clinical data and static US images of patients with MOTs, who underwent surgery from January 2010 to December 2019, were collected. Figure 1 shows the patient selection flowchart. The inclusion criteria were as follows: (I) ovarian US was performed before surgery, and (II) MOTs had been pathologically proven. The exclusion criteria were as follows: (I) primary ovarian cancer, (II) ovarian lesion without definite pathological diagnosis, and (III) MOTs without definite primary origin. Patient MOT data were collected, even for cases whose MOT lesions were not detectable by US. A total of 190 masses from 112 patients were assessed.
Data collection and image classification
The medical records of the included cases were reviewed to obtain the following information: patient age, primary origin of tumor, chronology of onset, and pathological analysis. Static US images were obtained via transabdominal or transvaginal US using a routine standardized examination technique. The frequency of the transvaginal probes varied between 5.0 and 9.0 MHz, and that of the abdominal probes between 3.5 and 5.0 MHz. Transvaginal US is advantageous when the MOTs are small or located in the lower pelvis. During transvaginal US, the transvaginal probe is placed into the patient’s vagina and pressed close to the cervix. Otherwise, transabdominal US is preferable, as the transabdominal probe can scan the whole abdomen and pelvis. The collected images were evaluated by an image interpretation committee. The committee comprised three gynecological oncology US specialists from the Shanghai Cancer Center. Two of these had 10 years of experience, and the other one had 20 years of experience. The US images of each lesion were first analyzed by at least two members of the committee. When interpretation was difficult, the images were evaluated by a third member.
The masses detected by US were classified into three subtypes (Figure 2). Type A mimicked primary epithelial ovarian tumor and consisted of multilocular solid masses with variable ratios of solid and cystic components and good US penetration. Type B comprised purely solid masses with inner echo, which could be uniform or not. Type C consisted of solid masses with round or oval cysts, which are plump, have smooth walls and good inner US penetration, and are of variable number, size, and position (Figure 3). Their shape is mostly regular, but sometimes it can be irregular or polylobate; their size can be large, and they can be adherent to peripheral tissues.
Statistical analysis
Statistical analyses were performed using SPSS version 22.0 for Windows (IBM Corp., Armonk, NY, USA). We conducted χ2 tests to analyze categorical variables. Statistical significance was set at P<0.05.
Results
Between January 2010 and December 2019, 190 MOTs in 112 women were surgically treated. Among these, 144 (75.8%) MOTs in 102 women (91.1%) were detected by US. The age of the 102 women was in the range of 26 to 78 years (mean age: 48±11.2 years). The sites of primary tumor histological diagnoses included the stomach, colon, breast, uterus, liver-pancreas-biliary (LPB) tract, appendix, lungs, and kidneys (Table 1). Except for one uterine endometrial stromal sarcoma and one uterine neuroendocrine carcinoma, the 144 masses in the US-detected group were classified as adenocarcinoma, including 73 gastric adenocarcinomas, 43 colorectal adenocarcinomas, 6 breast invasive ductal carcinomas, 1 invasive lobular carcinoma, 2 cervical adenocarcinomas, 2 uterine endometrial adenocarcinomas, 1 gallbladder adenocarcinoma, 2 cholangiocarcinomas, 3 pancreatic ductal adenocarcinomas, 6 appendicular adenocarcinomas, 1 lung adenocarcinoma, and 2 renal clear cell carcinomas.
Table 1
| Primary histopathology | Pathology detected | US detected | US undetected |
|---|---|---|---|
| Stomach | |||
| Adenocarcinoma | 86/58* | 73/50* | 13/8* |
| Colon | |||
| Adenocarcinoma | 54/6* | 43/6* | 11 |
| Breast | |||
| Invasive ductal carcinoma | 20 | 6 | 14 |
| Invasive lobular carcinoma | 3 | 1 | 2 |
| Uterus | |||
| Cervical adenocarcinoma | 2 | 2 | 0 |
| Endometrial adenocarcinoma | 2 | 2 | 0 |
| Cervical squamous carcinoma | 1 | 0 | 1 |
| Endometrial stromal sarcoma | 2 | 1 | 1 |
| Neuroendocrine carcinoma | 2 | 1 | 1 |
| L-P-B tract | |||
| Gallbladder adenocarcinoma | 2/2* | 1/1* | 1/1* |
| Cholangiocarcinoma | 2 | 2 | 0 |
| Pancreatic adenocarcinoma | 3 | 3 | 0 |
| Appendix | |||
| Adenocarcinoma | 7/3* | 6/3* | 1 |
| Lung | |||
| Adenocarcinoma | 2 | 1 | 1 |
| Kidney | |||
| Clear cell carcinoma | 2 | 2 | 0 |
| Total | 190/69* | 144/60* | 46/9* |
Marked with *: cases of SRCC. US, ultrasound; L-P-B, liver-pancreas-biliary; SRCC, signet-ring cell carcinoma.
Metastasis was identified before primary tumor diagnosis in 12 patients. Metastasis and primary tumors were simultaneously identified in 16 patients. Metastasis was identified after primary tumor diagnosis in 85 patients, and the time interval ranged from 1 month to 186 months [median: 18 months, interquartile range (IQR): 11.5 to 29 months; Table 2]. One patient had a unilateral MOT detected before a primary gastric cancer was found and then underwent gastric surgery and unilateral MOT surgery prior to the discovery of another MOT on the other side 7 months later.
Table 2
| Primary location | Metastasis first | Synchronous | Primary first [Min–Max] {Median (IQR)} |
|---|---|---|---|
| Stomach# | 8 | 7 | 35 [1–180] {16 (10.5, 23.5)} |
| Colon | 1 | 2 | 31 [4–120] {17 (12.0, 29.0)} |
| Breast | 0 | 0 | 13 [6–186] {33 (12.0, 60.0)} |
| Uterus | 1 | 3 | 1 [16] |
| LPB tract | 2 | 0 | 2 [11, 23] |
| Appendix | 0 | 4 | 0 |
| Lung | 0 | 0 | 1 [18] |
| Kidney | 0 | 0 | 2 [20, 83] |
| Total | 12 | 16 | 85 [1–186] {18 (11.5, 29.0)} |
[Min–Max]: time interval (month) between primary tumors and MOTs. {Median (IQR)}: median time interval (month) between detection of primary tumor and metastasis. Marked with #: one patient had unilateral MOT first before primary gastric cancer and then had gastric surgery and unilateral MOT surgery before MOT was found 7 months later on the other side. Min, minimum; Max, maximum; IQR, interquartile range; MOT, metastatic ovarian tumor; LPB, liver-pancreas-biliary.
The most common origin of MOTs was the stomach (45.3% and 50.7% via pathology and US, respectively). Breast origin had the highest nondetection rate (69.6%). In the nondetection group, unilateral nondetection of bilateral metastasis was found in 31 patients, unilateral nondetection of unilateral metastasis occurred in 2 patients, and bilateral nondetection of bilateral metastasis occurred in 6 patients. (Table 3). No significant difference in age was observed between the US-detected and US-undetected groups (P=0.770). The maximum tumor diameter of the US-undetected group was significantly smaller than that of the US-detected group (P<0.05, Table 4).
Table 3
| Origins | Pathological detected | US detected | US undetected | |||||
|---|---|---|---|---|---|---|---|---|
| Cases | Bilaterality | Cases | Bilaterality | Cases | Bilaterality | |||
| Stomach | 86 (45.3%) | 72§ | 73 (50.7%) | 48§ | 13 (15.1%) | 0 | ||
| Colon | 54 (28.4%) | 38§ | 43 (29.9%) | 20§ | 11 (20.4%) | 0 | ||
| Breast | 23 (12.1%) | 20 | 7 (4.9%) | 2 | 16 (69.6%) | 12 | ||
| Uterus | 9 (4.7%) | 8 | 6 (3.2%) | 4 | 3 (33.3%) | 0 | ||
| LPB tract | 7 (3.7%) | 6 | 6 (3.2%) | 4 | 1 (14.3%) | 0 | ||
| Appendix | 7 (3.7%) | 6¶ | 6 (3.2%) | 4 | 1 (14.3%) | 0 | ||
| Lung | 2 (1.1%) | 2 | 1 (0.7%) | 0 | 1 (50%) | 0 | ||
| Kidney | 2 (1.1%) | 0 | 2 (1.4%) | 0 | 0 | 0 | ||
| Total | 190 | 150 | 144 | 80 | 46 (24.2%) | 12 | ||
Marked with §: one patient had unilateral ovarian metastatic mass surgery twice within a 1-year interval. Marked with ¶: one patient had a previous unilateral oophorectomy for unknown reasons. US, ultrasound; MOTs, metastatic ovarian tumors; LPB, liver-pancreas-biliary.
Table 4
| Patients/masses | Age (years) (mean ± SD) | Maximum diameter (mm) (mean ± SD) | ||
|---|---|---|---|---|
| Left | Right | Both | ||
| Pathological detected (112/190) | 26–78 (47.4±11.0) | 6–250 (74.9±52.7) | 20–238 (86.0±49.6) | 6–250 (81.2±52.0) |
| US detected (102/144) | 26–78 (48.0±11.1) | 20–250 (89.4±52.7) | 20–238 (94.4±48.7) | 20–238 (92.0±50.5) |
| US undetected (38/46) | 32–73 (47.7±10.9) | 6–80 (33.8±16.1)* | 20–70 (37.2±13.3)* | 6–80 (33.8±15.9)* |
Marked with *: P<0.05 compared with ultrasound detected group. MOT, metastatic ovarian tumor; SD, standard deviation; US, ultrasound.
The masses that originated from the colon were mostly multilocular and solid (Type A; 28/43, 65.1%). Those that originated from the stomach (65/73 in total, 89.0%) were mostly solid and could be classified as Types B (23/73, 31.5%) and C (42/73, 57.5%). Furthermore, 60 SRCC cases were found, and their US features could be classified into Types B and C regardless of their origin (stomach, colon, gall bladder, or appendix) (Table 5). A total of 68.5% (50/73) MOTs that originated from the stomach were SRCCs (23.2% features Type B, 45.2% features Type C).
Table 5
| Subtype | Stomach | Colon | Breast | Uterus | LPB tract | Appendix | Lung | Kidney | Total |
|---|---|---|---|---|---|---|---|---|---|
| A | 8 | 28 | 2 | 3 | 3 | 2 | 0 | 0 | 46 |
| B | 23/17* | 6/2* | 2 | 3 | 1/1* | 1/1* | 1 | 2 | 39/21* |
| C | 42/33* | 9/4* | 3 | 0 | 2 | 3/2* | 0 | 0 | 59/39* |
| Total | 73/50* | 43/6* | 7 | 6 | 6/1* | 6/3* | 1 | 2 | 144/60* |
Marked with* cases of SRCC. MOTs, metastatic ovarian tumors; US, ultrasound; LPB, liver-pancreas-biliary; SRCC, signet-ring cell carcinoma.
Discussion
The histology of MOTs usually corresponds to that of the primary tumor. de Waal et al. reported that the histological type of the primary tumors of the gastrointestinal tract that had metastasized to the ovaries was most frequently adenocarcinoma (97%), and ductal invasive carcinoma was the histological type of breast cancer that gave rise to most ovarian metastases (41%) (14). Lewis et al. detailed and analyzed clinical and pathologic features of 86 cases of ovarian involvement of metastatic colorectal adenocarcinoma (15). In our series of 144 US-detected MOTs, 142 (98.6%) were adenocarcinomas, which is consistent with previous studies.
Colorectal metastases are difficult to differentiate from primary ovarian cancer via US and microscopy (16,17). We confirmed this observation in our relatively large study population, where 65.1% (28/43) of the colorectal metastases closely mimicked primary epithelial ovarian tumor morphologically (Type A). In this case, immunohistochemistry plays a major role in distinguishing primary from secondary ovarian tumors and may suggest the potential primary tumor site. The bilaterality characteristics agreed fairly well with the descriptions of MOTs in pathology textbooks. However, the detection rate of bilaterality using US was low. We speculated two possible reasons why metastatic tumors were not detected. First, the ovary was largely normal; therefore, detection via imaging was difficult. In these cases, focal metastasis was identified using histologic examination and immunohistochemistry, and this mostly occurred in breast cancer metastases. The latter observation is consistent with findings from a previous study (18), which found six cases of breast cancer-related ovariectomy. Second, the contralateral mass was too large and thus obstructed smaller masses. The maximum bilateral diameter ratio ranged from 1.3 to 14.2 (3.4±2.4).
Previous studies have classified metastatic tumors into solid, multilocular solid, or at least unilocular solid and not purely unilocular or multilocular masses based on US characteristics (17,19-22). This classification is too broad and does not provide proper schematic images for reference. A vivid schematic image can assist radiologists to identify MOTs, especially in the case of inexperienced radiologists and MOTs on first presentation. In addition to indicating the possibility of MOTs, the subtype predicts the origins of MOTs. Knowledge of the subtype of MOTs before surgery is highly likely to improve patient triage, and it also makes it possible to optimize treatment. In the present study, we classified metastatic tumors into three different subtypes (A, B, and C), which provide more vivid US images for reference. Aside from the commonly described multilocular solid (Type A) and purely solid (Type B) tumors, we described a novel sonographic feature of solid ovarian metastasis morphology, that is, Type C, which is characterized by a solid tumor with one or several round or oval cysts, that are plump and have a smooth wall and superior transparency. The cyst lumens contain a clear, mucinous, or hemorrhagic fluid. The presumed pathological reason is the presence of glands, many of which include dilated cysts, punctuate the peripheral cellular component, and are more conspicuous in the edematous central component. Guerriero et al. (23) reported a cystic component in 39% of solid metastatic ovarian cases, but they did not further explain these cases. In our study, this sonographic characteristic was readily recognizable and present in 41.7% (60/144) of the metastatic tumors. Furthermore, the metastatic SRCC in the ovary featured Type B and C characteristics regardless of their origin (stomach, colon, gall bladder, or appendix), and no metastatic SRCC featured Type A characteristics. Moreover, primary ovarian tumors with signet-ring cells are rare (16,24,25), and the prognosis is especially unfavorable if the primary histology of MOT is SRCC (26). Based on these observations, when an ovarian mass features Type B or Type C, not only should MOTs be taken into consideration but also SRCC, especially in patients with stomach carcinoma.
Although the relatively large number of cases included in our study permitted quite an accurate analysis of the different parameters of each group, the present study had some limitations. First, the sample size was relatively small, despite that data collection was conducted over 10 years. Except MOTs that originated from the stomach and colon, the single digits of MOTs that originated from the breast, uterus, LPB, appendix, lung, and kidney might be unrepresentative, as such, the results should be considered observational. Thus, more cases are needed for validation. Second, the patients enrolled in the study were diagnosed using US, and CT- or MRI-diagnosed MOTs without US diagnosis were not included; therefore, selection bias was unavoidable. Third, the collected static US images only reflect several typical sections of MOTs, which may have introduced a certain amount of subjectivity. Fourth, the static US images obtained during the past 10 years were collected from different US machines; hence, the image quality might not be consistent. Finally, no color Doppler flow imaging (CDFI) analysis was conducted because of the inconsistency of such imaging of the tumor vascularity using different US machines. Despite these factors, we took several measures to optimize data quality. (I) The cancer center through which patients were recruited has been admitting patients with all kinds of malignant tumors, and thus included as many MOTs as possible. (II) Data collection started in 2010, when high-definition US machines were available, which could gather high-definition US images. (III) An image interpretation committee was established to standardize the assessment criteria used for evaluation.
Conclusions
In summary, although US has certain nondetection rate because of the focal metastasis or high bilateral diameter ratio of some MOTs, we tested a novel US typing method, which provides more vivid images for classifying MOTs compared with existing typing methods and was found to be helpful when diagnosing MOTs.
Acknowledgments
Funding: This work was supported by the National Nature Science Foundation of China (Nos. 81901749 and 81801701) and the Shanghai Sailing Program (No. 19YF1410000).
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-21-1149/rc
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-21-1149/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The present study was approved by the Independent Ethics Committee of Shanghai Cancer Center, Fudan University (Shanghai, China), and individual consent for this retrospective analysis was waived.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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