Lymphadenopathy: Differentiation of Benign from Malignant Disease by Color Doppler Ultrasonography Assessment of Intranodal Angioarchitecture.

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1 Research Article International Journal of advances in health sciences (IJHS) ISSN Vol2, Issue1, 2015, pp Lymphadenopathy: Differentiation of Benign from Malignant Disease by Color Doppler Ultrasonography Assessment of Dhok Avinash and Mitra Kajal Department of Radiodiagnosis, NKP Salve Institute of Medical Sciences and Lata Mangeshkar Hospital Nagpur, India [Received-10/02/2015, Accepted-18/02/2015] ABSTRACT OBJECTIVE: To differentiate reactive from malignant lymphadenopathy by using color Doppler ultrasonographic findings of intranodal blood vessels and compare ultrasonographic findings with biopsy report. MATERIALS AND METHODS: Color Doppler ultrasonography was performed on 60 consecutive patients of cervical,axillary and inguinal lymphadenopathy by high frequency transducer(7-10 MHz) before performance of surgical biopsy and presence of malignant changes in intranodal angioarchitecture was evaluated in each lymph node and compared with biopsy report. Long axis/short axis ratio was also evaluated. RESULTS : Blood vessels in benign lymphadenopathy were dilated,whereas the vessels in malignant lymphadenopathy were compressed by tumor cells.the malignant lymphadenopathy showed high resistivity index value whereas the benign lymphadenopathy showed low resistivity index value. Malignant lymphadenopathy showed long axis/short axis ratio less than 2 and benign lymphadenopathy showed long axis/short ratio more than 2. CONCLUSION: Color Doppler spectral waveform analysis allows distinction between lymph nodes affected by benign versus malignant processes. When high resistivity index is identified in affected lymph nodes, it is almost always involved by metastasis. Keywords: Benign lymphadenopathy, Malignant lymphadenopathy, Color Doppler ultrasonography, Resistivity index,pulsatility index,intranodal angioarchitecture. INTRODUCTION: The diagnosis of superficial lymphadenopathy in the cervical, axillary, and inguinal region is crucial in planning therapy for patients thought to have cancer and in doing a workup for cancer staging. Ultrasonognaphy has been shown to have higher sensitivity than palpation for detecting enlarged lymph nodes in patients who have suspected regional lymph node metastases.(1) The ultrasonographic evaluation of lymph nodes is based primarily on evaluation of their shape

2 and size. Recently, however, the availability of high-frequency transducers have made consideration of internal structure possible. An important objective is to determine whether lymph node enlargement is due to inflammatory or neoplastic processes.(2) Although ultrasonographic criteria for distinguishing these two causes have been defined,ultrasonography alone may not be adequate. Color Doppler ultrasonography provides information about flow and morphology. The use of higher frequency transducers improves the ability to detect lowvelocity signals from superficial structures. Whereas blood vessels in inflammed lymph nodes are dilated, blood vessels in lymph nodes involved by metastases may be compressed by tumor cells.(3) The development of a non invasive, accurate method for assessing tumor vascularity may be useful in the initial differential diagnosis of tumors and in monitoring their response to therapy.(4) The histologic changes seen in lymph nodes in patients with nodal diseases have been used to explain morphologic changes in lymph nodes shown by gray-scale ultrasonography. Histologic changes in vascular structures in nodal disease are not well understood. Lymph nodes involved by malignant disease ( malignant nodes ) may have deformed vascular structures due to distortion of normal nodal architecture by tumor infiltration and neovascularization induced by angiogenesis factor. Therefore. the architecture and the hemodynamics of nodal vessels would differ among various nodal diseases.(5) MATERIALS AND METHODS Study period: 12 months. Sample size: 60 patients. Type of study: Prospective study. Inclusion/Exclusion criteria: Only superficial lymph nodes (Axillary,Cervical,Inguinal) of size 2 cm or more were included. The largest node was evaluated in case of multiple lymph nodes. The patient included men & women years old. Study done on color Doppler ultrasonography machine (Esaote mylab-50). Color Doppler ultrasonography is performed in 60 consecutive patients of superficial lymphadenopathy before performance of surgical biopsy and presence of malignant changes in intranodal angioarchitecture have been evaluated in each lymph node and findings compared with biopsy report. Color Doppler ultrasonography was performed with a linear high frequency Transducer.(7-10MHz.). Each lymph node was assessed completely by means of transverse movement of Transducer in both planes to obtain a virtually 3-D depiction of intranodal angioarchitecture.color Doppler signals were regarded as intranodal flow signals only if the flow could be located intranodally in both planes. Standardized parameter setting was used optimally for detection of slow flow velocities in small vessels. The size and exact location of assessed lymph node was reported to surgeon.in addition, skin markers were applied if necessary. After adequate observation of the lymph node with gray scale ultrasonography,the color Doppler examination was performed. In all examinations,flow towards the transducer was assigned as red & flow away from the transducer was assigned as blue.after color display of blood flow in the lymph node is stabilized,the flow velocity pattern was determined. Pulsed Doppler velocity signals were sampled under the guidance of color Doppler ultrasonography.to optimize flow velocity & waveform measurement,we observed color flow from various directions by changing the locations and angles of the transducer to minimize Doppler angle. Lymph node shape on high resolution Dhok Avinash and Mitra Kajal 83

3 ultrasonography was assessed in a prospective and blind manner by measuring the largest longitudinal (L) & transverse (T) diameter on the same scan and by calculating the L/T ratio.peripheral impedance was then assessed using resistivity index (RI),by Doppler flow analysis with peak systolic flow velocity(psv) and end diastolic flow velocity (EDV). Resistivity index (RI) and Pulsatility index (PI) was calculated. In the lymph nodes with multiple color flow patterns,the area of fastest flow or next fastest flow was selected for analysis.histopathologic diagnosis of these same lymph nodes were made from ultrasonographically guided fine needle aspiration biopsy and/or excisional biopsy. Thirty eight patients underwent ultrasonographically guided fine needle aspiration biopsy from the largest lymph node,twelve patients underwent excisional biopsy and ten patients had both types of examination for further clarification of the histopathologic picture.the region of interest was scanned slowly with minimal transducer pressure,because compression with the transducer can obliterate color signals. RI=PSV-EDV/PSV. PI=PSV-EDV/Time averaged MV. A pathologic diagnosis was made in all 60 patients by ultrasonographically guided biopsy or excisional biopsy. The 46 lymph nodes (patients with histological evidence of inflammatory or benign disease) were followed up clinically & ultrasonographically for 1-12 months. During this period,in which only antibiotics or no therapy was administered,those nodes that either disappeared at repeat ultrasonography or decreased markedly in size were considered to be affected by benign process. Pathologic examination of 14 of 60 lymph nodes involved with metastasis revealed ( 5 Squamous cell carcinoma,7 Adenocarcinoma,1 Melanoma,1 Poorly differentiated carcinoma ) & 46 lymph nodes affected by benign processes ( 21 Tubercular Lymphadenitis,13 chronic inflammation & 1 reactive hyperplasia).the remaining 11 lymph nodes were considered to be affected by benign processes because,they either disappeared at repeat ultrasonography or decreased markedly in size. RESULTS: Color Doppler Sonography showed blood flow in all cases. Out of 60 lymph nodes studied,14 enlarged lymph nodes (100%) with short axis diameter more than 1 cm were all malignant.44(95.6%) out of 46 lymph nodes with short axis diameter less than 1 cm were benign.2 lymph nodes with short axis diameter more than 1 cm were found benign.44 out of 44 enlarged lymph nodes with long axis /short axis ratio more than 2 were found benign,whereas out of 16 enlarged lymph nodes with long axis/short axis ratio less than 2,14 lymph nodes (87.5) were found malignant while 2 enlarged lymph nodes (12.5%) were benign. 14 out of 14 malignant lymph nodes (100%) had resistivity index more than 0.7,whereas 44 out of 46 benign lymph nodes (95.6 % ) had resistivity index less than 0.7. Two benign enlarged lymph nodes had resistivity index more than 0.7.The resistivity indexes from vessels of lymph nodes involved with metastasis showed mean value of 0.95+/ & the resistive indexes from vessels of lymph nodes affected by benign processes showed mean value of / The mean pulsatility index value was 2.61+/ in lymph nodes involved with metastasis & 0.91+/ in lymph nodes affected by benign processes. Lymph nodes involved with metastasis showed a characteristic high resistivity index (> 0.7) & high pulsatility index ( >1) in 14 of 14 lymph nodes. The resistivity and pulsatility indexes were significantly different (p < 0.005) between the two groups of lymph nodes. None of the lymph nodes affected by benign processes had high resistive index ( most were <0.7).High pulsatility index ( > 1) were found in 14 of 14 lymph nodes involved with metastasis.none of the lymph Dhok Avinash and Mitra Kajal 84

4 nodes affected by benign processes had high pulsatility index ( most were <1). The peak systolic velocity ( PSV) from vessels of lymph nodes involved with metastasis ranged from 7-44 cm/sec. with a mean of 24 +/- 1.6 cm/sec. The peak systolic velocities (PSV) from vessels of lymph nodes affected by benign processes ranged from 8-78 cm/sec.with mean of 24 +/- 14 cm/sec.the end diastolic velocities ( EDV) from vessels of lymph nodes involved with metastasis ranged from -11 cm/sec ( reverse flow in diastolic phase ) to 14 cm/sec.with mean of 2 +/- 6.3 cm/sec. the end diastolic velocities from vessels of lymph nodes affected by benign processes ranged from 3-51 cm/sec.with mean of 12+/- 9.1 cm/sec. Although the peak systolic velocities were not significantly different between the two groups of lymph nodes,the end diastolic velocities were significantly different (p <0.005 ) between the two groups. DISCUSSION: In 1973 Mountford & Atkinson(6) reported that pathologically enlarged lymph nodes gave rise to significant Doppler shift signals by means of Doppler flow meter.in 1992 Swischuk et al.(7) reported that all enlarged lymph nodes,whether affected by benign or malignant processes, showed flow signals. Later Chang et al.(1) reported that Color Doppler Sonography showed flow signals in 6 of 16 lymph nodes affected by benign processes & 29 of 32 lymph nodes affected by malignant processes. In our study,color Doppler Sonography showed blood flow in all affected lymph nodes. Why did the study by Chang et al.fail to reveal flow in some affected lymph nodes?.the reason is the use of different methods,equipment & techniques.the ability to detect color flow pattern within a small lymph node depends on transducer & equipment used. High frequency transducers have greatly improved the ability to detect superficial low velocity signals.failure to find a pulsed Doppler signal may be the result of faulty machine settings such as wall filter,velocity scale & Doppler gain. High filter level obliterates low velocity flow.a high velocity scale settings or gain setting that is too low will also obliterate low velocity flow.during evaluation of superficial lesions with Color Doppler ultrasonography,scanning with minimal probe pressure is important,because even light compression with the probe can obliterate low velocity flow.chang et al.reported that,lymph nodes affected by malignant processes shows low resistivity index (<0.6) in 26 of 32 cases. In our study,lymph nodes affected with metastasis showed high resistivity index in 14 of 14 cases.the difference in results reflects an important difference in methodology.chang et al.sampled spectral waveforms from eight different sites & selected the lowest resistivity index.we sampled spectral waveforms from the area of fastest flow or next fastest flow in lymph node.inflammation produces vasodilatation which increases blood flow to the area.it is reported that resistive index was decreased in patients who had Orchitis & Epididymitis(8,9).Chang et al.believed that the reasons,lymph nodes affected by malignant processes had a lower resistive index,were the lack of muscle layer in tumor vessels & presence of arterio-venous shunts.although arterio-venous shunts & lack of muscular element in some malignant tumors have been reported (10,11),they have not been reported in lymph nodes involved with metastasis.whereas inflammed lymph nodes are enlarged because of cellular infiltration & edema,lymph nodes involved with metastasis are enlarged because of the spread & growth of cancer cells or reactive hyperplasia.in the early stages of metastasis to lymph nodes,tumor emboli occupy small portion of lymph node.as tumor cells spread into lymph nodes & the tumor cells grow,tumor cells replace large portion of lymph node.finally the lymph node is totally replaced by tumor cells(12).at this stage,we postulate that,vessels in lymph nodes are compressed by Dhok Avinash and Mitra Kajal 85

5 tumor cells because the lymph node has a limited space.this vascular compression by tumor cells would increase vascular resistance,causing an increase in resistivity index.in our study,lymph nodes involved with metastasis showed high resistivity index (> 0.7),high pulsatility index ( >1) in 14 of 14 cases) & a low end diastolic velocity ( 2+/- 6.3 cm/sec.).lymph nodes affected by benign processes showed low resistivity index (<0.7), low pulsatility index ( <1) & high end diastolic velocity ( 12+/- 9.1 cm/sec).our study shows that resistivity indexes,pulsatility indexes & end diastolic velocities are significantly different(p <0.005),between the lymph nodes affected by benign versus malignant processes. Limitations to our study was,the number of lymph nodes involved with metastasis is small.a study of larger population is desirable to draw conclusions.a second limitation is the lack of histologic proof of the cause of high resistivity index & high pulsatility index in the lymph nodes involved with metastasis. We did not investigate how large a portion the lymph node was replaced by tumor cells in lymph nodes showing high resistivity index. CONCLUSION: Color Doppler ultrasonography can show blood flow in all lymph nodes,regardless of whether they are affected by benign or malignant process & a spectral waveform analysis allows distinction between lymph nodes affected by benign versus malignant processes.color Doppler ultrasonography is a non invasive adjunct to routine ultrasonography.when a characteristic high resistive index is identified in affected lymph nodes,the lymph nodes in question are almost always involved by metastasis. REFERENCES: 1. Chang DB, Yuan A, Yu CJ, Luh KT, Kuo SH,Yang PC.Differentiation of benign and malignant cervical lymph nodes with color Doppler sonography. AJR 1994;162: Rubaltelli L, Proto E, Salmaso R, Bortoletto P, Candiani F,Cagol P.Sonography of abnormal lymph nodes in vitro: correlation of sonographic and histologic findings. AJR 1990;155: Choi MY, Lee JW, Jang KJ.Distinction between benign and malignant causes of cervical,axillary, and inguinal lymphadenopathy: value of Doppler spectral waveform analysis. AJR 1995;165: Taylor GA,Perlman EJ,Scherer LR,Gearhart JP,Leventhal BG,Wiley J. Vascularity of tumors in children: evaluation with color Doppler imaging. AJR1991;157: Na DG,Lim HK,Byun HS, Kim HD, Ko YH,Baek JH.Differential diagnosis of cervical lymphadenopathy: usefulness of color Doppler sonography. AJR 1997;168: Mountford RA,Atkinson P.Doppler ultrasound examination of pathologically enlarged lymph nodes.br.j Radiol 1979;52: Swischuk LE,Desai PB,John SD.Exuberant blood flow in enlarged lymph nodes:findings on color flow Doppler.Pediatr Radiol 1992;22: Horstman WG,Middleton WD,Melson GL.Scrotal inflammatory disease:color Doppler US findings.radiology 1991;179: Lerner RM,Mevorach RA,Hulbert WC,Rabinowitz R.Color Doppler US in the evaluation of acute scrotal disease.radiology 1990;176: Strickland B,The value of arteriography in the diagnosis of bone tumors.br.j Radiol 1959;32: Okuda K,Musha H,Yamasaki T,et al.angiographic demonstrations of intrahepatic arterioportal anastomoses in hepatocellular carcinoma.radiology 1977;122:53-58 Dhok Avinash and Mitra Kajal 86

6 12. Jing BS,Wallace S,Zornoza J.Metastasis to retroperitoneal and pelvic lymph nodes.radiol Clin North Am 1982; 20: Vassalo P,Wernecke K,Roos N,Peters P.Differentiation of benign from malignant superficial lymphadenopathy:the role of high high-resolution US.Radiology 1992;183: Schor AM,Schor SL.Tumor angiogenesis.j pathol 1983;141: FIGURES AND TABLES: Figure: 1 Benign Cervical Lymphadenopathy. PI:0.74, RI:0.52, EDV:4.2 cm/sec Figure: 2 Carcinoma Tongue with submandibular lymphadenopathy. PI:1.94, RI:0.78, EDV:3.9 cm/sec Dhok Avinash and Mitra Kajal 87

7 Figure: 3 Carcinoma Penis with imguinal lymphadenopathy. PI:1.24, RI:0.76, EDV: -11.7cm/sec TABLE: Color Doppler ultrasonography Histopathology Dhok Avinash and Mitra Kajal 88