Lymphadenopathy is a common, nonspecific clinical finding in dogs. It is important to distinguish the cause because it greatly affects the treatment and prognosis of an individual animal. It is of particular interest to evaluate regional lymph nodes for presence of primary tumors or metastases. In most clinical practices, palpation is the most commonly used method to evaluate lymph node size, although several studies1,2 have confirmed that palpation is an insensitive technique for detection of malignancy. Ultrasonography has been shown to increase the sensitivity and specificity of the lymph node evaluation by providing information regarding size, shape, internal structure, acoustic enhancement, and vascularity.3–18 Color and power Doppler ultrasonography allow functional assessment of vascularization by mapping flow signals of the entire lymph node12–16,19–22 in real time and thus offer a noninvasive, easily applicable method for direct measurement of the amount and distribution of blood flow. The rationale behind flow assessment is that the vascularity of a lymph node changes secondary to development of arteriovenous shunts, necrosis, and other pathologic alterations and this change helps diagnosticians to distinguish benign from malignant lymphadenopathy. There is limited information about the ultrasonographic appearance of canine lymph nodes in the veterinary literature.17,18,23,24 In a recent study,17 our group reported the ultrasonographic characteristics of 318 superficial lymph nodes in dogs. To the authors' knowledge, studies to compare the ultrasonographic findings with histopathologic changes in canine lymph nodes have not been reported. Histologic examination of H&E-stained sections of lymph nodes can be used to detect areas of necrosis, inflammation, fat, tissue fibrosis, and metastases. The Verhoeff van Gieson method (referred to as the Verhoeff technique) stains elastic fibers, including those forming the internal elastic membrane of blood vessels, and can thus be used to identify the greater arterioles, muscular arteries, and some of the medium-sized veins. Arterioles have a luminal diameter of less than approximately 300 μm.25 This enables evaluation of vessels of dimensions similar to those detectable ultrasonographically. The purpose of the study reported here was to compare and correlate Bmode and Doppler ultrasonographic characteristics with histopathologic findings of benign and malignant superficial lymph nodes in dogs.
Materials and Methods
Study population—Fifty superficial lymph nodes in 30 dogs were examined in this study; nodes in any dog admitted to the Small Animal Hospital at the Department of Small Animal Clinical Sciences for staging procedures and surgery that would include removal of the node were considered suitable for inclusion. In general, these nodes were abnormally large on clinical examination or represented regional lymph nodes draining an area of suspected primary malignancy.
Ultrasonographic procedures—The lymph nodes were evaluated ultrasonographically immediately prior to surgical extirpation by use of 2 ultrasonographic machinesa,b and a linear array transducer (7 to 14 MHz for B-mode and 7 MHz for Doppler ultrasonographic evaluations) in a standard imaging mode for small body parts. The size of the lymph node was measured at its shortest and longest axes. Echogenicity, presence of a hilus, and acoustic enhancement were recorded; these variables were examined by use of Bmode ultrasonography at a depth of 2 to 3 cm.
Color flow mapping was used in different planes through each lymph node to evaluate and quantify the amount and distribution of the vascular supply within the node. Doppler imaging was performed by use of machine settings designed to optimize detection of low flow in small vessels. The color Doppler gain was increased until background noise appeared and then was decreased slightly to eliminate noise and retain maximal sensitivity to flow. The presence and distribution of vascular flow was recorded and classified as 1 of 3 flow patterns: hilar, peripheral, or mixed hilar and peripheral flow. The hilar part of the lymph node was classified as the most central part of the lymph node, corresponding to 50% of the whole lymph node area, whereas the periphery was defined as the rest of the node. Nodal blood flow was classified as peripheral flow when at least 80% of detected flow was localized to the periphery; as hilar flow when at least 80% of detected flow was localized to the hilar part of the lymph node; and as mixed hilar and peripheral flow when flow ratios < 80% were observed in both peripheral and hilar parts. An image in the sagittal plane (optimized to show the greatest amount of vessels) was chosen for quantification of flow within the lymph node and expressed as a percentage of color pixels by use of computer software.c The number of vessels in the image (recorded as individual Doppler signals) was also assessed. Data were recorded and digitally stored as individual images and 3- to 5-second cinematic loops on a magnetic optic disc in a standard imaging format.d Computer softwaree was used to view the images initially and to export images in formats suitable for analyses.
Histologic examination—All the lymph nodes were examined histologically. The lymph node was divided along the longitudinal midline and placed in ≥ 1 capsules (depending on the size of the node); tissue samples were fixed in neutral-buffered 4% formaldehyde for 24 hours, stored for another 24 to 72 hours in 70% ethanol, and then embedded in paraffin wax. The tissues were cut into 4-μm sections and underwent deparaffinization in xylene and rehydration in alcohol and water. The tissue sections were stained with H&E and with the Verhoeff technique.26 The nodes were classified as primary malignant, secondary malignant, or benign. The benign group contained both normal and reactively enlarged lymph nodes. The H&E-stained sections were evaluated for presence or absence of areas of fat and fibrous tissue in the hilar region, necrosis, metastases, and the overall tissue heterogeneity; for these aforementioned features, detection of an area of at least 1 mm2 was considered a positive finding. The overall tissue heterogeneity was evaluated subjectively and defined as heterogenic if at least 2 different tissue types were interspaced within the section. Slides prepared by use of the Verhoeff technique were evaluated for the number of stained blood vessels, as with the ultrasonographic images. The hilar part of the lymph node was defined as the most central part of the lymph node, corresponding to 50% of the whole lymph node area, whereas the periphery was defined as the rest of the node.
Statistical analysis—Categorical variables are described as relative proportions expressed in percentages, whereas continuous data are expressed as mean values. The ultrasonographic findings were correlated with the histopathologic findings. The κ statistic was used to correlate echogenicity and presence of acoustic enhancement with areas of tissue heterogeneity and necrosis, respectively. It was also used to correlate presence of a hilus (detected ultrasonographically) with areas of fat or fibrosis. The χ2 test was then used to evaluate fat and fibrosis in combination with respect to the hilus. A proportional odds analysis27 was used to determine the effect of the presence of a hilus on the combined features of fat and fibrous tissue (summarized as the sum of the 2 variables). Linear regression and a Bland-Altman plot were used to evaluate the correlation between the numbers of vessels detected ultrasonographically with the number of Verhoeffstained vessels in the tissue sections. The Bland-Altman plot compared the results obtained by each measure with the mean of the 2 measurements. This is used to determine agreement between 2 tests that involve modes of measurement for which the true value for the measurement is not known and determine whether any difference in results is a function of the magnitude of the result (ie, to detect bias). Linear regression was used to correlate the distribution of vascularity within the lymph node determined via ultrasonography and histology and correlate vascularity with the length of the lymph node; quadratic regression was used to correlate the vascularity with the short axis of the lymph node. A value of P < 0.05 was considered significant.
Results
Fifty lymph nodes in 30 dogs were examined via B-mode and color Doppler ultrasonography prior to excision (Table 1). After surgical removal, tissue sections from all nodes were examined histologically (Table 2). On the basis of histologic findings, the lymph nodes were classified into 3 groups: benign (n = 19), primary malignant (ie, lymphoma; 23), and secondary malignant (ie, metastatic; 8). Among the evaluated lymph nodes, there were 5 mandibular nodes, 4 superficial cervical nodes, 3 axillary nodes, 27 inguinal nodes, and 11 popliteal nodes.
B-mode and color Doppler ultrasonographic characteristics of 50 superficial lymph nodes that were either normal, abnormally large on clinical examination, or represented regional lymph nodes draining an area of suspected primary malignancy in 30 dogs.
| Characteristic | Type of lymph node* | ||
|---|---|---|---|
| Benign (n = 19) | Primary malignant (lymphoma [23]) | Secondary malignant (metastasis [8]) | |
| B-mode ultrasonography | |||
| Length (cm) | 1.8 | 2.7 | 1.6 |
| Echogenicity (No. of nodes) | |||
| Hypoechoic (uniform) | 1 | 13 | 4 |
| Isoechoic (uniform) | 14 | 4 | 1 |
| Varied | 4 | 6 | 3 |
| Appearance of tissue texture (No. of nodes) | |||
| Homogenous | 15 | 19 | 5 |
| Heterogenous | 4 | 4 | 3 |
| Acoustic enhancement (No. of nodes) | 3 | 9 | 2 |
| Doppler ultrasonography | |||
| Presence of vascular flow (No. of nodes) | 17 | 21 | 8 |
| Mean No. of vessels in node | 3.5 | 5.9 | 4.0 |
| Flow distribution (No. of nodes)† | |||
| Hilar | 12 | 5 | 0 |
| Peripheral | 0 | 0 | 1 |
| Mixed hilar and peripheral | 5 | 16 | 7 |
| Total flow in node (%)‡ | 6.5 | 6.6 | 8.7 |
| Hilar (No. of nodes) | 14 | 9 | 3 |
| Peripheral (No. of nodes) | 0 | 0 | 1 |
| Mixed hilar and peripheral (No. of nodes) | 3 | 12 | 4 |
The hilar region was defined as the central 50% of the total lymph node area.
Assessed via histologic examination of tissue sections of nodes after surgical removal.
Flow distribution was assessed subjectively during ultrasonographic examination.
Total flow amount was quantified by percentage of color pixels in the Doppler ultrasonographic image of the lymph node.
Histologic characteristics of 50 superficial lymph nodes that were either normal, abnormally large on clinical examination, or represented regional lymph nodes draining an area of suspected primary malignancy in 30 dogs.
| Characteristic | Type of lymph node* | ||
|---|---|---|---|
| Benign (n = 19) | Primary malignant (lymphoma [23]) | Secondary malignant (metastasis [8]) | |
| H&E-stained sections (No. of nodes) | |||
| Necrosis | 11 | 12 | 5 |
| Fibrosis | 18 | 15 | 8 |
| Fat | 9 | 12 | 5 |
| Tissue heterogeneity | 6 | 6 | 5 |
| Verhoeff-stained sections (No. of nodes) | |||
| Stain uptake in hilar region | 13 | 9 | 2 |
| Stain uptake in peripheral region | 0 | 0 | 1 |
| Stain uptake in hilar and peripheral regions | 0 | 11 | 2 |
| Mean No. of Verhoeff-stained vessels | 2.0 | 2.9 | 1.5 |
See Table 1 for key.
Histologic tissue heterogeneity correlated with ultrasonographic echogenicity (κ = 0.53; 95% CI, 0.28 to 0.78). Ultrasonographically, normal nodes were primarily uniformly isoechoic, whereas reactive nodes had a mixed echogenicity and texture, compared with the surrounding tissue (Figure 1). Compared with normal nodes, both primary and secondary malignant nodes were generally more hypoechoic, often with a varied texture (Figure 2). The subjective evaluation of tissue heterogeneity on the H&E-stained slides revealed that heterogeneity was present in both benign and malignant lymph nodes but more prevalent in malignant lymph nodes. A correlation was also found between the presence of a hilus (detected ultrasonographically) and the presence of fibrous tissue in the hilar region (κ = 0.46; 95% CI, 0.19 to 0.74); similarly, there was a correlation between the presence of a hilus and the presence of fat in the hilar region (κ = 0.31; 95% CI, 0.06 to 0.56; Figure 3). The proportional odds model indicated that these 2 variables, fat and fibrous tissue, were dependent of each other (P = 0.001) and that the odds of the presence of fibrous tissue and fat in the hilus region was 9.4 (95% CI, 2.4 to 36.9) times as high when the hilus was detected ultrasonographically as it was when the hilus was not detected. However, there was no significant difference in the ultrasonographic imaging of the hilus between benign and malignant lymph nodes. Acoustic enhancement was correlated with the presence of necrotic areas within the lymph node (κ = 0.4; 95% CI, 0.2 to 0.6), and it was more commonly seen in malignant lymph nodes, compared with benign nodes (Figure 1). However, although all lymph nodes with enhancement had necrotic areas, not all lymph nodes with necrosis were associated with enhancement.
Ultrasonographic and histologic characteristics of a reactive popliteal lymph node in a 1-year-old sexually intact male Mastiff. A—Gray scale ultrasonographic image. Notice the focal changes and varied echogenicity of the node; slight acoustic enhancement is present. B—Photomicrograph of a tissue section of the same lymph node. The region in this image corresponds to the central focal lesion in the ultrasonographic image. Notice the tissue heterogeneity and areas of necrosis. H&E stain; bar = 200 μm.
Citation: American Journal of Veterinary Research 67, 6; 10.2460/ajvr.67.6.978
Ultrasonographic and histologic characteristics of an inguinal lymph node affected with metastasis from a primary solid carcinoma in a 10-year-old sexually intact German Shepherd Dog. A—Gray scale ultrasonographic image. Notice that the lymph node is hypoechoic and a hilus is not detectable. The lymph node is large and is diffusely widened in the left part of the node. B—Photomicrograph of a tissue section of the same lymph node. Notice that the tissue is diffusely infiltrated by metastatic cells. Early metastases are usually detected in the capsular region of lymph nodes; the diffuse infiltration of this node may explain the widening of the node and the lack of a detectable hilus on the ultrasonographic image. H&E stain; bar = 80 μm.
Citation: American Journal of Veterinary Research 67, 6; 10.2460/ajvr.67.6.978
Ultrasonographic and histologic characteristics of an inguinal lymph node in a 2-year-old sexually intact male Flat-Coated Retriever with cutaneous T-cell lymphoma. A—Gray scale ultrasonographic image. Notice that the lymph node is hypoechoic with an echogenic hilus. B—Photomicrograph of a tissue section of the same lymph node. Notice that the hilar region contains primarily fat as well as some fibrous tissue. The area marked by an asterisk in this image corresponds to the area marked by an asterisk in the ultrasonographic image. H&E stain; bar = 200 μm.
Citation: American Journal of Veterinary Research 67, 6; 10.2460/ajvr.67.6.978
Blood flow that was sufficient to permit measurement was present in 46 of the 50 (92%) lymph nodes. There was a significant (P < 0.001) correlation between the number of vessels detected via ultrasonography and the number detected histologically (Figure 4). Linear regression was estimated as follows:
Ultrasonographic and histologic characteristics of a normal inguinal lymph node in a 12-year-old sexually intact German Shepherd Dog. A—Color Doppler ultrasonographic image. Notice that the lymph node is isoechoic and has an oval regular shape; the blood vessels are predominantly localized to the hilar region. B—Photomicrograph of a tissue section of the same lymph node. Notice that the elastic fibers in the internal elastic membrane of the arteriole are stained black. Verhoeff stain; bar = 50 μm.
Citation: American Journal of Veterinary Research 67, 6; 10.2460/ajvr.67.6.978
Summary of the correlation results of linear and quadratic regression analyses of total flow and lymph node size (measured ultrasonographically) in 50 superficial lymph nodes that were either normal, abnormally large on clinical examination, or represented regional lymph nodes draining an area of suspected primary malignancy in 30 dogs.
| Variable | Estimate | Total flow | Total flow2 | P value |
|---|---|---|---|---|
| Log width* | 0.22 ± 0.22 | −0.15 ± 0.05 | 0.007 ± 0.003 | 0.03 |
| Log length† | 0.88 ± 0.11 | −0.03 ± 0.01 | NA | 0.04 |
Data are presented as mean ± SE.
Analysis was performed by use of quadratic regression with size as the dependent variable.
Analysis was performed by use of linear regression.
NA = Not applicable.
Discussion
The present study was designed to correlate ultrasonographic and histologic characteristics of canine superficial lymph nodes that were being surgically removed because they were palpably enlarged or represented regional lymph nodes draining an area of suspected primary malignancy. Prior to excision, the nodes were evaluated via B-mode and color Doppler ultrasonography; after excision, H&E- and Verhoeffstained sections of lymph nodes were examined microscopically. The ultrasonographic finding of mixed echogenicity was significantly correlated with a heterogenic tissue structure detected histologically. The varied echogenicity observed, particularly in large reactive nodes and nodes affected by metastases or lymphoma, may be a consequence of necrosis, metastatic lesions, edema, and hemorrhage within the nodes. The benign lymph nodes were primarily isoechoic, compared with the surrounding tissue. Approximately one fourth of the benign, primarily reactive lymph nodes had a varied echogenicity. The primary malignant (lymphoma) nodes were primarily hypoechoic (13/23 nodes) or varied in echogenicity (6/23 nodes); among the secondary malignant (metastatic) nodes, these characteristics were detected in 4 and 3 of the 8 nodes, respectively. This is in accordance with findings of studies3,4,6,28 in humans.
From the κ statistical analysis, a significant correlation between the presence of acoustic enhancement and presence of necrosis was determined; all lymph nodes with enhancement had necrotic areas. However, there was a certain percentage of lymph nodes with necrosis that did not show enhancement. This suggests that necrotic areas may cause enhancement and that a certain amount of necrosis may be needed to result in enhancement.
The hilus region is primarily situated in the medulla of the lymph node. κ Statistical analysis also revealed a correlation between the presence of a hilus (detected ultrasonographically) and the presence of fibrous tissue or fat in the tissue sections. The correlation between the presence of fibrous tissue and a hilus was stronger than that between the presence of fat and a hilus. The proportional odds model indicated that the odds of presence of fibrous tissue and fat in the hilus regions was 9.4 times as high when the hilus was detectable ultrasonographically, compared with when it was not detectable. In a previous study5 in humans, it was concluded that the ultrasonographic detection of a hilus was a benign sign, whereas the lack of detection was a malignant sign because of metastatic or fatty infiltration of the hilus. This is in disagreement with our findings; in the present study, there was no significant difference in ultrasonographic detection of a hilus between benign and malignant lymph nodes, which was also a finding of a recent study17 by our group.
Color Doppler ultrasonography can be used to detect flow within superficial lymph nodes, and several authors11–15,22,29 have suggested the possibility of differentiating malignant and benign lymph nodes on the basis of flow parameters. In the present study, it was hypothesized that a significant correlation would be achieved with a staining method that stains vessels of the types and sizes that are detected via ultrasonography. The Verhoeff technique stains the elastic fibers in the internal elastic membrane of arterioles and arteries that are > 250 to 300 μm in diameter. These vessels are expected to be detected ultrasonographically because the image resolution in the frequency range used is approximately 2 to 3 mm. Because Doppler ultrasonography can detect vessels that are smaller than those stained by the Verhoeff technique, an underestimation of vessels counted on examination of tissue sections (compared with the number of vessels detected ultrasonographically) was expected. A significant correlation was found between the number of vessels detected via ultrasonography and the number counted on tissue sections, and the mean number of vessels determined ultrasonographically was 2.4 greater than that determined histologically. There was also a significant correlation in the distribution of flow within the lymph nodes measured by the 2 assessment methods. The size of the lymph node, measured as the length of the node, was used as the dependent variable in the analysis of the correlation between size and total flow amount. Linear regression analysis revealed that a significantly smaller vascular supply (as measured ultrasonographically) was present in the large lymph nodes, compared with smaller nodes. This is most likely attributable to the fact that nodes affected with lymphoma usually attain large sizes, as the disease causes rapid growth and expansion of the node. This may result in central necrosis, which may decrease the total flow area with respect to the total nodal area and cause vessel compression. Quadratic regression analysis was used to correlate the total flow amount measured ultrasonographically with the short axis of the lymph node because the data did not fit a linear regression model. The results from this analysis indicated that either a low- or high-grade flow amount was present in wide lymph nodes, whereas a medium-grade flow amount was present in thin nodes. An interpretation of these findings is that large nodes may have either a low amount of flow (perhaps because of central necrosis) or a high amount of flow, which may be a result, for example, of inflammation in reactive nodes. This, however, needs to be confirmed by further studies. The number of Verhoeff-stained vessels did not significantly correlate with the size of the lymph nodes when analysis that controlled for total flow amount was performed. In this type of correlation study, one needs to realize that many potentially variable factors determine whether a particular vessel will be identified on the color Doppler ultrasonographic image. Thus, counting the number of vessels displayed in an individual image only provides a crude index of vascular activity, and the vascular activity will always be underestimated by an amount that varies from scan to scan. The same is true when evaluating the tissue sections because the staining results are dependent on factors such as tissue treatment before fixation and staining procedures.
Our data collected from canine superficial lymph nodes suggest that there is a significant correlation between the echogenicity and acoustic transmission and the histologic assessment of tissue heterogeneity; the ultrasonographic detection of a hilus is significantly correlated with the presence of either fibrosis, fat, or both in the hilar region; color Doppler ultrasonography can be used to detect and evaluate blood flow in these lymph nodes; and the number and distribution of Verhoeff-stained vessels (although underestimated) significantly correlates with the ultrasonographic findings, indicating that the ultrasonographic assessment of vascularity is quantitative and related to histopathologic changes. Overall, the results of the present study indicate that histopathologic changes are represented by ultrasonographic characteristics in canine lymph nodes and suggest that lymph node ultrasonography has an important role in the evaluation of lymphadenopathy in general and in the evaluation of lymph nodes in dogs with neoplastic disease in particular.
ABBREVIATION
| CI | Confidence interval |
Siemens Sequoia, Siemens, Denmark.
Acuson Aspen, Acuson, Sweden.
Image J 1.33, Rasband, WS, Image J, National Institutes of Health, Bethesda, Md. Available at: rsb.info.nih.gov/ij/index.html. Accessed June 13, 2005.
DICOM (digital imaging and communications in medicine format), Nema, Rossyln, Va. Available at: medical.nema.org/dicom/geninfo/Strategy.htm. Accessed June 13, 2005.
Power ShowCase software, Trillium Technology, Ann Arbor, Mich.
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