Ultrasonographic evaluation of superficial lymph node metastases in melanoma

EUROPEAN JOURNALOF

RADIOLOGY ELSEVIER

European Journal of Radiology 24 (1996) 216 221

Ultrasonographic evaluation of superficial lymph node metastases in melanoma Alberto Tregnaghi *", Alessandro De Candia", Milena Calderone", Lisa Cellini", Carlo Riccardo Rossi b, Enrico Talent?, Stella Blandamura ~, Simonetta Borsato d, Pier Carlo Muzzio ;', Leopoldo RubaltellP "Departmcnt o! Radiology, t)m'ersity o[ Padua. Padua. Italy hDeparmn'nt o/ Surgery II, l :niversity qf Padua. Padua. Italy ~'Department o/ Pathology, l.)m'er~ity o! Padua, Padua, Itall' dD~Tartment O! Cytology. Unirersity oJ Pa~hm. Pa~hm. ltalv Received 9 May 1996: revised 4 September 1996: acceptcd 5 September 1996

Abstract The aims of the present work were to assess the diagnostic accuracy of ultrasonographic evaluation of superficial lymph nodes in patients with cutaneous melanoma and to describe the sonographic characteristics which permit early detection of neoplastic nodal involvement. Eighty-seven patients (89 lymph node sites) were studied for approximately a 3-year period, with a minimal surveillance time of 1 year. The ultrasonographic imaging equipment utilized were a 10 MHz scanner with a mechanical and one with 10 MHz electronic linear probe. The characteristics considered indicative of possible metastatic involvement were: round shape (short to long axis ratio > 0.5), no central hilus, nodular areas within the lymph node, sinuosity of the lymph node edges and lymph node with regular morphology and echostructure but with maximum diameter greater than 3 cm. Generally inguinal and axillary lymph nodes are larger than cervical ones. Of the 89 sites explored, 32 were considered "suspect'. All 32 of these were subjected to cytology using ultrasound-guided, fine needle aspiration. The remaining 56 came in for a periodic control examination during a year. Thirteen of the 32 'suspect' lymph nodes proved positive at the pathologic examination. Two patients whose ultrasound diagnosis was negative developed metastases within 2 to 4 months (ultrasound false negatives). Our study indicates that there are sonographic features indicative of lymph node metastases from melanoma even in the early stages of the disease. Ultrasound scanning, therefore, is a useful diagnostic tool in the follow-up of melanoma patients, identifying which should be subjected to further testing with needle biopsy. ~" 1997 Elsevier Science Ireland Ltd. Ke.vwords: l.ymphatic system: Diseases-lymphatic system; Neoplasms-lymphatic system: Ultrasound: melanoma

I. Introduction

Cutaneous melanoma is a neoplasm whose development is aggressive and often unpredictable. Its incidence has been estimated at approximately 1.6 new cases per 100 000 persons per year [1]. From histologic and surgical viewpoints, Breslow and Clark [2-8] classified its various stages of development, an expression of the disease's regional dissemination. It is known that dissemination of metastases from melanoma occurs primarily through the lymphatic system. involving the nodal group corresponding to the original cancer site [ 9 12]. The percent of patients who develop metastases from

a primary tumor varies from study to study, running at 42 59% for skin and lymph node, 18 36% for lung. 14 20% for liver. 12 20% for brain and 11-17% for bone tumors [9. 19]. The survival rate after 10 years is 85% for patients in Stage I, 60% for those in Stage 11, 25% for those in Stage III and 1% for those in Stage 1V [171. When monitoring patients who have been surgically treated for melanoma, periodic observation of the draining lymphatic vessels corresponding to the area of surgical resection is of vital importance. The aim of the present work is to assess the diagnostic accuracy of ultrasound evaluation of superticial lymph nodes in patients with cutaneous melanoma and

0720-048X97.SI7.00 "c 1997 Elsevier Sciencc Ireland Lid. All rights reserved PII S0720-048XI96)01102-3

A. Tregnaghi et al. : European Journal ~/ Radiology 24 (1997) 216 - 221

to identify sonographic features permitting an early detection of metastatic nodal involvement. Patients were controlled with histology or with echographic and clinical follow-up of 1 year.

2.

Materials

and

methods

Patient population Eighty-seven patients who had undergone surgical resection of cutaneous melanoma were subjected to sonographic evaluation of the nodal groups considered the primary drainage for the tumor. Sonographic examination was repeated at approximately 6-month intervals in almost all the patients over a 3-year period. The minimal surveillance time was 1 year. Patient age ranged from 20 to 88 years, with a sex distribution of 34 males (39'70) and 53 females (61%). Inguinal, axillary and cervical sites were examined in these patients utilizing an Ansaldo AU530 scanner (Esaote, Genoa, Italy) with a 10 MHz mechanical sector probe and with a Esaote AU4 Idea with a 10 M Hz electronic linear probe. Eighty-seven patients were considered. The overall number of sites investigated came to 89 (rather than 87) because melanoma in one patient was located in a dorsal position which was the same distance from the groin and the axilla, causing us to study both nodal basins. Moreover, one patient underwent two biopsy procedures because sonographic examination on two different occasions, was defined positive because of alterations in two different criteria. This patient was, thus, counted twice. So we considered 5 laterocervical and supraclavear, 33 axillary and 51 inguinal sites. All patients underwent periodic clinical examinations which permitted a comparison between the sonographic and clinical parameters. The sonomorphological features evaluated were: size, shape (round or oval), the transverse/longitudinal diameter ratio (T/L), type of" edges (sinuous or linear), absence or presence of a central hyperechogenic area, an expression of the medulla and lack of nodal architecture homogeneity, as demonstrated by the presence ot" focal hypoechogenic areas [18-21]. In view of these parameters, patients with lymph nodes showing the following characteristics were considered suspect: diameter greater than 3 cm, round shape (T:'L ratio greater than 0.5), absence of hyperechogenic medulla, sinuous edges, the presence of nodular areas which form a protuberance in the contour of the cortex and/or medulla. On the basis of these criteria our patients were classified in the following manner: true positive patients that were positive at histology:

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true negative -- patients with a 6-month diseasefree survival period following a negative ultrasound reading; -false positive patients whose ultrasound evaluation was positive while the histologic examination was negative, yet showed no sign of the disease for at least 6 months; -- false negative - presence of lymph node metastases within 6 months from a negative ultrasound evaluation. Of the 87 patients who were being monitored, 32 presented a sonographic picture that was considered suspect. All of these were referred for cytology by means of fine needle aspiration of the lymph node or ot" the intranodal area under suspicion. Round lymph nodes with hypertrophy of the medulla and corresponding cortical thinning (a manifestation of adipose metaplasia) were not considered suspect [18] (Fig. 1). Patients whose pathologic report was positive underwent surgical excision of the node, thus providing further histologic confirmation of the diagnosis. Cytologies were carried out using free-hand, fine needle aspiration accompanied by ultrasound guidance. In this way even small (5 mm) targets could be investigated and the sampling site within the lymph node could be inspected using more than one incision. Overall, two needle cytologies were carried out on average on each patient during a single sitting. --

Fig. 1. Drawing of a normal shaped, reactive lymph node above and of a lymph node with hypertrophic medulla and cortical narrowing below.

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A Fig. 3. Enlarged lymph node with round shape and the absence of cenmd hyperechogenic striae. The biopsy needle is evident at the center.

3. Results

None of the patients considered suspect because of size or because of diffuse sinuosity of lymph node edges were found positive at biopsy nor did they manifest signs of nodal involvement within the time limit of this protocol. Two patients who underwent sonographic examination of the axillary region were found negative. Two and 4 months, respectively, after their last sonographic examination, clinical examination revealed highly suspicious enlargement of the lymph nodes. Ultrasound evaluation, carried out immediately, revealed a number of largc, round nodes without hyperechogenic medulla. Pathologic examination after axillary excision was tbund to be positive. In fact. it confirmed metastatic involvement in 18 out of the 24 axillary lymph nodes in the first patient and in three out of 18 in the second.

On the basis of the sonographic parameters outlined above, the ultrasound picture of 32 out of the 87 melanoma patients (89 sites) examined were considered suspect and these were referred for cytology procedure. Of these, seven were considered positive because of the formation of a protuberance in the cortical and/or medullary contour, an expression of a focal lesion (Fig. 2), ten because of roundness and lack of central hyperechogenic striae (Fig. 3), two because of the diffuse sinuosity of lymph node edges (Fig. 4), and 13 because the long axis was greater than 3 cm. The pathologic report of 13 out of these 32 patients was tbund to be positive. Five presented nodular areas varying in dimension from 5 mm to 1 cm, causing a localized alteration of the cortical and.or medullary contour of the lymph node, whilc eight presented roundness and no central hyperechogenic striae (Table 1).

Fig. 4. Lymph node of normal dimensions with sinuous edges and ,*ithout central hyperechogemc striae.

Fig. 2. {A,B) Examples of lymph nodes with formation of a hypoechogenic protuberance at lhe border (arrows) detected by means of pathologic examination.

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A. Tregnaghi et al. : European Journal of Radiology 24 (1997) 216-221

Table I A total of 87 patients (89 sites): 32 positive at ultrasound

Table 3 Results obtained limiting the parameters of sonographic positivity to two

Sonographic features

Pathologic finding

7 Nodule with protuberance

5 Positive 2 Negative 8 Positive 2 Negative 0 Positive 2 Negative 0 Positive 13 Negative

10 Round without striae 2 Sinuous edge 13 Dimension > 3 cm

Incidence of various sonomorphologic features evaluated in 32 patients whose ultrasound was positive. T a b l e 2 shows h o w o u r p a t i e n t s were classified in terms o f true a n d false negatives a n d positives. C o n s i d ering the p a r a m e t e r s o f size, shape a n d internal n o d a l structure, s o n o g r a p h i c testing led to a m i s t a k e n d i a g n o sis in 21 p a t i e n t s (19 false positives a n d 2 false negatives) equal to 23.6°/,, o f the cases e x a m i n e d . U l t r a s o u n d e v a l u a t i o n , thus, was a c c u r a t e in 76.4°/,, o f the cases studied ( T a b l e 2). Its sensitivity was f o u n d to be 86.6%, while its specificity was 74.3°/,,. I f we were to limit the s o n o m o r p h o l o g i c features c o n s i d e r e d to: r o u n d s h a p e w i t h o u t striae, localized a l t e r a t i o n o f the c o r t e x a n d / o r m e d u l l a , an expression o f n o d u l a r f o r m a t i o n , u l t r a s o u n d ' s specificity w o u l d increase n o t a b l y , i n d i c a t i n g 17 p a t i e n t s at risk a n d f o u r false positives (three due to r o u n d s h a p e with no striae a n d one d u e to the presence o f i n t r a l y m p h n o d a l nodules) and, again, two false negatives with a p e r c e n t a g e o f incorrect d i a g n o s i s o f 6.7%. These results are statistically significant (Z2-test; P < / I T > = 0.000). T h e sensitivity value is, thereby, u n v a r i e d (86.6%) while the specificity rises to 94.6%, as s h o w n in T a b l e 3. O f the 11 p a t i e n t s w h o presented a d i p o s e m e t a p l a s i a o f the m e d u l l a n o n e d e v e l o p e d i n t r a n o d a l m e t a s t a s e s (Fig. 5). O n l y two p a t i e n t s showed, at the clinical e x a m i n a t i o n carried o u t at the s a m e time as u l t r a s o u n d , sure signs o f m e t a s t a t i c l y m p h n o d e involvement.

13 True positives 70 True negatives 4 False positives 2 False negatives

93.2% (correct diagnosis) 3 round without striae 1 nodular cortical widening 4.5'7,, 2.2%

Percent calculated omitting absolute size of the lymph node and the presence of sinuous edges.

It is k n o w n t h a t the t e g u m e n t a r y a n d regional l y m p h n o d e levels are the m o s t c o m m o n sites o f m e l a n o m a metastases. In two o f the 87 p a t i e n t s studied, regional n o d a l m e t a s t a s e s were detected when signs o f distant m e t a s t a s e s - - one o f the liver a n d the o t h e r o f the skin .... were a l r e a d y present. F o r the r e m a i n i n g 13 patients (the 11 true positives a n d two false negatives a c c o r d i n g to u l t r a s o u n d ) , l y m p h n o d e m e t a s t a s e s was the first sign o f cancer proliferation.

4.

Discussion

Several a u t h o r s have a t t e m p t e d to s t a n d a r d i z e ultras o u n d criteria for the d i f f e r e n t i a t i o n o f benign from m a l i g n a n t superficial l y m p h n o d e s in the v a r i o u s prim a r y t u m o r sites such as the e s o p h a g u s o r ear, nose a n d t h r o a t regions [23-28]. O u r first a n d m o s t difficult task, thus, was that o f a d a p t i n g these criteria to the specific characteristics o f m e l a n o m a . O n c e the u l t r a s o u n d criteria c o n s i d e r e d indicative o f n o d a l m e t a s t a s e s was defined the percent o f false positives was f o u n d to be quite low (4.5°/,,). T h e fact that these p a t i e n t s are needlessly subjected to needle b i o p s y seems an a c c e p t a b l e d i a g n o s t i c o p t i o n to us c o n s i d e r i n g the p r o c e d u r e ' s innocuousness, high t o l e r a b i l i t y a n d low cost.

Table 2 Results obtained utilizing 4 sonographic criteria 13 True positives 55 True negatives 19 False positives

2 False negatives

76.4% (correct diagnosis) 3 round without striae -- 1 nodulare cortical widening 21.3% - - 2 sinuous edge -13 dimension > 3 cm 2.2%

The percentage is calculated considering lymph nodes positive if round without hyperechogenic striae in the central zone. those containing nodular areas within the lymph node, those with sinuous edges and those with long axis greater than 3 cm.

Fig. 5. Lymph node (arrows) with marked adipose metaplasia and narrowing of the hypoechogenic cortex easily observable in the polar region.

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European Journal oJ Radiolog.v 24 (1997) 216 -221

C y t o l o g y r e p o r t o f o n e p a t i e n t w h o e x h i b i t e d small, round, axillary lymph nodes lacking central hypcrcchog e n i e striae d i a g n o s e d m e t a s t a s e s f r o m m e l a n o m a but this w a s n o t c o n f i r m e d by the h i s t o l o g i c e x a m i n a t i o n c a r r i e d o u t a f t e r s u r g i c a l e x c i s i o n (false p o s i t i v e o n u l t r a s o u n d a n d biopsy). T h e singlc case o f false p o s i t i v e u l t r a s o u n d a n d false p o s i t i v e p a t h o l o g i c r e p o r t , w h i c h was n o t c o n f i r m e d by a f u r t h e r h i s t o l o g i c e x a m i n a t i o n a f t e r s u r g i c a l excision, c a n bc e x p l a i n e d in v a r i o u s ways. Firstly, e r r o r s m a y h a v e b e e n m a d e . b o t h at the u l t r a s o u n d a n d b i o p s y p r o c e d u r e s . M o r c o v e r . it is p o s s i b l e t h a t the h i s t o l o g i c e x a m i n a t i o n o f the l y m p h n o d e s a f t e r surgical e x c i s i o n m a y n o t h a v e b e e n a i m e d c o r r e c t l y w i t h i n the s p e c i m e n a n d an i n l i n i t e s i m a l lesion m a y h a v e been missed. It is, i n s t e a d , m o r e difficult to e x p l a i n the rate o f s o n o g r a p h i c false n e g a t i v c s (scc T a b l e s 2 a n d 3). It can be h y p o t h e s i z e d t h a t the l y m p h n o d e s w c r c i n c o r r e c t l y diagnosed during ultrasound because of tcchnical or i n t e r p r e t a t i v e e r r o r s o r b e c a u s e at the t i m e the e x a m i n a t i o n was c a r r i e d o u t the l y m p h n o d e was, as yet, u n a f f e c t e d . M o r e o v e r , it is p o s s i b l e t h a t the d i n a e n s i o n s o f m e t a s t a s e s w e r e i n f e r i o r to the t h i c k n e s s o f the l y m p h n o d e p a r c n c h y m a while s o n o g r a p h i c a r c h i t e c t u r e w a s still n o r m a l . In this case, h u m a n e r r o r m a y be s u m m e d to a n o n - d e f i n a b l e t e c h n i c a l error. T h i s l a t t e r possibility could probably be demonstrated if m i c r o m e t a s t a s e s h a d a s o n o g r a p h i c a r c h i t c c t u r e different f r o m t h a t o f the l y m p h n o d e p a r e n c h y m a but it has b e e n e s t a b l i s h e d t h a t m e l a n o m a presents, at least at the p a r c n c h y m a l level, a h y p o e c h o i c s t r u c t u r e v e r y s i m i l a r to the s o n o g r a p h i c a r c h i t e c t u r e o f a n o r m a l l y m p h node. W h e n m e t a s t a s c s intiltrates to the p o i n t o f s u b s t i t u t i n g the e n t i r e l y m p h n o d e the s o n o g r a p h i c f i n d i n g is t h a t o f a solid, r o u n d , h y p o c c h o g e n i c n o d u l e w i t h no hypcrcchogenic medulla. T h r e e o f the 10 p a t i e n t s s h o w i n g this t y p e o f p a t t e r n w e r e u l t r a s o u n d false positives. Very small, r e a c t i v e l y m p h n o d e s m a y a p p e a r r o u n d a n d w i t h o u t h y p e r e c h o g e n i c striae o f the c e n t r a l hilus [18]. In c o n c l u s i o n , w h i l e u l t r a s o u n d c a n n o t g u a r a n t e e a sure d i a g n o s i s o f the state o f the l y m p h n o d e t h a t is the p r i m a r y d r a i n a g e for a m e l a n o m a , n o n e t h e l e s s , it has b e e n f o u n d t h a t it p r e s e n t s a low m a r g i n o f d i a g n o s t i c e r r o r in t e r m s o f false n e g a t i v i t y . M o r e o v e r , ultras o u n d - g u i d e d n e e d l e c y t o l o g y o f the l y m p h n o d e o r o f an a r e a u n d e r s u s p i c i o n p e r m i t s easy a n d f r e q u e n t t b l l o w - u p c o n t r o l s . In o u r institute, in fact, u l t r a s o u n d has b e c o m e a r o u t i n e d i a g n o s t i c p r o c c d u r e in t h e follow-up of melanoma patients. T h e p r e s e n t s t u d y c o n f i r m s u l t r a s o u n d ' s ability to i d e n t i f y l y m p h n o d e s o f e v e n tiny d i m e n s i o n s t h a t are n o t a p p a r e n t clinically.

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