Measurement of spleen stiffness by shear-wave elastography for prediction of splenomegaly etiology

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Measurement of Spleen Stiffness by Shear-Wave

Elastography for Prediction of Splenomegaly Etiology

Abdussamet Batur, MD,* Sumeyra Alagoz, MD,

† Fatma Durmaz, MD,†

Ali Irfan Baran, MD,

‡ and Omer Ekinci, MD§

Objective: The aim of this study was to evaluate the reproducibility of measurement of spleen stiffness at the time of the initial detection of splenomegaly, whether it is found incidentally or not, in determining the etiology of splenomegaly.

Methods: The pathologies that brought about the diffuse splenomegaly were evaluated in 3 main groups as follows: hepatoportal, myeloprolif-erative, and infectious causes. In addition, 17 healthy control patients were recruited. All patients were examined with acoustic radiation force impulse imaging with VTQ.

Results: The difference between the splenic parenchymal elasticity values in the hepatoportal group (3.27 ± 0.36 m/s), in the myeloprolif-erative disease group (2.98 ± 0.33 m/s), in the infectious disease group (2.44 ± 0.21 m/s), and in the control group (2.08 ± 0.19 m/s) was found to be statistically significant (P = 0.001). The intraclass correlation co-efficient for shear wave velocity measurement between hepatoportal causes and myeloproliferative causes was 71.2% (95% confidence

in-terval [CI], 54.9%–87.4%), between hepatoportal causes and infective

causes was 99.7% (95% CI, 98.6%–100.0%), and between

myelopro-liferative causes and infective causes was 83.3% (95% CI, 68.8%– 97.9%). In the same patient groups, spleen volumes were measured

as 64.08 ± 9.66, 78.18 ± 18.52, and 51.57 ± 7.44 cm2, respectively;

in the control group, it was 26.75 ± 6.57 cm2. The difference between

spleen volumes was found to be statistically significant (P = 0.001). Conclusions: Distinguishing the causes of splenomegaly is important because the disorders require different management strategies. In dis-eases that cause splenomegaly, tissue content may change according to pathogenesis. Such changes in the spleen are mechanical properties that can be quantified by elastography.

Key Words: acoustic radiation force impulse imaging, elastography, spleen stiffness, splenomegaly

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plenomegaly is a frequent yet challenging sign clinicians have to deal with in daily practice. A true diagnostic di-lemma hides in distinguishing pathologic conditions primarily

involving the spleen from those in which splenomegaly pre-sents itself as an epiphenomenon of hepatic or systemic dis-eases.1The list of conditions associated with splenomegaly is extensive, and nearly all diseases of spleen are of a secondary nature.2The difficulty with splenomegaly is that many signs, test results, and symptoms that may be elicited are common to various conditions: some benign and self-limiting, some in-fective and others malignant.2_{Such nonspecific pictures often}

cause patients to undergo extensive investigation by physicians of diverse subspecialties.1

B-mode ultrasonography (US) can provide key pieces of information regarding the echo texture of the splenic paren-chyma, allowing the detection of focal lesions with a high sensi-tivity. By contrast, B-mode US displays poor sensitivity when a diffuse effacement of the spleen occurs,1_{whereas elastography}

may help identify patients with liver-unrelated diseases of the spleen such as hematologic disorders.3An US-based elastography technique, acoustic radiation force impulse, provides elastograms and also defines some parameters of soft tissue such as peak dis-placement, period of time to reach peak disdis-placement, and recov-ery time. point shear wave elastography (P-SWE) was used.4It is based on a combination of the radiation force induced in tissue by a US beam and an ultrafast imaging sequence capable of captur-ing the propagation of the resultcaptur-ing shear waves, which is im-pacted by the local viscoelastic properties of tissue, and it can be used to estimate tissue stiffness.5,6

The aim of this study was to evaluate the reproducibility of measurement of spleen stiffness at the time of the initial de-tection of splenomegaly, whether it is found incidentally or not, in determining the etiology of splenomegaly while mini-mizing unnecessary investigations and anxiety for the patient.

MATERIALS AND METHODS

Patients

Ultrasound elastography and B-mode sonography were used for the evaluation of the patients who applied to our clinic with a splenomegaly diagnosis made at an external center, or who at our clinic were thought to have splenomegaly, and did not receive any treatment. Spleen size was calculated in the form of a cross-sectional spleen area in the US images by using the following formula: the cross-section area (cm2) = lon-gest diameter (cm) shortest diameter (cm), and a diagnosis of splenomegaly was made if the area was 40 cm2or greater.7 Seventy-three participants (42 men, 31 women) with detected splenomegaly were enrolled in our study between October 2014 and February 2017. The study was confirmed by a local ethics

Received for publication June 6, 2018; accepted July 16, 2018.

*Department of Radiology, Selcuk University School of Medicine, Konya, Turkey; †Department of Radiology, Yuzuncuyil University Dursun Odabas Medical Center, Van, Turkey;‡Department of Infectious Diseases and Clinical Mi-crobiology, Yuzuncuyil University Dursun Odabas Medical Center, Van, Turkey; and §Department of Hematology, Yuzuncuyil University Dursun Odabas Medical Center, Van, Turkey.

The authors declare no conflict of interest.

Address correspondence to: Abdussamet Batur, MD, Department of Radiology, Selcuk University School of Medicine, Yeniİstanbul St, 42130, Konya, Turkey (e‐mail: baturabdussamet@gmail.com).

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committee, and each patient was informed and showed consent to participate in this study.

B-mode and elastographic examinations were performed without having any knowledge about the patient's history and laboratory and imaging findings, and the obtained data were re-corded. The splenic shear wave velocity (SWV) values were compared after the pathologies, which caused the splenomeg-aly, were determined. The pathologies that brought about the diffuse splenomegaly were evaluated in 3 main groups as fol-lows: hepatoportal, myeloproliferative, and infectious causes. Splenomegaly secondary to portal hypertension was diagnosed on the basis of clinical features and dilatation of the splenic vein or associated varices. The myeloproliferative group of disorders was diagnosed by microscopic examination of peripheral blood and bone marrow samples. Splenomegaly secondary to infec-tious diseases was diagnosed on the basis of serologic tests (Brucellosis was diagnosed on the basis of significant titers de-termined to be≥1/160 in the standard tube agglutination test. In-fectious mononucleosis was diagnosed on the basis of elevated levels of VCA-IgM and VCA-IgG antibody with negative IgG anti-EBNA. Diagnosis of tuberculosis was established accord-ing to culture and polymerase chain reaction analysis. Diagnosis of typhoid was established according to culture and significant titers determined to be ≥1/200 in the Gruber-Widal test.), in-creased fever, and white blood cell with excluding hepatoportal and myeloproliferative disorders. In addition, 17 healthy control patients were recruited. They had no substantial medical his-tory, including diabetes or hypertension, alcohol intake, or hep-atitis serology and no biochemical or US features of liver or splenic disease.

Technique

All patients were examined with P-SWE imaging with VTQ that was conducted using an ACUSON S2000 US system (Siemens, Mountain View, Calif ) with a convex broadband (6 MHz) while the patients were lying in the right decubitus po-sition and with their left arm in maximum abduction. When the VTQ mode was activated, patients were told to hold their breath in neutral position. In each patient, we measured spleen stiffness by means of P-SWE, 1 to 2 cm under the spleen capsule. The region of interest was free of“visible” vessels. All elastographic examinations were performed by a single sonographer. The op-erator was blinded to the clinical and laboratory data.

Measurement of spleen stiffness was performed through left intercostal and subcostal examination at 3 sites: upper pole, hilum, and lower pole. Three measurements were performed at each site of the spleen. In each patient, median values from 9 successful measurements were calculated and expressed as me-ters per second (m/s). Spearman correlation test was used to

evaluate the relationship between spleen volume and splenic elasticity in all groups where splenomegaly was detected and in the control group.

RESULTS

Overall, 73 subjects (19 with hepatoportal diseases [cir-rhosis], 21 with myeloproliferative [8 patients with chronic myeloid leukemia , 4 with Hodgkin lymphoma, 4 with acute lymphocytic leukemiaacute, 3 with chronic lymphocytic leuke-mia and 2 with thalasseleuke-mia], 16 with infectious disease [7 patients with brucellosis, 4 with infectious mononucleosis, 3 with tuber-culosis, and 2 with typhoid], and 17 normal patients) were stud-ied. The main demographic characteristics of the patients are summarized in Table 1. In the elastographic evaluation, splenic parenchymal elasticity was found to be 3.27 ± 0.36 m/s in the hepatoportal group, 2.98 ± 0.33 m/s in the myeloproliferative disease group, 2.44 ± 0.21 m/s in the infectious disease group, and 2.08 ± 0.19 m/s in the control group.

The difference between the splenic parenchymal elasticity values was found to be statistically significant (P = 0.001). Receiver operating characteristic curve for distinguishing hepatoportal causes from myeloproliferative causes is shown in Figure 1A. An SWV cutoff value of greater than 3.10 m/s yielded sensitivity and specificity values of 68.4% and 71.4%, respectively, for differ-entiation. The intraclass correlation coefficient for SWV measure-ment was 71.2% (95% confidence interval [CI], 54.9%–87.4%). Receiver operating characteristic curve for distinguishing hepatoportal causes from infective causes is shown in Figure 1B. An SWV cutoff value of greater than 2.77 m/s yielded sensitiv-ity and specificsensitiv-ity values of 94.7% and 100%, respectively, for differentiation. The intraclass correlation coefficient for SWV measurement was 99.7% (95% CI, 98.6%–100.0%). Receiver operating characteristic curve for distinguishing myeloprolifer-ative causes from infective causes is shown in Figure 1C. An SWV cutoff value of greater than 2.75 m/s yielded sensitivity and specificity values of 85.7% and 89.9%, respectively, for dif-ferentiation. The intraclass correlation coefficient for SWV measurement was 83.3% (95% CI, 68.8%–97.9%). In the same patient groups, spleen volumes were measured as 64.08 ± 9.66, 78.18 ± 18.52, and 51.57 ± 7.44 cm2_{, respectively; in the control}

group, it was 26.75 ± 6.57 cm2. The difference between spleen volumes was found to be statistically significant (P = 0.001).

In the evaluation of splenic elasticity and spleen volume relationship in the disease groups and control group, the Spear-man correlation test results were found to be 0.687 (P = 0.001) in the hepatoportal disease group, 0.451 (P = 0.040) in the myeloproliferative disease group,−0.148 (P = 0.584) in the infective patient group, and−0.119 (P = 0.649) in the control group (Figs. 2A–D).

TABLE 1. Main Demographic Characteristics of the 73 Patients

Hepatoportal Diseases Myeloproliferative Diseases Infectious Diseases Normal Patients

No. cases 19 21 16 17

Sex (male/female) 13/6 13/8 6/10 10/7

Age, mean (SD), y 51 (10.1) 58 (11.7) 42 (9.6) 43 (12)

Spleen size, median (SD), cm2 67.0 (9.66) 86.1 (18.52) 50.3 (7.44) 27.0 (6.57)

Spleen stiffness, median (SD), m/s 3.27 (0.36) 2.96 (0.33) 2.45 (0.21) 2.15 (0.19)

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FIGURE 1. A, Receiver operating characteristic curve for distinguishing hepatoportal causes from myeloproliferative causes, (B) for distinguishing hepatoportal causes from infective causes, (C) for distinguishing myeloproliferative causes from infective causes.

FIGURE 2. In the evaluation of splenic elasticity and spleen volume relationship in the disease and control groups, the Spearman correlation test results were found to be 0.687 (P = 0.001) in the hepatoportal disease group, 0.451 (P = 0.040) in the myeloproliferative

disease group,−0.148 (P = 0.584) in the infective patient group, and −0.119 (P = 0.649) in the control group.

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DISCUSSION

The causes of splenomegaly are numerous, including he-matologic, vascular, neoplastic, infectious, and immunologic disorders, as well as storage diseases. Splenomegaly is conse-quently only a manifestation of a splenic disorder, not a specific entity, and is in fact the most common pathological finding.8 Distinguishing between aforementioned pathologies is important because the disorders require different management strategies.

Because gray-scale sonography displays poor sensitivity, elastography may help identify patients for the etiology of splenomegaly.1,3_{The density of the spleen changes in patients}

with an enlarged spleen because of tissue hyperplasia, fibrosis, and splenic congestion. Such changes in the spleen are mechan-ical properties that can be quantified by elastography.9,10

Although the precise pathogenic mechanisms causing splenomegaly are still poorly elucidated, it is likely due to pulp hyperplasia, congestion from increased blood flow, and fibrosis in patients with liver disease7,11; progressive enlargement of the spleen volume and vascularity with the expansion of red pulp, increased red cell pool, and expansion of reticular elements in patients with hematologic disorders3; and increase in lymphocytes and neutrophils, aggregate of organisms with necrosis, sometimes follicular and marginal zone hyperplasia, and vasculitis in large-caliber vessels in patients with infectious disorders.12,13

In our study, the mean spleen stiffness value in cirrhotic patients was 3.27 ± 0.36 m/s, which was similar with the value of 3.24 ± 0.44 m/s in a study by Ye et al,9_{and which was}

slightly higher than the value of 3.10 ± 0.55 m/s in a study by Bota et al.14The mean spleen stiffness value in myeloprolifera-tive disorders was 2.98 ± 0.33 m/s, which was lower than the value of 55.6 kPa (4.30 m/s) in a study by Fraquelli et al.3To our knowledge, there are no elastography studies on splenomeg-aly due to infective involvement. In our study, the SWV values of the patients in this group were found to be 2.44 ± 0.21 m/s. Our findings showed that elastography may play an important role in the differentiation of the 3 most common disease groups that are involved in the etiopathogenesis of splenomegaly.

In the splenomegaly, the spleen volume and spleen SWV values increase significantly in the hepatoportal and myelopro-liferative groups. However, in the comparison of the 2 groups, spleen stiffness was not observed to be correlated with volume increase. This finding suggests that both congestion and fibrosis play a significant role in the mechanism of hepatoportal spleno-megaly development.7When compared with the myeloprolifer-ative group, fibrosis limits spleen growth; however, it increases tissue stiffness due to its tight structure. In the myeloprolifer-ative group, where the cellular increase is at the forefront, the SWV values were lower than the hepatoportal group, as it does not provide tissue stiffness as much as fibrosis, despite having the largest spleen size. In the infection-induced splenic involvement, the expected increase in spleen stiffness could not be achieved because of cell-tissue damage caused by

vasodilatation and inflammation, although there is an increase in the inflammatory cells.13,15

CONCLUSIONS

The causes of splenomegaly are numerous, including he-matologic, vascular, neoplastic, infectious, and immunologic disorders, as well as storage diseases. Distinguishing between these pathologies is important because the disorders require dif-ferent management strategies. Although the precise pathogenic mechanisms are still poorly elucidated, in diseases that cause splenomegaly, tissue content may change according to patho-genesis. Such changes in the spleen are mechanical properties that can be quantified by elastography.

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12. O'Malley DP, George TI, Orazi A, et al. Armed Forces Institute of Pathology: Benign and Reactive Conditions of Lymph Node and Spleen. Silver Spring, MD: American Registry of Pathology Press; 2009:143–156. 13. Kumar V, Abbas AK, Fausto N, et al. Acute and chronic inflammation. In: Kumar V, Abbas AK, Fausto N, et al, eds. Robbins Basic Pathology. 8th ed. Philadelphia, PA: Saunders; 2007:31–44.

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