ARFI ĐO ĐỘ CỨNG GAN và LÁCH Ở BỆNH NHÂN VIÊM GAN B MẠN

Abstract

Objectives—To evaluate the performance of liver and spleen stiffness measured by acoustic radiation force impulse (ARFI) elastography for noninvasive assessment of liver fibrosis and esophageal varices in patients with chronic hepatitis B virus.

Methods—Two hundred sixty-four participants, of whom 60 were healthy volunteers (classified as stage 0), 66 were patients with chronic hepatitis B who had undergone liver biopsy, and 138 were patients with hepatitis B-related cirrhosis, were enrolled in this study. Median liver and spleen stiffness values (meters per second) from 10 successful measurements per participant were obtained. Patients with cirrhosis were examined by upper endoscopy.

Results—Significant linear correlations were found between liver (Spearman ρ= 0.87; P < .001) and spleen (Spearman ρ = 0.76; P < .001) stiffness and the fibrosis stage. Liver and spleen stiffness values increased as fibrosis progressed; however, overlaps in liver stiffness were detected in stages 0 and 1 and 1 and 2, and overlaps in spleen stiffness were observed in stages 0 and 1, 1 and 2, and 2 and 3. Liver stiffness cutoff values were 1.69 m/s for predicting stage 3 or greater (area under the receiver operating characteristic curve [AUROC] = 0.99) and 1.88 m/s for stage 4 (AUROC = 0.97). The spleen stiffness cutoff value was 2.72 m/s for stage 4 (AUROC = 0.96). Liver stiffness was not correlated with the varix grade, whereas a significant linear correlation (Spearman ρ = 0.65; P < .001) between spleen stiffness and the varix grade was found. The optimal spleen stiffness cutoff value for predicting varices was 3.16 m/s (AUROC = 0.83).

Conclusions—Liver and spleen stiffness values measured by ARFI elastography are reliable predictors of liver fibrosis. Spleen stiffness measured by ARFI can be used as a non-invasive method for determining the presence and severity of esophageal varices; however, evidence to support a similar role for liver stiffness is lacking.

Hepatitis B, which is caused by the hepatitis B virus (HBV), is a potential life-threatening liver infection and the most serious type of viral hepatitis. As the World Health Organization reported,1 approximately 2 billion people have been infected with HBV worldwide, and more than 350 million people have chronic hepatitis B. In China, the most common viral hepatitis is type B. The final evolutionary stage of chronic hepatitis B is liver cirrhosis. Portal hypertension is a major cause of esophageal varices, which have been reported to occur in up to 90% of patients with cirrhosis.2 The annual incidence of variceal bleeding is almost 5% to 15%, and the mortality rate may reach up to 20% in 6 weeks.3

The management and prognosis of chronic hepatitis B depend on the fibrosis stage. To date, liver biopsy, an invasive technique, is still considered the reference standard. However, its clinical application is limited because of its invasive nature, potential severe complications, sampling errors, and interobserver and intraobserver diagnostic discrepancies.4–6

In cirrhotic patients, screening for esophageal varices is highly recommended and extremely important because it is closely linked to the scheme of nonselective beta-blocker therapy or endoscopic prophylaxis to prevent variceal bleeding.7 The present screening method is endoscopy, which is performed every 2 to 3 years in patients without esophageal varices, every 1 to 2 years in those with mild varices, and annually in those with decompensated cirrhosis. However, this method is invasive, expensive, and not easily accepted by patients.

For the above-mentioned reasons, some noninvasive methods have been proposed to serve as markers for evaluating of the degree of liver fibrosis and that of esophageal varices, including serum markers,8–10 transient elastography,9–12 magnetic resonance elastography,13–15 and acoustic radiation force impulse (ARFI) elastography.10,16,17

Acoustic radiation force impulse imaging10,16,18 is a novel technology based on conventional B-mode sonography. An acoustic push pulse excites the tissue and produces shear waves that spread away from the tissue. The propagation of the shear waves can be measured, and their speed depends on the elasticity of the tissue. Therefore, ARFI provides numeric measurements of tissue stiffness as the shear wave velocity, expressed as meters per second. Publications have shown that liver stiffness values correlated well with liver fibrosis staging determined by liver biopsy.18,19 Spleen stiffness measured by ARFI elastography in patients with chronic liver disease has also been previously reported.16,17 However, those studies focused mostly on patients infected with the hepatitis C virus (HCV).

The aims of this study were to evaluate the accuracy of liver and spleen stiffness measured by ARFI elastography for noninvasive assessment of liver fibrosis in patients with chronic hepatitis B and to investigate whether liver and spleen stiffness values are suitable predictors of the presence and severity of esophageal varices.

Liver and Spleen Stiffness Measurements

Liver and spleen stiffness measurements were performed with an Acuson S2000 ultrasound system equipped with virtual touch tissue quantification software (Siemens Medical Solutions, Mountain View, CA). A 4C-1 curved linear array transducer was also used. Liver stiffness was measured while the patients were lying in the left lateral decubitus position and with their right arm in maximum abduction, whereas spleen stiffness was measured while the patients were lying in the right lateral decubitus position and with their left arm in maximum abduction. The size of the region of interest was fixed at 10 × 5 mm. The region of interest was at the parenchyma of the liver and spleen and free of “visible” vessels. Specifically, the location of the region of interest in the liver was the right lobe between the seventh and ninth intercostal spaces, between the midclavian and midaxillary lines, 2 to 3 cm below the liver capsule; that in the spleen was in the middle portion, 1 to 2 cm below the splenic capsule. These measurements were made through an intercostal space. During the procedure, the patients were asked to stop breathing for a moment at the end of expiration. Two or 3 measurements were made during each breath-holding period, and 4, 5, or more periods were needed to measure in one area. All of the measurements were performed by one experienced sonologist (Figures 1 and 2).

The interval between these measurements and the liver biopsy that 66 of the participants underwent ranged from 1 to 3 days (mean, 2.00 ± 0.84 days). Acoustic radiation force impulse imaging was not immediately performed after biopsy because the patients would not have been able to tolerate the pain caused by the biopsy and scanning immediately after the procedure and because they needed to rest in the dorsal decubitus position with a monitor for the first 6 hours.

The right lobe was chosen because ARFI measurements of the right lobe are reportedly potentially superior to those of the left lobe for diagnosis of liver fibrosis.20 A point 2 to 3 cm under the liver capsule was chosen because a study of 3 points under the liver capsule (0–1, 1–2, and 2–3 cm) found that the most reliable liver elasticity values are obtained when ARFI measurements are made 2 to 3 cm under the liver capsule.19

Discussion

The stage of liver fibrosis can be quantified by ARFI elastography. Recent studies have reported that measurement of liver stiffness using ARFI elastography is a novel, accurate, and reliable noninvasive method for assessment of liver fibrosis in patients with chronic liver disease.21,22 As liver fibrosis progresses, hemodynamic and pathologic changes can be found in the spleen, especially in late stages of fibrosis. One study23 found that the size of the spleen increased as liver fibrosis progressed and was more apparent in late stages. The density of the spleen changes in patients with an enlarged spleen because of tissue hyperplasia, fibrosis, and portal and splenic congestion.12 Such changes in the spleen are mechanical properties that can be quantified by ARFI elastography. Therefore, we tried to show that liver and spleen stiffness values are useful predictors for evaluation of liver fibrosis in chronic liver disease and to evaluate their performance in predicting the presence of esophageal varices in cirrhotic patients. Moreover, to our knowledge, a study assessing liver fibrosis and esophageal varices specifically in HBV-infected patients has not been reported previously.

Our data clearly showed that liver stiffness correlated well with fibrosis. The stiffness increased with the fibrosis stage. However, overlaps were detected between stages 0 and 1 and stages 1 and 2. Similarly, a study of 112 patients with chronic hepatitis C found overlaps between the consecutive stages F1 and F2 and stages F2 and F3 (METAVIR scores).18 Another study of 103 patients with chronic hepatitis of different etiologies observed overlaps between stages F0 and F1 and stages F3 and F4 (METAVIR scores).24 These findings suggest that overlaps between consecutive stages occur regardless of etiology. For the healthy volunteers (stage 0), the mean liver stiffness value in our study was 1.13 ± 0.12 m/s which is comparable to those published so far: 1.13 ± 0.23 m/s in healthy volunteers and 1.16 ± 0.17 m/s in stage F0 patients (METAVIR score)10 and 1.15 ± 0.21 m/s in another group of healthy volunteers.25 For cirrhotic patients, the mean liver stiffness value was 2.50 ± 0.50 m/s, comparable to 2.38 ± 0.74 m/s in 81 patients with HCV or HBV infection10 and 2.552 ± 0.7782 m/s in patients with HCV infection.18

We discovered high predictive values of liver stiffness for stage 3 or greater and stage 4, which were similar to the findings in a study of patients with chronic hepatitis C18 and another study of patients with different etiologies.21 The cutoff value for stage 3 or greater was 1.69 m/s, which was the same as the value in a study by Toshima et al22 including 79 patients with different etiologies and similar to the value in a study by Lupsor et al18 including 112 patients with chronic hepatitis C (1.61 m/s). The cutoff value for stage 4 was 1.88 m/s, which was slightly higher than the value in the study by Toshima et al22 (1.79 m/s) and lower than the value in the study by Lupsor et al18 (2.0 m/s).

This study compared the mean spleen stiffness values measured by ARFI elastography among fibrosis stages 0 to 4. There was a correlation between spleen stiffness and fibrosis (Spearman ρ = 0.76; P < .001). The spleen stiffness values for stages 0 to 3 did not statistically differ, whereas stage 4 had a significantly higher mean value than any other stage. In our study, the mean spleen stiffness value in the healthy volunteers (stage 0) was 2.17 ± 0.24 m/s, which was slightly higher than the previously reported value of 2.04 ± 0.28 m/s in 15 healthy volunteers17 and lower than the previously reported value of 2.44 m/s in 35 healthy volunteers.26 The mean spleen stiffness value in cirrhotic patients (stage 4) was 3.24 ± 0.44 m/s, which was slightly higher than the value of 3.10 ± 0.55 m/s in a study by Bota et al.17

To date, only 2 reports have analyzed spleen stiffness for predicting cirrhosis. One17 showed a cutoff value of 2.55 m/s for predicting cirrhosis with a good AUROC (0.91), and another16 showed a cutoff value of 2.73 m/s (AUROC = 0.82). Our results showed a high predictive value for the presence of cirrhosis (AUROC = 0.96), with the cutoff (2.72 m/s) being higher than that in the first study and similar to that in the second.

In this study, a combined analysis of liver and spleen stiffness measured by ARFI for predicting the presence of cirrhosis revealed that the sensitivity and specificity were higher when one of the methods in the combined analysis yielded positive results than when only one method was used, and the specificity was significantly elevated when both methods yielded positive results.

In cirrhotic patients, a severe consequence is portal hypertension, which is a contributing factor to the formation of esophageal varices and a direct cause of variceal hemorrhage. Publications have reported that liver stiffness measured using 1-dimensional transient elastography (Fibroscan) showed a statistically significant association with the hepatic venous pressure gradient.27–29 Some studies found that liver stiffness measured by 1-dimensional transient elastography was correlated with the esophageal varix grade,30 whereas others showed that liver stiffness correlated with the presence of varices but showed a weak correlation with the varix size31 or none at all.27 Acoustic radiation force impulse elastography is a 2-dimensional elastographic technique. To our knowledge, there have been no reports about the correlation between liver stiffness measured by ARFI and the hepatic venous pressure gradient or between liver stiffness measured by AFRI and the presence of esophageal varices. Only 1 study17 reported a correlation between spleen stiffness measured by ARFI and esophageal varices, in which the authors observed no significant differences in the mean spleen stiffness values between patients with and without varices of between those with different varix grades.

Our data on this issue were confusing. We found a correlation between spleen stiffness and the varix stage, and there was a significant difference between patients with and without varices. We determined a cutoff value of 3.16 m/s for predicting the presence of varices (AUROC = 0.83). We also found a significant difference between grades 2 and 3, but unfortunately, we were not able to distinguish the mean spleen stiffness values between grades 1 and 2. These results may be explained by 3 possible reasons. First, endoscopy was not performed by the same physicians, and the assessment of the varix grade was subjective. Second, not all patients consented to undergo endoscopy and ARFI elastography on the same day; the interval between spleen stiffness measurements and endoscopy ranged from 0 to 30 days, whereas the longest interval in the report by Bota et al17 reached up to 6 months. Third, the distribution of patients according to varix grades was unequal.

Our article clearly suggests that there was no correlation between liver stiffness measured by ARFI and the esophageal varix grade, and no significant difference was found among the varix grades. The different results between liver and spleen stiffness for assessment of varices may be explained by 2 possible reasons. First, we discovered that the cirrhotic patients with elevated ALT and AST levels had higher liver stiffness values than those with normal ALT and AST levels, whereas the difference was not significant for the spleen stiffness values between the patients with normal ALT and AST levels and those with elevated ALT and AST levels. Some publications have reported a correlation between liver stiffness values measured by ARFI and necroinflammation.18,21,32 These reports indicate that elevated ALT and AST levels may affect liver but not spleen stiffness values, which may be the major factor accounting for the above-mentioned findings. Second, the unequal distribution of patients according to varix grades may have led to different numbers in each subgroup.

In conclusion, liver and spleen stiffness values measured by ARFI elastography are reliable predictors of liver fibrosis, especially for patients who are at high risk or not willing to undergo liver biopsy. Spleen stiffness can be used as a noninvasive means for predicting the presence and grade of esophageal varices and can also be valuable for patients who refuse to undergo endoscopy. Moreover, further studies on liver and spleen stiffness for evaluating liver fibrosis and esophageal varices in a larger population have been planned.
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BÀN LUẬN

ARFI elastography có thể định lượng được các giai đoạn của xơ hoá gan. Các nghiên cứu gần đây đã thông báo rằng đo độ cứng gan bằng ARFI elastography là một phương pháp mới không xâm lấn, chính xác và đáng tin cậy của xơ hoá gan ở những bệnh nhân gan mạn tính. Khi xơ hoá gan tiến triển, thay đổi huyết động học và bệnh lý có thể  thấy được ở lách, đặc biệt là trong giai đoạn cuối của xơ hoá. Một nghiên cứu cho thấy kích thước của lách tăng khi xơ hoá gan tiến triển và rõ hơn trong giai đoạn cuối. Mật độ của thay đổi lách ở những bệnh nhân lách to vì tăng sản mô, xơ hóa, và sung huyết lách và tĩnh mạch cửa. Những thay đổi lách như vậy là những đặc tính cơ học định lượng được bởi ARFI elastography. Vì vậy, chúng tôi đã cố gắng chứng tỏ các giá trị độ cứng gan và lách là các yếu tố tiên đoán hữu ích cho việc đánh giá xơ hóa gan trong bệnh gan mạn tính và đánh giá hiệu suất của chúng trong tiên đoán của dãn tĩnh mạch thực quản ở bệnh nhân chai gan. Hơn nữa, theo chúng tôi được biết, nghiên cứu đánh giá xơ hoá gan và dãn tĩnh mạch thực quản đặc biệt ở bệnh nhân nhiễm HBV chưa từng được báo cáo.

Dữ liệu của chúng tôi rõ ràng cho thấy độ cứng gan tương quan với xơ hóa. Độ cứng tăng lên theo giai đoạn xơ hóa. Tuy nhiên, có chồng lấp giữa giai đoạn 0 và 1 và giai đoạn 1 và 2. Tương tự như vậy, một nghiên cứu ở 112 bệnh nhân viêm gan C được tìm thấy có trùng lặp giữa các giai đoạn liên tiếp F1 và F2 và giai đoạn F2 và F3 (tính điểm METAVIR). Một nghiên cứu khác của 103 bệnh nhân viêm gan mạn với nguyên nhân khác nhau có chồng lấp giữa giai đoạn F0 và F1 và giai đoạn F3 và F4 (tính điểm METAVIR).  Những phát hiện này gợi ý có xảy ra chồng chéo giữa các giai đoạn liên tiếp bất kể do nguyên nhân nào. Đối với các tình nguyện viên khỏe mạnh (giai đoạn 0), giá trị độ cứng gan trung bình trong nghiên cứu của chúng tôi là 1,13 ± 0,12 m/s so sánh với những công bố cho đến nay:1,13 ± 0,23 m/s ở người tình nguyện khỏe mạnh và 1,16 ± 0,17 m/s ở bệnh nhân giai đoạn F0 (tính điểm METAVIR) và 1,15 ± 0,21 m/s trong một nhóm khỏe mạnh tình nguyện. Đối với bệnh nhân chai gan, giá trị trung bình độ cứng gan là 2,50 ± 0,50 m/s, tương đương với 2,38 ± 0,74 m/s ở 81 bệnh nhân nhiễm HCV hoặc HBV và 2,552 ± 0,7782 m/s ở những bệnh nhân nhiễm HCV.

Chúng tôi phát hiện ra giá trị tiên đoán cao của độ cứng của gan ở giai đoạn 3 hoặc cao hơn và giai đoạn 4, tương tự như phát hiện trong một nghiên cứu khác ở bệnh nhân viêm gan C mạn, và một nghiên cứu khác nữa của bệnh nhân có các nguyên nhân khác. Giá trị cutoff cho giai đoạn 3 hoặc cao hơn là 1,69 m/s, tương tự như giá trị của Toshima và cs với 79 bệnh nhân với các nguyên nhân khác nhau và tương tự như giá trị của Lupsor và cs gồm 112 bệnh nhân viêm gan C (1,61 m/s ). Giá trị cutoff cho giai đoạn 4 là 1,88 m/s, cao hơn một ít so với nghiên cứu của Toshima và cs (1,79 m/s) và thấp hơn trong nghiên cứu của Lupsor và cs (2,0 m/s).

Nghiên cứu này nhằm so sánh các giá trị độ cứng lách trung bình đo bằng ARFI elastography giữa các giai đoạn xơ hóa 0-4. Có tương quan giữa độ cứng lách và xơ hóa (Spearman ρ = 0,76; P <.001). Giá trị độ cứng lách cho các giai đoạn 0-3 không có khác biệt thống kê, trong khi giai đoạn 4 có giá trị trung bình cao hơn có ý nghĩa hơn bất kỳ giai đoạn nào khác. Trong nghiên cứu của chúng tôi, giá trị độ cứng lách trung bình của các tình nguyện viên khỏe mạnh (giai đoạn 0) là 2,17 ± 0,24 m/s, đó là hơi cao hơn giá trị báo cáo trước đây của 15 người tình nguyện khỏe mạnh là 2,04 ± 0,28 m/s và thấp hơn so với giá trị của 35 người tình nguyện khỏe mạnh là 2,44 m/s đã báo cáo trước đó. Giá trị độ cứng lách trung bình ở bệnh nhân chai gan (giai đoạn 4) là 3,24 ± 0,44 m/s, cao hơn so với giá trị 3,10 ± 0,55 m/s trong một nghiên cứu Bota và cs.

Cho đến nay, chỉ có 2 báo cáo đã phân tích độ cứng lách để tiên đoán xơ gan. Một nghiên cứu cho giá trị cutoff là  2,55 m/s để dự đoán xơ gan với một AUROC tốt (0,91), và bài khác cho giá trị cutoff là 2,73 m/s (AUROC = 0,82). Kết quả của chúng tôi cho giá trị tiên đoán cao cho sự hiện diện của chai gan (AUROC = 0,96), với cutoff (2,72 m/s) cao hơn nghiên cứu đầu tiên và tương tự như lần thứ hai.

Trong nghiên cứu này, một phân tích kết hợp của độ cứng gan và lách đo bằng ARFI để tiên đoán chai gan cho thấy rằng độ nhạy và độ đặc hiệu cao hơn khi phương pháp phân tích kết hợp mang lại kết quả dương tính hơn là chỉ có một phương pháp được sử dụng, và độ đặc hiệu tăng đáng kể khi cả hai phương pháp mang lại kết quả dương tính.

Ở bệnh nhân chai gan, hậu quả nghiêm trọng là cao áp tĩnh mạch cửa, là một yếu tố góp phần vào sự hình thành dãn tĩnh mạch thực quản và là nguyên nhân trực tiếp gây xuất huyết dãn tĩnh mạch thực quản. Y văn cho thấy đo độ cứng gan bằng cách sử dụng 1-D elastography thoáng qua (FibroScan) có kết hợp có ý nghĩa thống kê với gradient áp lực tĩnh mạch gan [hepatic venous pressure gradient]. Một số nghiên cứu thấy rằng độ cứng gan đo bằng FibroScan có tương quan với giai đoạn dãn tĩnh mạch thực quản, trong khi những khảo sát khác cho thấy độ cứng gan liên quan với có dãn tĩnh mạch thực quản, nhưng có tương quan yếu với kích thước dãn tĩnh mạch hoặc không có tương quan nào hết. Đo đàn hồi ARFI là kỹ thuật đo đàn hồi 2 chiều. Theo chúng tôi biết, chưa có báo cáo về tương quan giữa độ cứng gan đo bởi ARFI và gradient áp lực tĩnh mạch gan hoặc giữa độ cứng gan đo bằng AFRI với hiện diện của dãn tĩnh mạch thực quản. Chỉ có 1 báo cáo về tương quan giữa độ cứng lách đo bằng ARFI và dãn tĩnh mạch thực quản, trong đó các tác giả quan sát thấy không có sự khác biệt đáng kể trong giá trị độ cứng lách trung bình giữa các bệnh nhân có và không có dãn tĩnh mạch và giữa những người có giai đoạn dãn tĩnh mạch thực quản khác nhau.

Dữ liệu của chúng tôi về vấn đề này là khó hiểu. Chúng tôi thấy có tương quan giữa độ cứng lách và giai đoạn dãn tĩnh mạch thực quản, và có khác biệt có ý nghĩa giữa bệnh nhân có và không có dãn tĩnh mạch. Chúng tôi xác định một giá trị cutoff là 3,16 m/s để dự đoán sự hiện diện của dãn tĩnh mạch (AUROC = 0,83). Chúng tôi cũng tìm thấy có khác biệt đáng kể giữa giai đoạn 2 và 3, nhưng thật không may, không thể phân biệt các giá trị độ cứng lách trung bình giữa giai đoạn 1 và 2. Những kết quả này có thể được giải thích bởi 3 khả năng. Một, nội soi không được thực hiện bởi các bác sĩ, và việc đánh giá giai đoạn dãn tĩnh mạch thực quản là chủ quan. Thứ hai, không phải tất cả các bệnh nhân đồng ý được nội soi và ARFI elastography trong cùng một ngày, khoảng thời gian giữa đo độ cứng lách và nội soi khoảng 0-30 ngày, trong khi khoảng thời gian dài nhất trong báo cáo của Bota và cs là 6 tháng. Thứ ba, phân bố của bệnh nhân theo giai đoạn dãn tĩnh mạch thực quản không đồng đều.

Bài báo này của chúng tôi, cho thấy rõ không có mối tương quan giữa độ cứng gan đo bằng ARFI với giai đoạn dãn tĩnh mạch thực quản, và không có khác biệt có ý nghĩa giữa các giai đoạn dãn tĩnh mạch thực quản. Các kết quả khác nhau giữa độ cứng gan và lách trong đánh giá dãn tĩnh mạch thực quản có thể được giải thích bằng 2 khả năng. Một, chúng tôi phát hiện ra rằng các bệnh nhân chai gan với mức ALT và AST cao có giá trị độ cứng gan cao hơn những người có mức ALT và AST bình thường, trong khi khác biệt giá trị độ cứng lách không có ý nghĩa giữa các bệnh nhân có mức độ ALT và AST bình thường và những bệnh nhân có ALT và AST cao. Một số báo cáo cho thấy có tương quan giữa giá trị độ cứng gan ARFI và viêm hoại tử [necroinflammation]. Các báo cáo này chỉ ra rằng mức ALT và AST cao có thể ảnh hưởng đến gan, nhưng không ảnh hưởng đến giá trị độ cứng lách, có thể là nhân tố chính cho phát hiện đề cập ở trên. Thứ hai, phân bố các bệnh nhân không đồng đều theo giai đoạn dãn tĩnh mạch thực quản có thể dẫn đến khác biệt về số lương trong mỗi phụ nhóm.

Để kết luận, giá trị độ cứng gan và lách đo bằng ARFI elastography là yếu tố tiên đoán đáng tin cậy của xơ hoá gan, đặc biệt là đối với những bệnh nhân có nguy cơ cao hoặc không sẵn sàng để sinh thiết gan. Độ cứng lách có thể được dùng như một phương tiện không xâm lấn để tiên đoán có và giai đoạn của dãn tĩnh mạch thực quản và cũng có thể có giá trị cho các bệnh nhân từ chối làm nội soi. Hơn nữa, các nghiên cứu sâu hơn về độ cứng gan và lách nhằm đánh giá xơ hoá gan và dãn tĩnh mạch thực quản trong một dân số lớn hơn đã được lên kế hoạch.

OCCULT CANCER of BREAST POST LUMPECTOMY

Abstract

Objective. The purpose of this study was to investigate the efficacy of ultrasonography in detecting an occult malignancy after surgery for breast cancer and to assess the imaging and clinical findings associated with a recurrence. Methods. During a 4-year period, 3329 bilateral whole-breast ultrasonographic examinations were performed to detect occult malignancies clinically and mammographically in 1968 asymptomatic patients after breast cancer surgery. All questionable lesions were confirmed with ultrasonographically guided intervention. This study reviewed ultrasonographic findings and pathologic results of the questionable lesions along with the clinical parameters of the patients. We searched for false-negative cases from the hospital database. Results. Among the 1968 patients, ultrasonography revealed questionable lesions in 57 (2.9%). The questionable lesions were lymph nodes in 42 and masses in 15; of these lesions, 24 were malignant (true-positive) and 33 were benign (false-positive). Ten false-negative cases were identified. The sensitivity and specificity were 70.6% and 98.3%, respectively. The locations of the recurrent lesions were the regional lymph nodes in 14 cases (4, axillary fossa; 4, interpectoral; 4, internal mammary; and 2, supraclavicular lymph nodes) and the breast and mastectomy bed in 7 cases. The mean size of the malignant lymph nodes was larger than that of the benign lymph nodes. Among those with positive examination results, the clinical parameters in the recurrent and nonrecurrent groups were similar. Conclusions. Postoperative follow-up ultrasonography showed occult malignancies clinically and mammographically in 1.2% of the patients who had been treated for breast cancer. Familiarity with the common location of a tumor recurrence is essential for making an accurate ultrasonographic evaluation in these patients.

Most clinicians use mammography to screen women who have been treated previously for breast cancer. Although it has been reported that breast ultrasonography is the best imaging method for evaluating the chest wall and the axilla, which cannot be visualized on mammograms,¹ the routine use of ultrasonography is usually limited, with the exception of characterizing palpable lesions or mammographic abnormalities in treated breasts. Several reports have shown that ultrasonography can contribute to the detection of occult malignancies clinically and mammographically in asymptomatic women with dense breast tissue.^2,3

Considering that a history of breast cancer is one of the major risk factors for recurrence, it is believed that breast ultrasonography is more valuable for the early detection of an occult new primary malignancy and for identifying a recurrence in asymptomatic patients who had surgery for breast cancer than it is in those who have not had breast cancer. Previous reports have also suggested that early detection of a recurrence is better for the treatment of the patient, although no data have shown an improvement in overall survival rates.^1,4 The aim of this study was to investigate the efficacy of breast ultrasonography for the detection of occult malignancies clinically and mammographically during the postoperative follow-up of breast cancer and to assess the ultrasonographic and clinical findings associated with a recurrence.

Discussion

A follow-up of patients with breast cancer is an integral part of the treatment in most breast oncology centers, but there have been no standardized programs until recently. Although even a close follow-up with intensive investigations has not led to improved postoperative survival, there is a prevailing belief among both patients and clinicians that if a recurrence is detected early, when tumor burden is low, there is a greater likelihood of controlling the disease and improving the quality of life and, possibly, overall survival. There are definite disadvantages, however, of a close follow-up, including increased patient anxiety, excessive cost and physician time, and false-positive and -negative results. Indeed, only 14% of all recurrences have been reported to be asymptomatic.⁶

To date, surveillance mammograms are routinely included in various follow-up programs for breast cancer, but investigations into the effect of other imaging modalities have not been performed widely. Balu-Maestro et al⁷ reported that tumor recurrences were identified in 95.5% of cases by mammography, 90.9% by ultrasonography, and 45.5% by a physical examination. Mammography in a treated breast is less sensitive than in an untreated breast because of poor visibility of the lesions situated deep in the muscle layer, some distance from the scar, or in the axilla,¹ and the mammographic examination itself is more uncomfortable. In our experience, ultrasonography is a useful surveillance method that can overcome the limitations and discomfort associated with a mammogram in those patients treated for breast cancer. Magnetic resonance imaging is known to be a highly sensitive modality for the recurrence of breast cancer⁸; however, ultrasonography is more beneficial because of its high specificity, widespread availability, easily accessible biopsy procedures, comfort, and lower cost. In our community, it costs approximately $120 for bilateral breast ultrasonography and $160 for an ultrasonographically guided breast biopsy, whereas it costs $580 for contrast-enhanced breast magnetic resonance imaging.

In this study, it was shown that ultrasonography was effective clinically and mammographically for the detection of an occult malignancy in the asymptomatic patients after breast cancer surgery. These malignancies were observed more frequently as lymphadenopathy. We do not believe that these results are representative of all postoperative recurrences. This study was designed to be focused on nonpalpable recurrences. It is important to know which area to carefully evaluate during postoperative breast ultrasonography in patients and which findings are more likely to be verified as a recurrence. Although the overall survival rate after the detection of a local recurrence is poor (21% to 36% at 5 years) and the prevalence of a distant metastasis is high (45% to 90%), a recurrence is not necessarily a sign of a systemic metastasis and a poor prognosis.⁹ Of the 21 recurrent patients, 7 (33%) showed other organ metastases, but all of them were still alive.

There were 10 cases with false-negative ultrasonographic findings. In 5 (50%), the internal mammary and supraclavicular lymph nodes were overlooked, and in 4, local recurrences, which were revealed to be isolated microcalcifications on mammography and were pathologically diagnosed as DCIS, could not be identified. Ultrasonography does not show microcalcifications well. Of the occult malignancies shown by ultrasonography in this study, there was no case with microcalcifications on mammography. Although several limitations with ultrasonography have been reported in a conservatively treated breast, such as parenchymal scarring mimicking or concealing a carcinoma,¹⁰ upgraded ultrasonographic scanners can depict the ultrasonographically questionable lesions. The smallest one detected was 0.5 cm, and no cases with false-negative results, which were locally recurrent near the conserving surgery scar, were found except for a skin lesion.

The resulting 1.2% cancer detection rate in this study is slightly higher than that reported for screening mammography,^11–,¹³ as well as that for screening ultrasonography in previous studies in a healthy population.^2,3 These malignancies may have gone undetected until the patients’ follow-up visit, unless they appeared palpable in the interval between the follow-up examinations.

Recht et al¹⁴ studied the time course of treatment failure after breast-conserving surgery and irradiation and showed that the risk of ipsilateral breast recurrences peaks at a rate of 2.5% per year between 2 and 6 years after treatment, and then the risk of recurrent breast cancer decreases; however, patients remain at risk even 10 years after therapy.^14–,¹⁶ In this study, the longest postoperative duration was 9 years, the shortest duration of the recurrence after surgery was 8 months, and the mean postoperative duration was 36 months; therefore, a periodic ultrasonographic evaluation, starting from the sixth postoperative month to up to at least 3 years is believed to be necessary.

Concerning the questionable lesion on ultrasonography, although this study investigated whether the clinical parameters related to a recurrence were present to lower the rate of unnecessary ultrasonographically guided interventions, no statistically significant difference was found in the current group except for the larger size of the lymph node in the recurrent group. Although there is some concern about the small increase in the local recurrence rate after breast-conserving surgery or the sentinel node biopsy technique,^17,18 no cases of recurrence had a sentinel node biopsy in our series.

This study had several limitations. The positive biopsy rate of the ultrasonographically guided intervention was somewhat low (42.1%). It is possible that such an intensive investigation may lead to unnecessary invasive procedures resulting in increased medical cost and patient anxiety, but the immediate verification can prevent undertreatment in a high-risk group. Furthermore, the imaging findings had overlapping features. A recurrent case showed a 0.5-cm, round, cystlike, hypoechoic mass at the mastectomy bed on ultrasonography (Figure 2⇑). In general, even if the lesion appears benign, if it is new in the postoperative patient, efforts must be made to obtain a histologic diagnosis. Second, this long-term follow-up was not linked with other institutions or direct calls to the patients to detect curable local recurrences. A matter of concern is the successive increase in postoperative breast ultrasonographic examinations.

In conclusion, postoperative follow-up breast ultrasonography showed occult malignancies clinically and mammographically in 1.2% of patients who had been treated previously for breast cancer. Surveillance ultrasonography, as an adjuvant to mammography, is helpful for the detection of an occult malignancy, clinically and mammographically, during the postoperative follow-up. Familiarity with the common location of the tumor recurrence is a prerequisite to an accurate ultrasonographic evaluation of these patients.

          © 2005 by the American Institute of Ultrasound in Medicine

_________________________

Breast MRI is usually utilized to inspect a lumpectomy site, Copyright Steven B. Halls, MD Last edited 28-November-2010

Following a lumpectomy, MRI has proven to be very helpful in assessing possible residual breast cancer in patients who have had a breast lump removed. With MRI, it is a little bit easier to determine whether the margins are negative or positive for breast very small amounts of breast carcinoma.

The mammogram image below, taken over 10 years after a lumpectomy was performed, shows an an apparent area of dense fibroglandular breast tissue and architectural distortion.
However, the contrast enhanced MRI image of the same breast, shown below, reveals an area of apparent tumor recurrence adjacent the scar tissue evident in the mammogram.

After lumpectomy and radiation treatement, a breast cancer tumor will enhance, while inactive scar tissue will not. For this reason, the 'confirmed negative' predictive value of MR for recurrence is more than 98%. Ultrasound is somewhat more limited in its ability to discriminate between scar and breast cancer tumor, but is still useful for guiding the biopsy process.

DIAPHRAGMATIC PARALYSIS: M mode US and SNIFF TEST

Abstract

To evaluate the technical feasibility and utility of ultrasonography in the study of diaphragmatic motion at our institution.

The study consisted of 2 parts. For part I, in 23 volunteers we performed 23 studies on 46 hemidiaphragms with excursions documented on M-mode ultrasonography For part II, in 22 patients we performed 52 studies in 102 hemidiaphragms. In 50 studies both hemidiaphragms were studied, and in another 2 studies only 1 hemidiaphragm was studied. Patients' ages ranged from birth to 66 years (mean, 23 years). There were 16 male and 6 female patients. Indications for the study were (1) suggestion of paralysis of the diaphragm (n = 22); (2) if the diaphragm was already known to be paralyzed, for evaluation of response to phrenic nerve or pacer stimulation (n = 9); and (3) follow-up of previous findings (n = 21). Patients were examined in the supine position in the longitudinal semicoronal plane from a subcostal or low intercostal approach. Motion was documented with real-time ultrasonography and measured with M-mode ultrasonography.

Of the 102 clinical hemidiaphragms studied, findings included normal motion (n = 42), decreased motion (n = 22), no motion (n = 6), paradoxical motion (n = 10), positive pacer response (n = 13), negative pacer response (n = 2), positive phrenic stimulation (n = 6), and negative phrenic stimulation (n = 1). There were no failures of visualization.

Ultrasonography proved feasible and useful in evaluating diaphragmatic motion. In our practice it has replaced fluoroscopy. Ultrasonography has advantages over traditional fluoroscopy, including portability, lack of ionizing radiation, visualization of structures of the thoracic bases and upper abdomen, and the ability to quantify diaphragmatic motion.

DIAPHRAGMATIC PARALYSIS at MEDIC CENTER

 

Objectives:

To evaluate the use of M mode ultrasonography in the evaluation of diaphragmatic paralysis in adults.

Setting:

Radiology department, Princess Alexandra Hospital, Brisbane, Australia.

Methods:

Ten patients who were referred for evaluation of suspected diaphragmatic paralysis were evaluated using M mode ultrasound.

Results:

Three of the patients who were scanned demonstrated normal diaphragmatic movement. The M mode trace demonstrated normal movement of the diaphragm bilaterally with quiet respiration and a sharp upstroke on the sniff test (indicating normal caudal movement of the diaphragm). Six patients were found to have a unilateral diaphragmatic paralysis. Four of these patients were noted to have a raised hemi-diaphragm on chest radiography. Of the two who did not have a raised hemi-diaphragm on chest radiography, one was permanently ventilated. The M mode trace of the paralyzed side showed no active caudal movement of the diaphragm with inspiration and abnormal paradoxical movement (ie cranial movement on inspiration) particularly with the sniff test.

Conclusion:

M mode ultrasonography is a relatively simple and accurate test for diagnosing paralysis of the diaphragm, in the adult population. It can be performed, if necessary, at the bedside and can be easily repeated if paralysis is not thought to be permanent.

Abstract

Objective: The aim of this study was to evaluate the effect of hemiplegia on diaphragmatic movements using motion-mode ultrasonography.

Methods: 23 hemiplegic patients who were diagnosed with a single-hemisphere lesion (mean age 60.5 years; 13 males and 10 females) and a control group of 20 patients (13 males and 7 females) were all evaluated by ultrasonography. Ultrasonography recordings were made of the amplitude of diaphragmatic movement during spontaneous and deep breathing. The patients underwent lung function tests.

Results: When the hemiplegic and control groups were compared, the forced vital capacity, forced expired volume in 1 s, maximum inspiratory pressure and maximum expiratory pressure values were significantly lower in the groups with right and left hemiplegia (p <0.05). When a comparison was made between the right hemiplegic group and the control group and between the left hemiplegic group and the control group in terms of diaphragmatic excursions, for both groups, no significant difference was determined between the movements of the right hemidiaphragm during spontaneous and deep breathing and those of the left hemidiaphragm in spontaneous respiration. In contrast, for both hemiplegic groups, a significant decrease was noted in the movements of the left hemidiaphragm in deep respiration.

Conclusion: The diaphragm is both contralaterally innervated and ipsilaterally innervated, and innervation exhibits marked variations from person to person. This provides an explanation for varying diaphragmatic movements in hemiplegic cases during deep respiration.

Abstract

The diaphragm is the primary muscle of ventilation. Dysfunction of the diaphragm is an underappreciated cause of respiratory difficulties and may be due to a wide variety of entities, including surgery, trauma, tumor, and infection. Diaphragmatic disease usually manifests as elevation at chest radiography. Functional imaging with fluoroscopy (or ultrasonography or magnetic resonance imaging) is a simple and effective method of diagnosing diaphragmatic dysfunction, which can be classified as paralysis, weakness, or eventration. Diaphragmatic paralysis is indicated by absence of orthograde excursion on quiet and deep breathing, with paradoxical motion on sniffing. Diaphragmatic weakness is indicated by reduced or delayed orthograde excursion on deep breathing, with or without paradoxical motion on sniffing. Eventration is congenital thinning of a segment of diaphragmatic muscle and manifests as focal weakness. Treatment of diaphragmatic paralysis depends on the cause of the dysfunction and the severity of the symptoms. Treatment options include plication and phrenic nerve stimulation. Supplemental material available at http://radiographics.rsna.org/lookup/suppl/doi:10.1148/rg.322115127/-/DC1

Krukenberg Tumors: A Review

Talia K. Ben-Jacob, Chad R. Gordon, and Frank Koniges

Department of Surgery, UMDNJ-Robert Wood Johnson Medical School, Cooper University Hospital, Camden, New Jersey.

A Krukenberg tumor is a rare tumor of the ovary derived from metastatic gastrointestinal tissue. Although the eponym is attributed to Dr. Friedrich Krukenberg, a German gynecologist and pathologist, the Krukenberg tumor was actually described by both Paget (1854) and Wilks (1859). Worldwide, they account for about 1% of all ovarian neoplasms. Gastric cancer is the most frequent primary source, followed by breast, colon and appendix. For those carcinomas originating from the intestinal tract, about 80% are found within either the sigmoid colon or rectum. Presenting symptoms include nonspecific abdominal pain, distention, ascites, virilization, hirsutism and menometrorrhagia.

 Discussion

The Krukenberg tumor was originally described by Paget (1854). The eponym is attributed to Dr. Friedrich Krukenberg, a German gynecologist and pathologist. In 1896, he published five case reports on what he believed to be at the time a new type of ovarian tumor. However, in 1902, Dr. Schlagenhauffer determined that these tumors were in fact of metastatic gastrointestinal tract origin.

Krukenberg tumors are pathologically “signet ring cell” ovarian adenocarcinoma. They account for 1-2% of all ovarian tumors world-wide. In Japan, their prevalence is greatly increased to almost 20% (due to the increased prevalence of gastric cancer).³ The stomach is the primary site in 70% of these cases, followed by breast, colon, and appendix, in that order.¹ For those tumors originating from the intestinal tract, 80% are found to be within the sigmoid colon or rectum.¹ Unfortunately, these primary colonic tumors are often too small for endoscopic detection (i.e. colonoscopy), thereby necessitating either CT scan or ultrasound.

Women are typically diagnosed with Krukenberg tumors in the perimenopausal fifth decade of life, with the average age of diagnosis being 45 years-old. It is hypothesized that this young age of diagnosis is related to the great vascularity of their ovaries, which facilitates vascular metastasis.¹ It is interesting to note that for those patients with Krukenberg tumors originating from the colon, the mean age of presentation is subsequently delayed. Presenting symptoms usually include, but are not limited to, vague abdominal pain, distention, and/or ascites. Occasionally, abnormal vaginal bleeding, virilization and hirsutism can be seen.⁴

Krukenberg tumors are bilateral in 80% of cases.³ The route of metastasis from the gastrointestinal tract to the ovaries is hypothesized to be via lymphatics. The mortality rate for Krukenberg tumors is relatively high and a majority of patients die within two years of diagnosis, with a median 5-year survival of 14 months.³ The prognosis is poor if the primary tumor is identified after ovarian metastasis has occurred, and even worse if the primary is unidentified.⁵

Metastatic adenocarcinoma to the uterine cervix from the gastrointestinal tract is rare and very few cases are reported. The route of metastasis to the cervix is surmised to be retrograde via lymphatics, similar to the pathway of metastases to the ovary.⁶ Cervical metastasis may often be the presenting symptom, discovered either synchronously or after the diagnosis of gastro-intestinal carcinoma has been made. Unfortunately, for this subset of Krukenberg tumor patients, their diagnosis is poor no matter when their cervical metastasis is identified.⁶

Gross findings of a Krukenberg tumor-containing ovary include asymmetrical enlargement, lobular contour, and either solid or cystic consistency. Commonly, the ovaries are spared from intra-peritoneal adhesions and present without any peritoneal deposits.³ Kiyokawa et al. reported that Krukenberg tumors can range in texture from firm and solid to edematous and gelatinous, with only approximately 30% containing cysts. They also found the mean size to be 10.4 cm.⁴

Microscopically, the Krukenberg tumor is composed of mucin-laden signet-ring cells and ovarian stromal cells. Krukenberg tumors can either display a prominent tubular pattern or one that is clustered. Lobular patterns, with nodules separated by stroma, can also be seen. Mucin-laden signet ring cells are essential for the diagnosis of a Krukenberg tumor.³ However, sometimes the desmoplastic reaction of the stromal cells can be so severe that it obscures the signet-ring pattern. The literature describes great variation in the different cellular atypia. The stroma can range from cellular to paucicellular and from edematous to mucoid. The degree of signet-ring cell prominence also varies from case to case.⁴ The overall morphology of the adenocarcinoma is graded based on the presence of mucin, edema, stromal patterns and the number of signet-cells. Often it is difficult to differentiate between primary and metastatic ovarian carcinoma. Careful attention must be paid to the microscopic finding of invasion and implantation to distinguish the two metastatic modes.¹ Based on 120 Krukenberg tumor cases, Kiyokawa determined that the histological spectrum is much more diverse than what has been previously reported.⁴

In these aforementioned cases, special diagnostic stains can be used to highlight the presence of signet cells. Immunohistochemistry can also be used to decipher metastatic carcinoma from primary ovarian neoplasms.¹ The ovarian tumors that are immunoreactive to CEA, stain positive for cytokeratin 20 (CK20) and negative for cytokeratin 7 (CK7), are more likely to be of colorectal origin and increase the pathologist’s confidence in making the diagnosis of a Krukenberg tumor.³ This differs from primary ovarian tumors, since they usually test positive for CK 7 and negative for CK 20. Other immunohistochemicals currently under investigation include CD44v6, vascular endothelial growth factor, and matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9). Lou et al. compared 35 cases of Krukenberg tumor to normal tissue and found that the expression rate of CD44v6, VEGF, MMP-2 and MMP-9 were significantly higher in those with Krukenberg tumors.⁷ However, these factors were also found within primary epithelial ovarian carcinomas and were therefore not exclusive to Krukenberg tumors.⁵ CA-125 is a tumor marker elevated in patients with Krukenberg tumors and usually found to decrease after resection. Therefore CA-125 can be used either for post-operative follow up and/or for patients with a history of adenocarcinoma with no identifiable ovarian metastasis.³

There is currently no optimal or curative treatment strategy for Krukenberg tumors. Surgical resection has only been shown to be effective in patients with limited metastasis confined to the ovaries.³ Patients often experience recurrence after curative surgery thereby preventing them from receiving further treatment. For these types of patients, Cheong et al. investigated the role of metastectomy for the management of metachronous tumors following curative surgery. Their study found the median survival for patients undergoing metastatic resection was significantly increased versus the non-resection control group (17 months vs. 3 months).⁵ Further investigation is warranted to decide the optimal role of surgery in patients with Krukenberg tumors.

Chirurgia (Bucur). 2008 Jan-Feb;103(1):23-38.

[Features of Krukenberg-type tumors--clinical study and review].

Mateş IN, Iosif C, Bănceanu G, Ionescu M, Peltecu G, Dinu D, Constantin A, Hoară P, Mitru C, Constantinoiu S.

Source

Clinica de Chirurgie Generală şi Esofagiană Sfânta Maria, U.M.E Carol Davila, Bucureşti. dmates@gmail.com

Abstract

Krukenberg-type tumors (KT) are rare among ovarian metastases, but responsible for the most frequent diagnostic confusions with ovarian cancer. They are peculiar: uncertain pathogenesis, challenging etiological diagnosis, poorer prognosis for the primary. We studied 9 cases, with a mean age of 52 years, operated since 2001; no case was discovered as a result of prophylactic oophorectomy. Timing of TK diagnosis: 3--metachronous, 4--synchronous, as incidental discovery and 2--retrospective pathological diagnosis. Site of primary: 3--gastric, 5--colonic or appendiceal, 1--breast. Imaging appearance was useful only if interpreted in clinical conditions. Morphology: 7/9 bilateral, solid or mixed gross appearance, oval, mean diameters 9.4/7.8 cm. Microscopy: in 8 KT of digestive origin, 3--signet-ring cell carcinoma, 3--mucinous adenocarcinoma, 2--mixed pattern; 1 KT or breast origin was diagnosed by immunohistochemistry; 6/9 presented microscopic peritoneal despite a lack of strong correlation with the appearance of carcinomatosis or cytology of ascites. Survival: 3--no evidence, 5--disease-free after 4-13 months, 1--survived 2 years after debulking (4 years after colectomy). Clinical, evolutive and prognostic features of KT are determined by the biologically behavior of the primary (rapid lymphatic and hematogenous spread to the ovary), so the benefit of surgery is limited. Bilateral ovarian tumors, particularly in premenopausal women, must raise a high index of suspicion for KT, before or during surgery; diagnosis is a team challenge.

Adv Anat Pathol. 2006 Sep;13(5):205-27.

From krukenberg to today: the ever present problems posed by metastatic tumors in the ovary: part I. Historical perspective, general principles, mucinous tumors including the krukenberg tumor.

Young RH.

Source

James Homer Wright Pathology Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. ryoung@partners.org

Abstract

This review considers historical aspects of metastatic tumors to the ovary, general principles that aid in their evaluation, and metastatic mucinous tumors, including the Krukenberg tumor. The historical timeline on the Krukenberg tumor dates back to the legendary Sir James Paget and the story is followed through the well-known, albeit flawed, contribution of Friedrich Krukenberg and others who have contributed important papers over the years, including the overlooked contribution of the French investigator Gauthier-Villars. Knowledge of metastatic colorectal carcinoma is traced back to the famed British surgeon Sir John Bland-Sutton and followed through to more recent contributions, including the important one of Lash and Hart. Contributions on mucinous tumors conclude the historical perspective, note being made of the recent evidence suggesting that the long held contention of Dr Robert E. Scully that ovarian mucinous tumors in patients with pseudomyxoma peritonei usually originate from the appendix is correct. The section on general principles highlights the many clinical, gross, microscopic, and special techniques such as immunohistochemistry that may aid in determining that an ovarian tumor is metastatic with emphasis on the first 3 mentioned aspects. Problematic features such as a tendency for metastatic tumors to be cystic, even when the primary tumors are not, and for many metastatic tumors to mature in the ovary (so-called maturation phenomenon), are emphasized. Of the many helpful findings that resolve the problem, the characteristic features of surface implants are highlighted. The contribution on the Krukenberg tumor reviews the varied microscopy of this tumor pointing out that the well-known pattern of signet-ring cells in a cellular stroma, albeit characteristic, is often not striking and frequently overshadowed by other microscopic features. The latter include, in many cases, a rather unique microcystic pattern. The final portion of the essay reviews mucinous tumors of non-Krukenberg type, beginning with those that originate from the appendix. The appendiceal neoplasms have distinctive features in most cases being particularly well differentiated, and this is also seen in their ovarian metastases. Other mucinous tumors that commonly simulate closely metastatic neoplasms, include those from the pancreas in particular, but also diverse other sites, are then reviewed.

Vel, PI and RI in Primary Ovarian Carcinoma and KRUKENBERG Tumors

Abstract

OBJECTIVE:

The aim of this study was to compare the effectiveness of transvaginal power Doppler sonography with spectral Doppler analysis as an aid in preoperatively distinguishing primary ovarian carcinoma and metastatic carcinoma to the ovary (Krukenberg tumors).

METHODS:

Fifty women with ovarian disease were preoperatively examined with transvaginal power Doppler sonography. Six basic parameters were measured, including intratumoral peak systolic velocity, end-diastolic velocity, time-averaged maximum velocity, pulsatility index (PI), resistive index (RI), and velocity index (VeI). Blood flow analyses were detectable in all patients. Twelve patients with metastatic carcinoma to the ovary were classified as group 1; 38 patients with primary ovarian carcinoma were classified as group 2. Comparison of intratumoral blood flow analyses between the two groups was performed.

RESULTS:

The PI, RI, and VeI were significantly lower in patients with metastatic carcinoma to the ovary than those with primary ovarian carcinoma (P < .05). There were no significant differences in the peak systolic velocity (P = .871), end-diastolic velocity (P = .508), and time-averaged maximum velocity (P = .850) between the two groups.

CONCLUSIONS:

Transvaginal power Doppler sonography with spectral Doppler analysis is an effective method in evaluating intratumoral blood flow of Krukenberg tumors. Low impedance (PI, RI, and VeI) might assist us in making differential diagnoses between primary ovarian carcinoma and Krukenberg tumors according to our preliminary results.

It has been more than 100 years since Krukenberg¹ originally recognized 6 patients with unusual ovarian tumors as carcinomatodes and thought they were sarcomatous in nature. The term “Krukenberg tumor” has been widely applied to any metastases to the ovary, even though some authors consider that there should be a more strict histologic definition, such as located in the ovaries, with a sarcomatouslike stroma, and composed of signet ring cells with intracellular mucin.² However, more than one fourth of all ovarian metastases present as probable primary ovarian carcinomas,³ and 5% to 10% of all ovarian malignancies are metastatic carcinomas, which are difficult to discriminate.⁴

Several reports in the literature have shown the possibility of differential diagnosis from the characteristics of sonography, computed tomography, and magnetic resonance imaging.^5–8 The application of transvaginal sonography, color flow imaging, and Doppler waveform analysis allows a closer approach to pelvic hemodynamics. Various blood velocity measurements have been used to show the low impedance of intratumoral circulation in ovarian malignancy.⁹ Although excellent results in differentiating benign from malignant tumors have been reported by some authors, there are others who have described less encouraging findings.^10–13 One previous report analyzed primary ovarian cancer and metastatic tumors to the ovary by transvaginal gray scale and color Doppler sonography.¹⁴ It revealed that the presence of a purely solid tumor indicates a higher probability of metastatic carcinoma than primary ovarian cancer. However, with the use of gray scale and color Doppler sonography, it is difficult to differentiate primary ovarian carcinomas from metastatic tumors to the ovary. To the best of our knowledge, none of the previous reports provided us with data from blood flow analysis within Krukenberg tumors. We assessed intratumoral blood flow analysis from 12 Krukenberg tumors using power Doppler sonography with spectral Doppler analysis and made comparisons with primary ovarian carcinoma.

Discussion

Krukenberg tumors are widely defined as the presence of any metastasis to the ovaries. Among the primary lesions in the gastrointestinal tract, the colon is the most common site in Western countries, and the stomach is the most common site in Asian countries.^15,16 The other sites of primary tumors include the breast, pancreas, lung, gallbladder, small intestine, and kidney, as well as melanoma, sarcoma, and carcinoid tumors.¹⁷ The clinical incidence is approximately 5% to 10% in the United States and 15% to 20% in Asia.^18–20 The presence of ovarian metastasis is universally a poor prognostic sign and commonly occurs during a woman’s reproductive years. Early, prompt, and aggressive therapy is beneficial for the patient’s quality of life and symptom relief. Asymmetrically enlarged bilateral encapsulated masses, variable intratumoral echogenic density, and ascites are the major characteristics on sonography.

In 1975, Ingersoll and Scully²¹ first described a patient with ovarian carcinoma, metastatic from the colon, with a complex lesion containing cystic and solid features on combined B-scan and A-mode sonography. Rochester et al⁵ also described a patient with a Krukenberg tumor (colon origin) that showed homogeneous low-level echoes with the usual gain, and excellent transmission of sound was seen on low-gain and high-frequency (3.5-MHz) sonography. Later, Choi et al¹⁵ studied 16 Krukenberg tumors from patients with gastric carcinoma. They found varied echogenicity within tumors on sonography: solid in 8 patients, mixed in 6, and predominantly cystic in 2. Shimizu et al²² further classified Krukenberg tumors in 9 patterns by the tumor wall, solid part, and cystic part. They found that 14 of 15 Krukenberg tumors had clear tumor margins, irregular hyperechoic solid patterns, and “moth-eaten” cyst formations on real-time gray scale sonography.²² In our study, 5 Krukenberg tumors had clear tumor margins, but only 2 patients (40%) had irregular hyperechoic solid parts; 3 patients (60%) had diffuse homogenous solid parts around internal small clear cystic formations. Only 1 patient had a moth-eaten cyst formation; the others had irregular cystic formations.

Transabdominal color Doppler sonography has provided us with a new assessment method in Krukenberg tumors. An abnormal vascular pattern with high-velocity, low-impedance signals within heterogeneous solid masses was the important sonographic characteristic.²³ Moreover, Cho et al²⁴ showed that power Doppler sonography was superior to conventional color Doppler sonography in detecting slow blood flow, especially in showing relatively prominent vascular signals along the walls of intramural cysts, which were located in solid masses in 2 patients with Krukenberg tumors from gastric carcinoma. Additionally, 3-dimensional (3D) transvaginal power Doppler imaging better defined the morphologic and vascular characteristics of ovarian lesions.²⁵ The ovarian malignancies were correctly identified by both 2-dimensional and 3D imaging; however, the specificity significantly improved with the addition of 3D power Doppler sonography. To the best of our knowledge, no previous studies reported that 3D power Doppler indices could be useful tools in differentiating primary ovarian cancer and metastatic ovarian tumors. Alcázar²⁶ reported that vascularization, as assessed by 3D power Doppler sonographic indices, was higher in advanced stage and metastatic ovarian cancers than in early-stage ovarian cancer. However, no differences were found in the PI, RI, and PSV in early-stage ovarian cancer, advanced ovarian cancer, and metastatic ovarian cancer.²⁶

In our study, the mean PI and RI in the group with primary ovarian cancer showed no significant differences with previous reports.^27,28 However, the mean PI and RI values of Krukenberg tumors were lower than those of primary ovarian tumors (P < .05). We may assume that the vasculature of metastatic ovarian cancer is much different from that of primary ovarian tumors and normal ovarian vessels. Active angiogenesis might be the key factor of these findings. After attaching to ovaries, the metastatic cells activate the quiescent vasculature to produce new blood vessels with wall structures that have little or no smooth muscle support.²⁸ These abnormal vessels, along with arteriovenous shunting in some metastatic tumors, contribute to diminished vascular resistance and, therefore, are reflected by PI and RI values that are much lower than those of primary ovarian tumors. Furthermore, increased permeability of abnormal vessels could cause stasis of blood flow and short shunts, which result in low impedance.

In this study, the patients with Krukenberg tumors had a significantly lower VeI (PSV/EDV) than those with primary ovarian tumors. This result might indicate that metastatic tumors could not establish organized intratumoral vasculature, especially when they seeded on other organs or tissues. The unhealthy vasculature reflected the lower VeI. On the contrary, primary ovarian tumors could have been directly and abundantly nourished by ovarian vessels, which resulted in the higher PSV.

In conclusion, power Doppler sonography might be a useful tool in evaluating intratumoral blood flow analysis of ovarian carcinoma before surgery. According to our results, lower impedance (such as a lower PI, RI, and VeI) could be a guideline when making differential diagnoses between primary and metastatic ovarian carcinoma. However, further studies are needed to determine the cutoff values of the PI, RI, and VeI for differentiating primary and metastatic ovarian tumors.

 

Virchow Node and Troisier Sign

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It is named after Rudolf Virchow (1821-1902), the German pathologist who first described the gland and its association with gastric cancer in 1848.

The French pathologist Charles Emile Troisier noted in 1889 that other abdominal cancers, too, could spread to the node.

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It is quite significant because, it is also called a sentinel node or a signal node as in carcinomas its presence strongly indicates the abdominal (especially, gastric) cause of the malignancy.

It becomes hard which is quite palpable, and this is called Troisier's sign.

VALUE of ARFI and TE in HBV and HCV LIVER FIBROSIS

Abstract

Our aim was to compare liver stiffness (LS) measurements by means of acoustic radiation force impulse (ARFI) elastography and transient elastography (TE) in patients with chronic hepatitis B and C, according to the severity of fibrosis. We also compared the correlation strength of ARFI and TE measurements with liver fibrosis. We included 53 patients with hepatitis B and 107 with hepatitis C in which liver biopsy, ARFI and TE measurements were performed in the same session. The mean LS values measured with ARFI were similar in patients with chronic hepatitis B and C and depended on the stage of fibrosis. The correlation strength of LS measurements by ARFI and by TE with fibrosis was similar in chronic hepatitis B and C patients. In conclusion, for the same stage of fibrosis, the mean LS values by ARFI were similar in patients with chronic hepatitis B and C. ARFI had similar predictive value with TE in both chronic viral hepatitis.