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British Journal of Radiology (2009) 82, 41-48
© 2009 British Institute of Radiology
doi: 10.1259/bjr/99732265
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British Journal of Radiology 82 (2009),41-48 ©2009 The British Institute of Radiology

Full paper

Sentinel lymph node biopsy using dynamic lymphoscintigraphy combined with ultrasound-guided fine needle aspiration in penile carcinoma

J W CRAWSHAW, FRCR1, P HADWAY, MSc, MRCS2, D HOFFLAND, DCR1, S BASSINGHAM, DCR, DRI1, C M CORBISHLEY, FRCPath3, Y SMITH, MRCS2, J PILCHER, FRCR1, R ALLAN, FRCR1, N A WATKIN (Urol), MA, FRCS2 and S D HEENAN, FRCP, FRCR1

Departments of 1 Radiology, 2 Urology and 3 Cellular Pathology, St George's Hospital, Blackshaw Road, London, UK

Correspondence: James W Crawshaw, Department of Radiology, St George's Hospital, Blackshaw Road, London, UK. E-mail: jameswcrawshaw{at}hotmail.com


   Abstract
Top
 Abstract
Introduction
 Methods and materials
 Results
 Discussion
 Conclusions
 References
 
The purpose of this study was to assess the utility of sentinel lymph node lymphoscintigraphy (SLNL) and ultrasound-guided fine needle aspiration cytology (FNAC) in patients with penile carcinoma. A prospective study was undertaken of 64 patients with stage T1 (or greater) clinically N0 squamous cell carcinoma of the penis. Patients underwent SLNL and bilateral groin ultrasonography with or without FNAC. Following intradermal blue dye, patients underwent unilateral or bilateral sentinel lymph node excision biopsy (SNB). 17 patients had sentinel nodes that contained metastases (21 nodal basins). Lymphatic drainage was demonstrated in all patients by lymphoscintigraphy. Bilateral drainage was seen in 57/64 patients. 61/64 patients had ultrasonography of the inguinal basins on the same day as FNAC of 38 basins. FNAC showed malignancy in eight basins. FNAC was negative in six basins, which were subsequently shown to be positive following SNB. 82 inguinal basins did not warrant FNAC by ultrasound criteria, of which 5 contained metastases at SNB. The sensitivity and specificity of ultrasonography was 74% and 77%, respectively. The positive and negative predictive values were 37% and 94%, respectively. Two patients had a negative initial SNB; however, ultrasonography identified a metastatic node and re-evaluation of the sentinel node confirmed micro-metastases. There has been no evidence of recurrence in any patients with negative SNB (during 6–28 months' follow-up). In conclusion, when investigating clinically stage N0 penile cancer, the combination of SNB and groin ultrasonography, with or without FNAC, identifies accurately those with occult nodal metastases. Ultrasonography alone is not adequate as a staging technique, and SNB alone might miss between 5% and 10% of metastases.


   Introduction
Top
 Abstract
 Introduction
Methods and materials
 Results
 Discussion
 Conclusions
 References
 
Squamous cell carcinoma of the penis is rare in the UK, being seen in 0.1–0.9 per 100 000 population. This represents approximately 350–400 new cases annually in the UK. Aetiological factors include poor hygiene and smoking; there is also a link to human papilloma virus (HPV), particularly HPV-16 and -18 [1]. Patients with a phimosis are at an increased risk, and circumcision is protective. The incidence is far greater in areas of Africa and South America.

The treatment options depend upon the stage of the tumour. In patients with clinically node-negative disease, accurate staging is essential, as unnecessary inguinal lymph node dissection is associated with significant morbidity, such as haemorrhage, infection, deep vein thrombosis, lymphocoele and lymphoedema [2]. In moderate- to high-risk patients (T1G2 or greater tumours), approximately 20% of those that are clinically node-negative have occult nodal metastases [3]; therefore, 80% do not require node dissection and it is this group that provide the management dilemma. The options for assessing the nodal status of the patient include clinical examination, ultrasound with or without fine needle aspiration cytology (FNAC), exploratory surgery and radioguided sentinel node biopsy (SNB).

Gould et al [4] first coined the term "sentinel node" in parotid tumours in 1960. The theory was further developed in penile cancer by Cabañas in 1977 [5]. The theory states that the sentinel node is any node that receives direct lymphatic drainage from a tumour. Histological scrutiny of such a node will determine whether metastasis to regional lymph nodes has occurred. Morton et al [6] have more recently introduced the technique of SNB for malignant melanoma. Kumar et al [7] identified the sentinel lymph node in penile cancer anatomically as the node at the junction of the saphenous vein and the superficial epigastric vein, quoting a sensitivity of 78%. The use of the SNB technique for staging carcinoma of the penis has only recently been re-evaluated [8], and this is the first study describing this technique in the UK, the aim of which was to assess the utility of sentinel lymph node lymphoscintigraphy (SLNL) and ultrasound-guided FNAC in patients with penile carcinoma.


   Methods and materials
Top
 Abstract
 Introduction
 Methods and materials
Results
 Discussion
 Conclusions
 References
 
A 2-year prospective trial was conducted with approval of the New and Novel Therapeutics Committee and under an Administration of Radioactive Substances Advisory Committee (ARSAC) research certificate. Patients underwent dynamic SLNL with localization and bilateral groin ultrasound with or without FNAC, followed by SNB.

Patient selection
66 consecutive male patients with Stage T1 Grade 2 or greater and clinically N0 squamous cell carcinoma of the penis were studied between October 2004 and May 2006. The TNM classification system and World Health Organization grading system were used to classify the tumours [9, 10]. Patient ages ranged from 26 years to 88 years (mean, 59 years). One patient was excluded because of previous tuberculous infection of the left groin and contralateral groin dissection for metastases from penile cancer. A second patient was excluded owing to a history of local radiotherapy for penile cancer 2 years earlier. No patients were currently on chemotherapy. The primary tumour remained in situ in 31/64 patients, and 33/64 patients had undergone previous resection or partial resection of the primary tumour. The time from surgery to SNB ranged between 1 month and 2 years.

64 patients were entered into the study in 2 groups: (i) those with the primary tumour in situ at the time of SNB (Group A), and (ii) those who had had the primary tumour excised or partly excised (Group B).

Sentinel lymph node lymphoscintigraphy
All patients were admitted either the night before, or the morning of, surgery, and informed written consent was obtained. 30 min after xylocaine (10% spray) and using an aseptic technique, a mean of 19 MBq (range, 11–32 MBq) technetium-99m-labelled nanocolloid (Nanocoll; Amersham Health, Milan, Italy) was injected intradermally in 8–12 fractionated doses either around the post-operative scar or the foreskin. The total volume of tracer injected ranged from 0.6–0.8 ml. Anterior dynamic acquisition of 90 x 10 s frames for 15 min was performed, which were displayed as summed 1 min images. These were followed 1–2 h later by delayed anterior and lateral static images using a dual head ECAM gamma camera (Siemens ECAM signature series, Berkshire, UK) with a low-energy general purpose collimator. Supplementary transmission images were acquired to give anatomical correlation using a cobalt-57 flood source (GoGoFigures 1–3Go). Lymphatic drainage tracks were only seen extending to inguinal nodes; therefore, other drainage basins were not imaged.


Figure 1
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  		Figure 1. Anterior planar dynamic scan(summed 1 min image) of the groins, demonstrating bilateral drainage to three lymph nodes on the right and one on the left (arrows).

 

Figure 2
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  		Figure 2. Anterior and lateral planar static images of the groin of a different patient, with an additional anterior transmission scan showing lymphatic drainage to bilateral sentinel lymph nodes. Labels A1–3 represent the right sentinel lymph nodes; label B1 indicates a left sentinel lymph node.

 

Figure 3
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  		Figure 3. Anterior and lateral planar static images of the groin, demonstrating unilateral drainage to a cluster of lymph nodes in the left groin. Labels A1–3 represent three left sentinel lymph nodes.

 
Ultrasonography
Ultrasonography of both groins using a high-frequency linear probe on either a GE Logiq 9 (GE Healthcare, Chalfont St Giles, UK) or a Philips HDI 5000 (Philips Medical Systems, Reigate, UK) ultrasound machine was performed and the lymph nodes assessed. Scans were performed by a consultant radiologist or specialist registrar under direct supervision. If the ultrasound showed any abnormal nodes, FNAC was performed using 21 G or 23 G needles, as is standard practice at our institution. FNA samples were placed in Hanks' solution for cytology assessment.

The criteria used for ultrasound abnormality included increased size, abnormal shape, abnormal vascularity and loss of an echogenic fatty hilum. Ahuja and Ying [11] suggested criteria for the identification of abnormal cervical lymph nodes, whereas Hall et al [12] looked at inguinal node metastases in vulval cancer. Table 1Go summarizes the criteria used to indicate abnormality and to proceed to FNAC. Figure 4aGo shows a normal lymph node by ultrasound criteria; Figure 4bGo shows an abnormal lymph node.


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  		Table 1. Criteria used for the identification of abnormal groin nodes by ultrasonography

 

Figure 4
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  		Figure 4. (a) High-resolution ultrasound image showing a normal lymph node in the right groin. It has a normal echogenic fatty hilum, with peripheral hypoechogenicity. (b) High-resolution ultrasound image showing an abnormal lymph node in the right groin. The node is hypoechoeic, irregularly shaped and has lost the central fatty hilum. The node demonstrated abnormal vascularity (not shown). Fine needle aspiration cytology was performed, which confirmed metastatic disease.

 
Sentinel lymph node labelling
Patients returned to the nuclear medicine department for skin marking and sentinel node depth estimation using a cobalt-57 pen and a permanent marker. To avoid bias in the interpretation of the ultrasound findings, sentinel nodes were marked following ultrasound examination. The time between radionuclide injection and marking ranged from 1–2 h. The sentinel lymph nodes were labelled according to the drainage basin. The same identification of nodes continued with excision and histopathological examination. Second echelon nodes that received drainage from the sentinel node(s) were not marked.

Surgery
Approximately 10 min before surgery, blue dye (methylene blue; Martindale Pharmaceuticals, Essex, UK) was injected intradermally at the same location as the nanocolloid injections. The time between radioisotope injection and surgery was between 2 h 25 min and 6 h 30 min (mean, 4 h 20 min). The sentinel lymph nodes were then located using a hand-held gamma probe (Neoprobe®; Johnson and Johnson Medical, West Lothian, UK) and excised (Figure 5Go). The depth estimation from SLNL was used as a guide to the location of the sentinel nodes. Additional nodes visualized with blue dye were also excised.


Figure 5
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  		Figure 5. Intra-operative image locating a sentinel lymph node in the left groin using a hand-held gamma probe.

 
Pathological assessment
The resected lymph nodes were fixed and then sliced into 2 mm slices. Haematoxylin and eosin sections were prepared, as well as immunohistochemistry with CAM5-2, MNF116 and LP34 (Figure 6Go). All slides were reviewed by a single pathologist, and the size of the metastases together with the presence or absence of extranodal spread was recorded.


Figure 6
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  		Figure 6. Immunohistochemistry with a LP34 stained section, which stains high molecular weight keratins, indicating metastatic squamous cell carcinoma(arrow).

 

   Results
Top
 Abstract
 Introduction
 Methods and materials
 Results
Discussion
 Conclusions
 References
 
Sentinel lymph node lymphoscintigraphy
Lymphatic drainage was demonstrated in all 64 patients by lymphoscintigraphy. Bilateral drainage was seen in 57/64 patients (89%). Of the seven patients with unilateral drainage, two patients had undergone previous unilateral lymph node dissections for palpable nodal metastases from penile cancer. One patient had severe lymphoedema extending from the groin to the penis and scrotum. One patient declined exploratory surgery and is being followed up with observation and imaging. The remaining three patients underwent surgical exploration of the groin.

Sentinel node biopsy
206 nodes in 121 groins were identified and marked using dynamic lymphoscintigraphy. At surgery, 223 nodes were excised. 15 nodes identified by lymphoscintigraphy were not excised at surgery, as these nodes were above the inguinal ligament and thought to be second echelon nodes and not sentinel nodes. 35 (16%) excised nodes were hot but did not stain with blue dye. All excised nodes contained radioactivity. The findings from the patients with the primary tumour in situ and those who had undergone previous surgery are summarized in Table 2Go.


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  		Table 2. Summary of the findings at sentinel lymph node lymphoscintigraphy, sentinel node biopsy and ultrasonography in the pre- (Group A) and post-operative (Group B) groups

 
Ultrasonography with/without FNAC
61/64 patients (95%) had ultrasonography of the inguinal basins on the same day as SNB. Three patients did not have an ultrasound scan, as they were operated on early in the study, before this investigation was introduced into the protocol. One patient had ultrasonography of only one groin, as they had recently undergone unilateral groin dissection. FNAC was performed in 38 inguinal basins (31%). FNAC was positive for malignancy in eight basins, which was confirmed at surgery. FNAC was negative for malignancy in 24 basins, which were also negative at SNB. FNAC was negative in six basins that were positive for metastases on histology following SNB. 82 inguinal basins (68%) were deemed normal by ultrasonography and did not warrant FNAC. 77 of these had normal SNB; however, 5 inguinal basins were positive for metastases following SNB. One patient had bilateral metastases at SNB, but did not have an ultrasound scan. These findings are summarized in Table 3Go.


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  		Table 3. Summary of the histological findings compared with ultrasound and fine needle aspiration cytology results in the pre- (Group A) and post-operative (Group B) groups

 
17 patients had sentinel lymph nodes containing metastases (21 nodal basins). All node-positive patients had at least Grade 2 primary tumours. All metastatic nodes were identified by lymphoscintigraphy. Two patients were initially node-negative by SNB and positive by FNAC. On subsequent histological re-examination of the sentinel nodes, they were found to contain micro-metastases. There were no significant complications from SNB.

Statistical analysis
Using a spreadsheet-based statistical software package, no statistical difference was found between the number of positive nodes in Groups A and B ({chi}2 = 0.71). There was also no statistical difference between the number of nodes marked or excised in the two groups. Based on SNB, the positive predictive value of ultrasound alone in assessing malignant infiltration of inguinal lymph nodes is 37%. The negative predictive value is 94%. Sensitivity and specificity for ultrasound are 74% and 77%, respectively.

Median follow-up was 11 months (range, 6–28 months). There has been no evidence of recurrence in any patient with negative SNB; therefore, the negative predictive value for the combined technique of SNB and groin ultrasonography is currently 100%. These patients will continue to be followed up to determine the true false-negative rate for SNB.


   Discussion
Top
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion
Conclusions
 References
 
As clinical evaluation will miss a significant group of men with occult nodal metastases, more accurate staging in penile cancer is required. The use of SNB techniques is increasing. It is now recommended practice in breast cancer following the ALMANAC (Axillary Lymphatic Mapping Against Nodal Axillary Clearance) trial in the UK and NSABP (National Surgical Adjuvant Breast and Bowel Project) in the USA [13–15]. SNB has also been described in gynaecological malignancy, head and neck cancer and colonic cancer [16–19]. Its use in urological malignancy is limited at present; however, pelvic and inguinal lymph node dissections with the associated morbidity and mortality could be reduced by better staging with sentinel lymph node studies [20].

The role of SNB in penile cancer remains an area of controversy. Several early studies suggested that there was an unacceptably high rate of false-negative results from SNB, but these studies involved small sample sizes and did not use lymphoscintigraphy and blue dye to localize the sentinel lymph node [21–23]. More recently, other groups using lymphoscintigraphy and blue dye injection report high sensitivity, low post-operative complication rates, and increased disease-free survival following sentinel node-negative disease [24, 25]. Tanis et al [26] have shown that SNB in patients with penile carcinoma provides prognostic information on both 3- and 5-year survival rates, with survival rates being 98% for sentinel lymph node-negative disease and 71% for node-positive disease at 3 years; the corresponding values at 5 years are 96% and 66%, respectively [27].

In melanoma, Morton et al [28] have shown that sentinel node status is the most important prognostic factor for disease recurrence. Early results from the Multicenter Selective Lymphadenectomy Trial-1 have shown that the presence of sentinel node metastases is the most important prognostic factor for 5-year survival rates, with values of 88% in patients whose sentinel node(s) are negative vs 71% for those whose sentinel nodes contain metastases.

When comparing patients who had a positive SNB and early lymph node dissection with those who had nodal observation and delayed node dissection for clinically apparent recurrent nodal disease, the 5-year survival rates were 71% and 55%, respectively [28].

For penile cancer, lymph drainage is far more predictable than for melanoma, with only two potential drainage basins. The incidence of skip metastases in melanoma is thought to be 1% [6, 29], whereas the incidence in penile cancer is lower, according to the available literature. Perdona et al [30] compared elective bilateral lymph node dissection with SNB in penile carcinoma and found similar rates of nodal metastases (39% vs 36%), but SNB was associated with considerably lower post-operative morbidity . In addition, a recent 10-year review by Kroon et al [31] claims that, when patients have only micro-metastases (2 mm or less) present in the sentinel node, all other inguinal nodes should be clear of tumour, and may therefore be spared further nodal dissection.

Ultrasonography has been used as a staging technique for a wide variety of malignancies. The appearances of nodes containing metastases have some overlap with reactive or infected lymph nodes, and it is well-recognized that micrometastatic disease within nodes cannot be accurately identified by ultrasonography alone. As shown in our study, ultrasonography failed to identify five nodal basins containing metastases, whereas FNAC failed to find metastases in six cases of metastatic disease. Both of these results can be explained either by micrometastatic disease failing to cause any morphological change in the lymph node or by sampling error by FNAC. The high rate of false-positive ultrasonographic findings (24 nodal basins) may be a result of the high incidence of reactive nodal enlargement in penile cancer secondary to coexistent infection. The criteria for suspected malignancy are sensitive but not specific, thus increasing false-positive ultrasonographic findings.

The major benefit from ultrasonography is in identifying nodes that are infiltrated with tumour but are bypassed by both nanocolloid and the blue dye during SNB. In our study, two patients initially showed no tumour in the sentinel node as identified by lymphoscintigraphy; however, ultrasonography and FNAC were positive. These were probably examples of lymphatic re-routing as a consequence of obstruction of drainage by a non-functioning sentinel node that had been completely replaced by metastatic tumour, thereby resulting in no uptake at SLNL. This phenomenon has been described in breast cancer, where extensive nodal involvement by tumour has been shown to cause false-negative SNB results by obstructing the flow of lymphatics and diverting flow to normal lymph nodes [32]. Kroon et al [33] initially used just lymphoscintigraphy to identify the sentinel node, and introduced ultrasonography before SNB to reduce the number of false-negative results in penile cancer. Although our findings suggest that ultrasound may not be required, this has not been the experience of other centres, and the numbers in this study are still small [33]. Also, if the ultrasound scan and FNAC confirm bilateral disease, then SNB may not be necessary and the patient can proceed to bilateral groin dissection.

Kroon et al [34] used ultrasound-guided FNAC prior to SNB to correctly identify 9 out of 23 positive inguinal basins showing similar results to our study, in which 8/19 basins were positive. They suggested that the number of SNB investigations needed could be reduced by 10%, as nine fewer groins needed exploration; however, the patient would still require SNB of the contralateral groin and therefore the advantages are less significant.

The use of CT relies mainly on measuring the size of lymph nodes. In penile cancer, size alone is an unreliable sign, with the large proportion of benign reactive nodes being present in penile carcinoma. In vulval carcinoma, Land et al [35] showed that ultrasonography with FNAC was superior to CT for assessing groin nodes, with a sensitivity of 58% vs 87% for ultrasonography. When CT is combined with single photon emission CT (SPECT), there is an improved anatomical correlation, which can aid localization of the sentinel nodes [36, 37]. Positron emission tomography (PET) imaging using 18F-fluorodeoxyglucose (18F-FDG) and PET–CT have been shown to have a high sensitivity and specificity for detecting metastases and disease recurrence in a variety of malignancies [38, 39]. PET is less reliable, however, when nodes are less than 1 cm in size and for differentiating metastases from infection. It is a relatively insensitive test for identifying malignant infiltration of groin nodes in vulval cancer [40] and sentinel nodes in melanoma [41–43]. The radiation dose from PET or PET–CT is high when compared with that from SNB, and the availability of PET systems remains limited in the UK. In combination, PET and SNB have been shown to improve head and neck cancer staging [44] and there are reports of the use of hand-held high-energy PET probes that can identify foci of 18F-FDG uptake within nodes at surgery [45].

MRI has been used to identify both sentinel nodes and metastatic nodes with some success using MR lymphangiography [46, 47]. MRI has been combined with SPECT to further localize sentinel nodes when multiplanar anatomical correlation is required [48]. All of these alterative techniques suffer from a lack of correlation at the time of surgery. Use of the gamma probe enables the surgeon to excise the nodes accurately identified by dynamic lymphoscintigraphy. As SNB is increasingly being used in the staging of other cancers, so the expertise will increase in imaging, surgical and pathological departments.


   Conclusions
Top
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion
 Conclusions
References
 
In the investigation of clinical stage N0 penile cancer, the combination of SNB and high-frequency groin ultrasonography with or without FNAC accurately identifies those with occult nodal metastases. Ultrasonography (with or without FNAC) alone is not sufficient to accurately stage penile cancer and, at present, is still needed to address the potential false-negative rate. Compared with lymph node dissection, the complication rate from SNB is low and, as suggested by Kroon et al [49], the greatest complication is recurrence after a negative SNB. It is a reproducible and clinically important technique. Our results compare well with other centres, and currently no alternative method approaches it in terms of sensitivity or positive predictive value. Long-term follow-up is required to determine the true false-negative rate; however, early results are very promising.

Received for publication October 22, 2007. Revision received January 23, 2008. Accepted for publication February 5, 2008.


   References
Top
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion
 Conclusions
 References
 

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