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The Tail and the String Sign: New Sonographic Features of Subcutaneous Melanoma Metastasis
Ultrasound in Med. & Biol., Vol. 43, No. 1, pp. 370–374, 2017 Copyright Ó 2016 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/$ - see front matter
http://dx.doi.org/10.1016/j.ultrasmedbio.2016.09.008
d
Clinical Note THE TAIL AND THE STRING SIGN: NEW SONOGRAPHIC FEATURES OF SUBCUTANEOUS MELANOMA METASTASIS ANTONIO CORVINO,*y FABIO CORVINO,* ORLANDO CATALANO,y FABIO SANDOMENICO,y and ANTONELLA PETRILLOy * Department of Advanced Medical Biosciences, University Federico II of Naples (UNINA), Biostructures and Bioimmages Institution (IBB), National Research Council (CNR), Naples, Italy; and y Department of Radiology, National Cancer Institute, Pascale Foundation, Naples, Italy (Received 20 December 2015; revised 6 September 2016; in final form 8 September 2016)
Abstract—No highly specific sonographic imaging findings to evaluate melanoma spread along the lymphatic vessels have ever been described. Between January 2009 and December 2012, a consecutive group of 531 melanoma patients at their initial stage or during follow-up for nodal or extra-nodal superficial metastasis were evaluated retrospectively to assess the presence of two sonographic findings demonstrating superficial lymphatic metastasis: a ‘‘tail’’ sign (a thin hypoechoic prolongation from one or both poles of a superficial metastasis) and a ‘‘string’’ sign (multiple in-transit lesions connected to each other in a rosary image). The total number of superficial metastatic lesions was 222. The tail sign was seen in 13 of the 222 lesions (5.9%). The string sign was detected in four patients (4.5%). These signs showed a low sensitivity with a very high specificity (100%). Tail and string signs may represent an additional finding of high specificity to be employed in the differential diagnosis of melanoma patients. (E-mail: [email protected]) Ó 2016 World Federation for Ultrasound in Medicine & Biology. Key Words: Melanoma, High-resolution ultrasound, Metastasis, Lymph node metastasis, Subcutaneous tissue.
High-resolution ultrasound (US) allows detection of very small melanoma deposits, with a high pathologic correlation (Catalano 2011). In this paper, we illustrate two new US findings recognizable in patients with superficial lymphatic metastasis from cutaneous melanoma. The ‘‘tail’’ sign consists of a thin hypoechoic prolongation from one or both poles of a superficial melanoma metastasis (Fig. 2). Sometimes these prolongations connect multiple in-transit lesions, becoming attached to each other in a rosary image we called the ‘‘string’’ sign (Fig. 3). We believe the tail and string signs are due to the lymphatic vessels filled of melanoma cells, representing a possible presentation of the lymphatic spread.
INTRODUCTION Melanoma cells spread along the lymphatic ducts, from the primary cutaneous lesion toward the lymph node station, draining that area (Dasgupta and Brasfield 1964). Lymph node metastases develop in up to 70% of patients with metastatic melanoma, while in the remaining 30% of cases, tumor cells spread via the bloodstream. The lymphatic diffusion is termed ‘‘satellitosis,’’ when the lesion develops within 2 cm from the primary cutaneous tumor (or its scar, if the tumor has already been excised), and as in-transit metastasis, when the lesion grows at a greater distance (Fig. 1) (Tregnaghi et al. 1997). In the clinical history of many melanoma patients, there are multiple cutaneous or subcutaneous lesions developing along a lymphatic pathway. This is also demonstrated by the so-called interval node metastasis, which is located along the lymphatic course toward the regional lymph node stations, such as epitrochlear, popliteal and locoregional lymph nodes (Thompson et al. 2000).
MATERIALS AND METHODS Patients From a radiology information system/picture archiving and communication system database, we assessed, by using a consensus assessment of two radiologists, the high-resolution US images of 531 consecutive melanoma patients examined between January 2009 and December 2012. These patients underwent sonographic examination in our radiology department at their
Address correspondence to: Antonio Corvino, Via B. Croce n. 82, 81033 Casal di Principe (CE), Italy. E-mail: [email protected] 370
New sonographic features of subcutaneous melanoma metastasis d A. CORVINO et al.
371
Fig. 1. Drawing of loco-regional spread of cutaneous melanoma. Melanoma metastasis is described as satellite metastasis when found within 2 cm from the primary tumor (or its scar) and as in-transit metastasis if the lesion is located at a greater distance.
initial stage or during follow-up for nodal or extra-nodal superficial metastasis. All patients were imaged once and those with lack of adequate US examination available were excluded. All patients with evidence of single or multiple suspected lesions at US examination had undergone free-hand fine-needle cytologic aspiration by US guidance to confirm their nature. Moreover, for every patient, two needle cytologies were carried out on average on each patient during a single setting. Patients’ age ranged from 20–88 y, with a sex distribution of 208 males (39%) and 323 females (61%). US examination The 531 patients underwent a standardized US examination (Catalano et al. 2010), which included a tissue harmonic imaging mode and a power and color Doppler assessment performed with a MyLab 70 XVG and a My-
Fig. 2. (a) The drawing illustrates the tail sign, seen as a small prolongation seen on one or both poles of the nodule. (b) Highresolution ultrasound image shows a melanoma in-transit metastasis in the inguinal region with the tail sign at one pole of the nodule (arrowheads).
Lab 70 Twice scanner (Esaote, Genoa, Italy) equipped with high-resolution multi-frequency linear probes (up to 13 MHz). We used higher frequencies for superficial lesions and lower frequencies for deeper lesions, focusing the beam immediately below the area of interest. For very superficial lesions, we used a gel standoff pad to better focus the beam at the level of the lesion on B-mode scans and to detect intra-lesional flow signals on Doppler imaging. Adopting a trapezoidal field of view or acquiring a real-time extended field of view image were also used to display larger melanoma metastatic lesions and to measure the distance between multiple lesions or between a given lesion and an anatomic landmark such as primary melanoma, melanoma scar or vessels. Color and power Doppler imaging were employed to assess flow signals. We prefer using the power Doppler mode, which on our scanners is more sensitive to slow flow than the color Doppler mode. Power Doppler was set for detecting slow flows, with low pulse repetition frequency (750 Hz), high color gain (just below the noise threshold), high transmission frequency (6.3–7.1 MHz) and minimal filter. We first scanned the skin at the level of the primary tumor (or its scar), 10 cm all around, to rule out satellite metastases. Then, we moved the transducer along the presumable course of the lymphatic vessels, toward the regional lymph nodes, to detect in-transit metastases. We widely explored the lymphatic stations appropriate for each primary melanoma site. In trunk melanomas, we scanned not only the supra-clavicular and axillary nodes, but also the deep pectoral and infra-clavicular nodes. When the primary melanoma was in the head or neck, we explored the cervical stations but also the supraclavicular stations bilaterally. In upper limb and upper trunk melanomas, we also included the supra-clavicular and infra-clavicular stations. When the primary
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Ultrasound in Medicine and Biology
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them were aware of the clinical and other imaging information of patients, except for the cytopathologic results. We recorded the presence of the tail and string signs. The tail sign was defined as a small hypoechoic prolongation seen on one or both poles of the nodule (Fig. 4). The string sign was defined as a hypoechoic band connecting two or multiple nodules. RESULTS
Fig. 3. (a) The drawing illustrates the string sign, seen as a band connecting two or multiple nodules. (b) High-resolution ultrasound image, longitudinal view, shows melanoma in-transit metastasis of the axillary region with the string sign.
melanoma site was at the level of the limbs, we assessed the status of both axillary and inguinal lymphatic basins. We also explored the contra-lateral (axillary or inguinal) lymphatic station. Two radiologists retrospectively reviewed the US imaging examinations of all patients in consensus at an electronic workstation: one (O.C.), a staff radiologist with more than 20 y of experience; and one (A.C.), a current radiology resident with 3 y of experience. Both of
The total number of the superficial lesions suspected for malignancy at US was 222 in 112 patients, with a maximum diameter of 5–44 mm (mean, 16 mm) and a range of 1–12 lesions per patient (mean, three lesions). All 112 patients were subjected to cytology using USguided fine needle aspiration, which proved positive at the cytopathologic examination of satellite and/or intransit metastases in 89 of the 112 patients. Moreover, the tail sign was seen in only 13 patients of 531 (2.4%). It was present at a single lesion pole in eight nodules of 13 (61.5%) and at both poles in the remaining five nodules (38.5%). The lesions were located in eight cases at lower extremities, in three cases at trunk and in two cases at upper extremities. The string sign was detected in four patients (0.75%), all located at lower extremities. All these patients were positive at the cytopathologic examination for metastases. Overall, these two
Fig. 4. High-resolution ultrasound image, longitudinal view. Left image: Melanoma in-transit metastasis in the inguinal region which shows the tail sign (arrowhead). Right image: Directional color-Doppler image rules out the possibility of a vessel (arrow).
New sonographic features of subcutaneous melanoma metastasis d A. CORVINO et al.
diagnostic signs—tail and string—showed low sensitivity (14.6% and 4.5%, respectively), but very high specificity (100% for both signs). DISCUSSION Cutaneous melanoma is one of the most aggressive solid tumors, and its incidence and mortality rates are increasing in most countries (Marks 2000). The aggressiveness of melanoma is characterized by its high metastatic ability and resistance to chemotherapy (Gajewski 2007; Satyamoorthy and Herlyn 2002). Cutaneous melanoma metastasizes frequently via lymphatic systems, which is one of the major prognostic factors for tumor recurrence and survival (Balch et al. 2001). It is fundamental to establish the lymph node status in melanoma patients for the initial staging, therapeutic management, follow-up and prognosis. The N status, that is, the spread to nearby lymph node according to TNM Classification of Malignant Tumours staging, is the best predictor of overall survival, which is considerably greater if only one lymph node is involved and if the diameter of this node is less than 15 mm (Catalano 2011). The impact of US imaging on patient survival is still debated. However, high-resolution US is helpful in assessing all aspects of loco-regional melanomatous diffusion (Solivetti et al. 2014; Voit et al. 2002). Indeed, detection of regional spreading can be proved by US, particularly when it is combined with the color and power Doppler assessment of nodal vasculature and with the sonographically guided fine-needle cytologic analysis, with high sensitivity and specificity, although it has the limitation of missing micrometastases (i.e., intra-nodal deposits ,2 mm) (Catalano et al. 2010). Melanoma metastasis appears in US as superficial hypoechoic nodules, often with low-level internal echoes owing to the poor beam reflection of the melanin. These lesions show irregular or lobulated margins and may carry a posterior enhancement (Uren et al. 1999). Color and power Doppler US may be helpful in demonstrating metastatic lesions because flow signal are encountered in up to 70% of lesions, especially in large ones (Catalano 2011). Melanoma nodules are frequently multiple, and in this case, they are typically aligned along a longitudinal line, pointing toward the regional lymph node station. In many cases, the multiple hypoechoic nodules are of variable size, with the larger one being farther from the primary tumor and closer to the regional lymph nodes (Solivetti et al. 2006; Zbytek et al. 2008). To date, the possibility of sonographically detecting the lymph nodes duct itself along which the metastasis has grown has not been described. Sonographically guided fine-needle aspiration biopsy is the only way to
373
establish the lesion’s nature and for comprehensive genomic analyses currently needed for research and personalized care of melanoma patients (Bohelay et al. 2015; Fornage and Lorigan 1989). However, these US signs are very interesting to better understand the phenomenon of metastasis spread, being illustrative of the type of tumor diffusion. We believe that the small hypoechoic prolongation seen on one or both poles of the nodule in the tail sign represents the dilated lymphatic duct filled with metastatic cells emerging from the nodule and directed toward the lymphatic station draining that area. Moreover, the string sign is seen when lymphatic ducts are completely dilated and filled with tumor cells along their course. Inevitably, we do not have a pathologic confirmation for our hypothesis. However, this theory is supported by the fact that the lesions are positive for malignant cells at cytologic analysis and because patients with superficial melanoma metastasis developing hematogenously (i.e., out of the lymphatic basin of the primary tumor) never showed in our series of the two US findings. This is correct because superficial hematogenous lesions, so frequent in melanoma patients, do not grow along the lymphatic ducts. These two US features we have identified, the tail sign and the string sign, are uncommon, so their use in clinical practice is probably limited. However, they may represent an additional finding to be employed in the differential diagnosis, particularly when the hypoechoic lesion suspected to be a superficial melanoma metastasis is small and shows scarce or absent flow signals. Metastatic melanoma patients undergo a number of post-
Fig. 5. Differential diagnosis between tail sign and lymphatic edema. High-resolution ultrasound image longitudinal view. The image shows two in-transit nodules of the thigh (between calipers) surrounded by lymphatic edema (arrowheads), due to a previous radical inguinal lymphadenectomy. The thin hypoechoic lines due to the accumulated fluid simulate the tail sign.
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expression of the melanoma spread along the lymphatic vessels; however, other studies that can demonstrate direct correlation with histopathologic findings are necessary. These findings may be useful in the differential diagnosis of superficial lesions encountered in melanoma patient. Fig. 6. Differential diagnosis between the string sign and a venous thrombosis. High-resolution ultrasound, longitudinal view, with the use of extended field of view scan. The image shows an in-transit melanoma nodule (arrow) grown adjacent to an external saphenous vein filled with echoic material (arrowheads) due to thrombosis.
treatment changes (surgical and nonsurgical), and may have lymphedema, abnormal vessels or benign cutaneous lesions. The recognition of the tail and string signs can help in the differentiation of these abnormalities. If the operator is not aware of these two findings, they may determine an interpretative mistake. The differential diagnosis of the tail sign and of the string sign includes, on the basis of our experience, the longitudinal hypoechoic bands of lymphedema when adjacent to the subcutaneous nodules (Fig. 5), the normal veins adjacent to the nodules (Fig. 6) and varicose thrombosis changes. However, we believe that these occurrences, and particularly varicose thrombosis, represent more a theoretical problem of diagnosis than a real one. In any case, an adequate knowledge of the US findings allows a proper assessment of the lesions. Moreover, the more common location of these findings at lower extremities appears to be correlated only to our melanoma population and not to a direct correlation because this is the localization more common in our patients. It is important to highlight the limitations of our study. This is a non-randomized, retrospective study where all data were collected through a review of each patient’s medical documents and imaging studies. Being a retrospective analysis, the radiologists were not blinded to patients clinical and other imaging information; consequently, it was not possible to define the inter-observer variability. In addition, the low number of cases, particularly of those exhibiting our two uncommon findings, and the absence of a follow-up study reduce the clinical impact of our study. Finally, we could not obtain a direct histopathological correlation definitely confirming our sonographic hypothesis, but only a cytologic examination; however, these signs are so obvious that it is unlikely that they are related to another cause. CONCLUSIONS In conclusion, we believe that high-resolution US allows displaying the tail sign and the string sign as a direct
REFERENCES Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS, Cascinelli N, Urist M, McMasters KM, Ross MI, Kirkwood JM, Atkins MB, Thompson JA, Coit DG, Byrd D, Desmond R, Zhang Y, Liu PY, Lyman GH, Morabito A. Prognostic factors analysis of 17,600 melanoma patients: Validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2001; 19:3622–3634. Bohelay G, Battistella M, Pages C, de Margerie-Mellon C, Basset-Seguin N, Viguier M, Kerob D, Madjlessi N, Baccard M, Archimbaud A, Comte C, Mourah S, Porcher R, Bagot M, Janin A, De Kerviler E, Lebbe C. Ultrasound-guided core needle biopsy of superficial lymph nodes: An alternative to fine-needle aspiration cytology for the diagnosis of lymph node metastasis in cutaneous melanoma. Melanoma Res 2015;25:519–527. Catalano O. Critical analysis of the ultrasonographic criteria for diagnosing lymph node metastasis in patients with cutaneous melanoma: A systematic review. J Ultrasound Med 2011;30:547–560. Catalano O, Caraco C, Mozzillo N, Siani A. Locoregional spread of cutaneous melanoma: Sonography findings. AJR Am J Roentgenol 2010;194:735–745. Dasgupta T, Brasfield R. Metastatic melanoma. A clinicopathological study. Cancer 1964;17:1323–1339. Fornage BD, Lorigan J. Sonographic detection and fine-needle aspiration biopsy of nonpalpable recurrent or metastatic melanoma in subcutaneous tissues. J Ultrasound Med 1989;8:421–424. Gajewski TF. Failure at the effector phase: Immune barriers at the level of the melanoma tumor microenvironment. Clin Cancer Res 2007; 13:5256–5261. Marks R. Epidemiology of melanoma. Clin Exp Dermatol 2000;25: 459–463. Satyamoorthy K, Herlyn M. Cellular and molecular biology of human melanoma. Cancer Biol Ther 2002;1:14–17. Solivetti FM, Desiderio F, Guerrisi A, Bonadies A, Maini CL, Di Filippo S, D’Orazi V, Sperduti I, Di Carlo A. HF ultrasound vs PET-CT and telethermography in the diagnosis of in-transit metastases from melanoma: a prospective study and review of the literature. J Exp Clin Cancer Res 2014;33:96. Solivetti FM, Di Luca Sidozzi A, Pirozzi G, Coscarella G, Brigida R, Eibenshutz L. Sonographic evaluation of clinically occult intransit and satellite metastases from cutaneous malignant melanoma. Radiol Med 2006;111:702–708. Thompson JF, Hunt JA, Culjak G, Uren RF, Howman-Giles R, Harman CR. Popliteal lymph node metastasis from primary cutaneous melanoma. Eur J Surg Oncol 2000;26:172–176. Tregnaghi A, De Candia A, Calderone M, Cellini L, Rossi CR, Talenti E, Blandamura S, Borsato S, Muzzio PC, Rubaltelli L. Ultrasonographic evaluation of superficial lymph node metastases. Eur J Radiol 1997;24:216–221. Uren RF, Howman-Giles R, Thompson JF, Shaw HM, Roberts JM, Bernard E, McCarthy WH. High-resolution ultrasound to diagnose melanoma metastases in patients with clinically palpable lymph nodes. Australas Radiol 1999;43:148–152. Voit C, Schoengen A, Schw€urzer-Voit M, Weber L, Ulrich J, Sterry W, Proebstle TM. The role of ultrasound in detection and management of regional disease in melanoma patients. Semin Oncol 2002;29: 353–360. Zbytek B, Carlson JA, Granese J, Ross J, Mihm MC Jr, Slominski A. Current concepts of metastasis in melanoma. Expert Rev Dermatol 2008;3:569–585.
http://dx.doi.org/10.1016/j.ultrasmedbio.2016.09.008
d
Clinical Note THE TAIL AND THE STRING SIGN: NEW SONOGRAPHIC FEATURES OF SUBCUTANEOUS MELANOMA METASTASIS ANTONIO CORVINO,*y FABIO CORVINO,* ORLANDO CATALANO,y FABIO SANDOMENICO,y and ANTONELLA PETRILLOy * Department of Advanced Medical Biosciences, University Federico II of Naples (UNINA), Biostructures and Bioimmages Institution (IBB), National Research Council (CNR), Naples, Italy; and y Department of Radiology, National Cancer Institute, Pascale Foundation, Naples, Italy (Received 20 December 2015; revised 6 September 2016; in final form 8 September 2016)
Abstract—No highly specific sonographic imaging findings to evaluate melanoma spread along the lymphatic vessels have ever been described. Between January 2009 and December 2012, a consecutive group of 531 melanoma patients at their initial stage or during follow-up for nodal or extra-nodal superficial metastasis were evaluated retrospectively to assess the presence of two sonographic findings demonstrating superficial lymphatic metastasis: a ‘‘tail’’ sign (a thin hypoechoic prolongation from one or both poles of a superficial metastasis) and a ‘‘string’’ sign (multiple in-transit lesions connected to each other in a rosary image). The total number of superficial metastatic lesions was 222. The tail sign was seen in 13 of the 222 lesions (5.9%). The string sign was detected in four patients (4.5%). These signs showed a low sensitivity with a very high specificity (100%). Tail and string signs may represent an additional finding of high specificity to be employed in the differential diagnosis of melanoma patients. (E-mail: [email protected]) Ó 2016 World Federation for Ultrasound in Medicine & Biology. Key Words: Melanoma, High-resolution ultrasound, Metastasis, Lymph node metastasis, Subcutaneous tissue.
High-resolution ultrasound (US) allows detection of very small melanoma deposits, with a high pathologic correlation (Catalano 2011). In this paper, we illustrate two new US findings recognizable in patients with superficial lymphatic metastasis from cutaneous melanoma. The ‘‘tail’’ sign consists of a thin hypoechoic prolongation from one or both poles of a superficial melanoma metastasis (Fig. 2). Sometimes these prolongations connect multiple in-transit lesions, becoming attached to each other in a rosary image we called the ‘‘string’’ sign (Fig. 3). We believe the tail and string signs are due to the lymphatic vessels filled of melanoma cells, representing a possible presentation of the lymphatic spread.
INTRODUCTION Melanoma cells spread along the lymphatic ducts, from the primary cutaneous lesion toward the lymph node station, draining that area (Dasgupta and Brasfield 1964). Lymph node metastases develop in up to 70% of patients with metastatic melanoma, while in the remaining 30% of cases, tumor cells spread via the bloodstream. The lymphatic diffusion is termed ‘‘satellitosis,’’ when the lesion develops within 2 cm from the primary cutaneous tumor (or its scar, if the tumor has already been excised), and as in-transit metastasis, when the lesion grows at a greater distance (Fig. 1) (Tregnaghi et al. 1997). In the clinical history of many melanoma patients, there are multiple cutaneous or subcutaneous lesions developing along a lymphatic pathway. This is also demonstrated by the so-called interval node metastasis, which is located along the lymphatic course toward the regional lymph node stations, such as epitrochlear, popliteal and locoregional lymph nodes (Thompson et al. 2000).
MATERIALS AND METHODS Patients From a radiology information system/picture archiving and communication system database, we assessed, by using a consensus assessment of two radiologists, the high-resolution US images of 531 consecutive melanoma patients examined between January 2009 and December 2012. These patients underwent sonographic examination in our radiology department at their
Address correspondence to: Antonio Corvino, Via B. Croce n. 82, 81033 Casal di Principe (CE), Italy. E-mail: [email protected] 370
New sonographic features of subcutaneous melanoma metastasis d A. CORVINO et al.
371
Fig. 1. Drawing of loco-regional spread of cutaneous melanoma. Melanoma metastasis is described as satellite metastasis when found within 2 cm from the primary tumor (or its scar) and as in-transit metastasis if the lesion is located at a greater distance.
initial stage or during follow-up for nodal or extra-nodal superficial metastasis. All patients were imaged once and those with lack of adequate US examination available were excluded. All patients with evidence of single or multiple suspected lesions at US examination had undergone free-hand fine-needle cytologic aspiration by US guidance to confirm their nature. Moreover, for every patient, two needle cytologies were carried out on average on each patient during a single setting. Patients’ age ranged from 20–88 y, with a sex distribution of 208 males (39%) and 323 females (61%). US examination The 531 patients underwent a standardized US examination (Catalano et al. 2010), which included a tissue harmonic imaging mode and a power and color Doppler assessment performed with a MyLab 70 XVG and a My-
Fig. 2. (a) The drawing illustrates the tail sign, seen as a small prolongation seen on one or both poles of the nodule. (b) Highresolution ultrasound image shows a melanoma in-transit metastasis in the inguinal region with the tail sign at one pole of the nodule (arrowheads).
Lab 70 Twice scanner (Esaote, Genoa, Italy) equipped with high-resolution multi-frequency linear probes (up to 13 MHz). We used higher frequencies for superficial lesions and lower frequencies for deeper lesions, focusing the beam immediately below the area of interest. For very superficial lesions, we used a gel standoff pad to better focus the beam at the level of the lesion on B-mode scans and to detect intra-lesional flow signals on Doppler imaging. Adopting a trapezoidal field of view or acquiring a real-time extended field of view image were also used to display larger melanoma metastatic lesions and to measure the distance between multiple lesions or between a given lesion and an anatomic landmark such as primary melanoma, melanoma scar or vessels. Color and power Doppler imaging were employed to assess flow signals. We prefer using the power Doppler mode, which on our scanners is more sensitive to slow flow than the color Doppler mode. Power Doppler was set for detecting slow flows, with low pulse repetition frequency (750 Hz), high color gain (just below the noise threshold), high transmission frequency (6.3–7.1 MHz) and minimal filter. We first scanned the skin at the level of the primary tumor (or its scar), 10 cm all around, to rule out satellite metastases. Then, we moved the transducer along the presumable course of the lymphatic vessels, toward the regional lymph nodes, to detect in-transit metastases. We widely explored the lymphatic stations appropriate for each primary melanoma site. In trunk melanomas, we scanned not only the supra-clavicular and axillary nodes, but also the deep pectoral and infra-clavicular nodes. When the primary melanoma was in the head or neck, we explored the cervical stations but also the supraclavicular stations bilaterally. In upper limb and upper trunk melanomas, we also included the supra-clavicular and infra-clavicular stations. When the primary
372
Ultrasound in Medicine and Biology
Volume 43, Number 1, 2017
them were aware of the clinical and other imaging information of patients, except for the cytopathologic results. We recorded the presence of the tail and string signs. The tail sign was defined as a small hypoechoic prolongation seen on one or both poles of the nodule (Fig. 4). The string sign was defined as a hypoechoic band connecting two or multiple nodules. RESULTS
Fig. 3. (a) The drawing illustrates the string sign, seen as a band connecting two or multiple nodules. (b) High-resolution ultrasound image, longitudinal view, shows melanoma in-transit metastasis of the axillary region with the string sign.
melanoma site was at the level of the limbs, we assessed the status of both axillary and inguinal lymphatic basins. We also explored the contra-lateral (axillary or inguinal) lymphatic station. Two radiologists retrospectively reviewed the US imaging examinations of all patients in consensus at an electronic workstation: one (O.C.), a staff radiologist with more than 20 y of experience; and one (A.C.), a current radiology resident with 3 y of experience. Both of
The total number of the superficial lesions suspected for malignancy at US was 222 in 112 patients, with a maximum diameter of 5–44 mm (mean, 16 mm) and a range of 1–12 lesions per patient (mean, three lesions). All 112 patients were subjected to cytology using USguided fine needle aspiration, which proved positive at the cytopathologic examination of satellite and/or intransit metastases in 89 of the 112 patients. Moreover, the tail sign was seen in only 13 patients of 531 (2.4%). It was present at a single lesion pole in eight nodules of 13 (61.5%) and at both poles in the remaining five nodules (38.5%). The lesions were located in eight cases at lower extremities, in three cases at trunk and in two cases at upper extremities. The string sign was detected in four patients (0.75%), all located at lower extremities. All these patients were positive at the cytopathologic examination for metastases. Overall, these two
Fig. 4. High-resolution ultrasound image, longitudinal view. Left image: Melanoma in-transit metastasis in the inguinal region which shows the tail sign (arrowhead). Right image: Directional color-Doppler image rules out the possibility of a vessel (arrow).
New sonographic features of subcutaneous melanoma metastasis d A. CORVINO et al.
diagnostic signs—tail and string—showed low sensitivity (14.6% and 4.5%, respectively), but very high specificity (100% for both signs). DISCUSSION Cutaneous melanoma is one of the most aggressive solid tumors, and its incidence and mortality rates are increasing in most countries (Marks 2000). The aggressiveness of melanoma is characterized by its high metastatic ability and resistance to chemotherapy (Gajewski 2007; Satyamoorthy and Herlyn 2002). Cutaneous melanoma metastasizes frequently via lymphatic systems, which is one of the major prognostic factors for tumor recurrence and survival (Balch et al. 2001). It is fundamental to establish the lymph node status in melanoma patients for the initial staging, therapeutic management, follow-up and prognosis. The N status, that is, the spread to nearby lymph node according to TNM Classification of Malignant Tumours staging, is the best predictor of overall survival, which is considerably greater if only one lymph node is involved and if the diameter of this node is less than 15 mm (Catalano 2011). The impact of US imaging on patient survival is still debated. However, high-resolution US is helpful in assessing all aspects of loco-regional melanomatous diffusion (Solivetti et al. 2014; Voit et al. 2002). Indeed, detection of regional spreading can be proved by US, particularly when it is combined with the color and power Doppler assessment of nodal vasculature and with the sonographically guided fine-needle cytologic analysis, with high sensitivity and specificity, although it has the limitation of missing micrometastases (i.e., intra-nodal deposits ,2 mm) (Catalano et al. 2010). Melanoma metastasis appears in US as superficial hypoechoic nodules, often with low-level internal echoes owing to the poor beam reflection of the melanin. These lesions show irregular or lobulated margins and may carry a posterior enhancement (Uren et al. 1999). Color and power Doppler US may be helpful in demonstrating metastatic lesions because flow signal are encountered in up to 70% of lesions, especially in large ones (Catalano 2011). Melanoma nodules are frequently multiple, and in this case, they are typically aligned along a longitudinal line, pointing toward the regional lymph node station. In many cases, the multiple hypoechoic nodules are of variable size, with the larger one being farther from the primary tumor and closer to the regional lymph nodes (Solivetti et al. 2006; Zbytek et al. 2008). To date, the possibility of sonographically detecting the lymph nodes duct itself along which the metastasis has grown has not been described. Sonographically guided fine-needle aspiration biopsy is the only way to
373
establish the lesion’s nature and for comprehensive genomic analyses currently needed for research and personalized care of melanoma patients (Bohelay et al. 2015; Fornage and Lorigan 1989). However, these US signs are very interesting to better understand the phenomenon of metastasis spread, being illustrative of the type of tumor diffusion. We believe that the small hypoechoic prolongation seen on one or both poles of the nodule in the tail sign represents the dilated lymphatic duct filled with metastatic cells emerging from the nodule and directed toward the lymphatic station draining that area. Moreover, the string sign is seen when lymphatic ducts are completely dilated and filled with tumor cells along their course. Inevitably, we do not have a pathologic confirmation for our hypothesis. However, this theory is supported by the fact that the lesions are positive for malignant cells at cytologic analysis and because patients with superficial melanoma metastasis developing hematogenously (i.e., out of the lymphatic basin of the primary tumor) never showed in our series of the two US findings. This is correct because superficial hematogenous lesions, so frequent in melanoma patients, do not grow along the lymphatic ducts. These two US features we have identified, the tail sign and the string sign, are uncommon, so their use in clinical practice is probably limited. However, they may represent an additional finding to be employed in the differential diagnosis, particularly when the hypoechoic lesion suspected to be a superficial melanoma metastasis is small and shows scarce or absent flow signals. Metastatic melanoma patients undergo a number of post-
Fig. 5. Differential diagnosis between tail sign and lymphatic edema. High-resolution ultrasound image longitudinal view. The image shows two in-transit nodules of the thigh (between calipers) surrounded by lymphatic edema (arrowheads), due to a previous radical inguinal lymphadenectomy. The thin hypoechoic lines due to the accumulated fluid simulate the tail sign.
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Volume 43, Number 1, 2017
expression of the melanoma spread along the lymphatic vessels; however, other studies that can demonstrate direct correlation with histopathologic findings are necessary. These findings may be useful in the differential diagnosis of superficial lesions encountered in melanoma patient. Fig. 6. Differential diagnosis between the string sign and a venous thrombosis. High-resolution ultrasound, longitudinal view, with the use of extended field of view scan. The image shows an in-transit melanoma nodule (arrow) grown adjacent to an external saphenous vein filled with echoic material (arrowheads) due to thrombosis.
treatment changes (surgical and nonsurgical), and may have lymphedema, abnormal vessels or benign cutaneous lesions. The recognition of the tail and string signs can help in the differentiation of these abnormalities. If the operator is not aware of these two findings, they may determine an interpretative mistake. The differential diagnosis of the tail sign and of the string sign includes, on the basis of our experience, the longitudinal hypoechoic bands of lymphedema when adjacent to the subcutaneous nodules (Fig. 5), the normal veins adjacent to the nodules (Fig. 6) and varicose thrombosis changes. However, we believe that these occurrences, and particularly varicose thrombosis, represent more a theoretical problem of diagnosis than a real one. In any case, an adequate knowledge of the US findings allows a proper assessment of the lesions. Moreover, the more common location of these findings at lower extremities appears to be correlated only to our melanoma population and not to a direct correlation because this is the localization more common in our patients. It is important to highlight the limitations of our study. This is a non-randomized, retrospective study where all data were collected through a review of each patient’s medical documents and imaging studies. Being a retrospective analysis, the radiologists were not blinded to patients clinical and other imaging information; consequently, it was not possible to define the inter-observer variability. In addition, the low number of cases, particularly of those exhibiting our two uncommon findings, and the absence of a follow-up study reduce the clinical impact of our study. Finally, we could not obtain a direct histopathological correlation definitely confirming our sonographic hypothesis, but only a cytologic examination; however, these signs are so obvious that it is unlikely that they are related to another cause. CONCLUSIONS In conclusion, we believe that high-resolution US allows displaying the tail sign and the string sign as a direct
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