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SYMPOSIUM
Year : 2006  |  Volume : 22  |  Issue : 4  |  Page : 345-350
 

Diagnosing metastatic disease in inguinal nodes in penile cancer: Do we have a test and the evidence?


Department of Surgery, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry, India

Correspondence Address:
N Ananthakrishnan
Department of Surgery, JIPMER, Pondicherry - 605 006
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0970-1591.29123

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   Abstract 

Nodal metastasis is the most important prognostic factor in carcinoma of the penis. Clinical examination is inaccurate for diagnosing nodal involvement. Routine prophylactic block dissection carries a high risk of morbidity and a small but definite incidence of mortality. Procedures such as fine needle aspiration cytology with or without imaging guidance, anatomic sentinel node sampling, medial inguinal lymph node biopsy and dynamic sentinel node mapping, have all been tried, of which the last has proved most useful. Newer investigations like lymphotropic nano-particle enhanced MRI, squamous cell carcinoma antigen estimation and DNA flow cytometry are still experimental. It appears that in spite of numerous tests available for diagnosing metastatic disease in nodes before it becomes clinically apparent, the only test which currently holds promise is dynamic sentinel node mapping using radio isotopes with or without intraoperative colored dye, to identify the draining nodes for sampling. The only other alternative may be to recommend prophylactic node dissection in all T2, T3 or T4 patients or in all patients with Grade 2 or 3 T1 tumors, in whom the risk of nodal metastases is very high.


Keywords: Carcinoma penis, inguinal node metastasis, sentinel node sampling


How to cite this article:
Ananthakrishnan N. Diagnosing metastatic disease in inguinal nodes in penile cancer: Do we have a test and the evidence?. Indian J Urol 2006;22:345-50

How to cite this URL:
Ananthakrishnan N. Diagnosing metastatic disease in inguinal nodes in penile cancer: Do we have a test and the evidence?. Indian J Urol [serial online] 2006 [cited 2019 Jun 26];22:345-50. Available from: http://www.indianjurol.com/text.asp?2006/22/4/345/29123


Carcinoma of the penis is a relatively uncommon cancer, with the incidence between 0.5-1.5 per 100,000 population in the west.[1] It is slightly more common in South India, with an incidence of 2.9 per 100,000 population.[2]

The infrequency of this cancer is directly responsible for the paucity of reliable evidence, which can contribute to the management of the disease, particularly with reference to detection and management of nodal metastases. The lymphatics of the penile skin and prepuce converge on the dorsum of the penis and coalesce into several trunks which terminate in the superficial inguinal nodes, particularly the superomedial lymph node. The lymphatics of the glans and shaft on the other hand, may bypass these channels and drain directly into pelvic nodes.[3] However, such a direct spread has been questioned by others.[4]


   Importance of nodal metastases Top


Nodal metastasis is relatively common in carcinoma of penis, but distant dissemination is very rare.[5] Lymphatic spread from carcinoma of penis is generally bilateral. In a study by Voldes Olmos et al , using radiocolloid, it was found that lymphatic drainage was bilateral in 81%, exclusively to the left groin in 13% and only to the right groin in 6%.[6]

Lymph node metastasis is the most important prognostic factor in patients with carcinoma of the penis.[7] It has been said that the battle for control of squamous cell carcinoma of the penis is either won or lost at the level of the inguinal nodes.[8] Ravi has reported a crude five-year survival of 95% for patients with negative nodes, 76% when only inguinal lymph nodes were positive and 0% when pelvic nodes are positive.[9] The adverse prognostic factors reported were, involvement of more than three inguinal nodes, perinodal involvement and pelvic node involvement.[9] In another study, the three-year disease-specific survival dropped from 98% in node negative patients, to 71% for tumor positive nodes.[10] In a study by Pandey et al, it was found that the five-year overall survival (OS) for patients with metastatic groin disease was only 51.1%.[7] Patients with inguinal lymph node disease alone had OS of 64.6%, whereas none of the patients with pelvic metastases survived five years.[7] Lymphatic metastasis has even been described in a patient with carcinoma in situ of the penis.[11]


   Incidence of nodal metastases Top


In a study of 135 node dissection specimens from our Institute, it was found that metastases to inguinal nodes were found in 74% of patients and to the iliac nodes in 32%. The risk of involvement was equal on either side, whether or not the nodes were palpable. Inguinal node metastases correlated with the size of lymph nodes and histological differentiation of the primary whereas iliac node involvement was more likely in patients with inguinal nodes larger than 2 cm or fixity of inguinal nodes. Involvement of the penile shaft also led to a higher incidence of nodal metastases.[12] The rate of positivity of inguinal nodes reported in the literature is generally lesser than these figures. Inguinal lymph node positivity in the literature lies between 35-60%,[13],[14],[15],[16] whereas iliac node positivity lies between 15-35%.[12],[17]

Slaton et al found that pathological tumor stage, vascular invasion and presence of greater than 50% poorly differentiated cancer were the strongest predictors of nodal metastases. The incidence of nodal metastases was nil in pT1, whereas 64% of patients with pT2 or greater had vascular invasion and 55% had nodal metastases.[18] Only four of 25 patients with 50% or less poorly differentiated cancer in the penile tumor had metastases, compared to 14/23 patients with greater than this proportion of poorly differentiated tumor.[18] The grade of primary tumor not only predicted nodal metastases, but also groin relapse after inguinal lymphadenectomy.[19]


   Clinical examination in detecting nodal disease Top


The inaccuracy of clinical examination in detecting nodal metastasis is well known.[12],[13],[20],[21] Palpable inguinal lymph nodes are reported to be present in 20-96% of patients with carcinoma penis.[22] The incidence approaches the upper value in India due to the habit of barefoot walking. False positivity rates of nodal involvement based on clinical examination have been as high as 43-70%.[23] More important is the false negativity of clinical examination, which has ranged from 0% - to as high as 66%.[24] Mortality from such missed metastases has ranged from 4-44%.[25]

In another study, clinical assessment was reported to be inaccurate in 22.5% of cases.[26] Hence, clinical examination cannot be relied upon to pick patients for inguinal lymphadenectomy. In a study from our Institute, it was found that clinical examination had a specificity of 61%, a PPV of 57% and a NPV of 77%.[22]


   Prophylactic node dissection Top


In view of the inaccuracy of clinical examination, attention was focused on prophylactic node dissection. This of course ran the risk of over- treatment of 30-70% of groins, where the excised lymph nodes would be reported as being histologically negative.[22] Some reports suggested that there is no survival advantage for those subjected to prophylactic dissection compared to others with dissection for delayed lymphadenopathy.[13],[27],[28],[29],[30] However, others disagree with this view. Pizzocaro et al mention that an expectant policy can be dangerous, because results of delayed lymphadenectomy are poor.[31] Mosconi et al recommend prophylactic node dissection for patients with T2 or greater and for those with vascular invasion or those with high-grade tumors.[32]

Sanchez-Ortiz and Pettaway have recommended prophylactic lymphadenectomy in select patients at high risk of metastases, in lieu of randomized trials which are difficult to conduct, since modifications in technique of block dissection had significantly decreased the morbidity of surgical staging.[33] Pizzocaro et al found nodal metastases in 100% of T3 and T4 patients, in 82% of T2 patients, in 60% of Grade 2 and 3 T1 and only in 16% of Grade 1 T1. They recommended prophylactic lymphadenectomy in all T2, T3 and T4 patients and Grade 2 or 3 T1 patients.[34]

Ravi et al have reported the results of 423 patients with negative groin nodes, of whom 113 were subjected to prophylactic lymphadenectomy and 258 were observed in a nonrandomized fashion. The five-year disease-free survival of node-positive patients in the lymphadenectomy group was 100%, as opposed to 76% in the observation group.[35] Lubke has also opined that awaiting development of nodal metastasis carries the risk of a significantly lower survival time.[8] Ricos et al reported a survival rate of 100% for patients subjected to prophylactic lymphadenectomy, compared to 51% after therapeutic lymphadenectomy.[36] They also commented on the poor results of RT, compared to surgery.

Johnson and Lo published the survival rates of patients who underwent early therapeutic dissections at the time the primary tumor was detected, as opposed to those who underwent late therapeutic dissection when regional node disease became apparent. The three and five-year survival rates were 71 and 57% for early dissection, versus 50 and 13% for late dissection.[3]

Morbidity of ileo-inguinal lymphadenectomy

In spite of the clear advantage of prophylactic lymphadenectomy, what has prevented this from being the gold standard in the management of carcinoma of the penis bypassing the need for identifying those with positive nodes, is the reported incidence of mortality and morbidity of this procedure.[26],[31],[37] Lymphadenectomy for carcinoma of the penis was reported to be associated with a 30-50% incidence of major morbidity[13],[38],[39] and a 3% mortality rate.[13],[28] Recent data however suggest, that the morbidity may be lower if the plane of raising of flaps is just superficial to the membranous layer of the superficial fascia of the thigh, thus preserving the arterial plexus in the fatty layer.[40] The major morbidity reported earlier included wound breakdown in 61%, wound infection in 18% and lymphedema in 25% of patients.[35] This was reduced to nil in a limited series of eight patients reported by Jacobellis.[40]

In order to avoid the morbidity of inguinal node dissections, other modifications of the conventional block have been suggested.[41],[42]


   Identification of nodal metastases Top


In view of the inaccuracy of clinical examination in identifying nodal disease and the risk of complications of prophylactic node dissection - which meant subjecting patients without pathologic nodal disease to an unwarranted risk, a logical corollary would be to see whether there was any diagnostic modality which enabled a reliable preoperative lymphatic staging in patients with clinically negative nodes.

Routine investigations

US, CT and MRI

Procedures such as echography have been proposed, but have proved to be of limited diagnostic value in identifying nodal disease, because of unacceptable false positive and false negative findings.[22],[37] Ultrasound (US) can identify an enlarged nonpalpable node. However, US criteria of a malignant lymph node as opposed to a reactive lymph node based on size, shape and US appearance, have not proved reliable enough for diagnosing metastatic disease. The main role of US, therefore lies in identifying nonpalpable inguinal and pelvic nodes for guided fine needle aspiration cytology (FNAC). Likewise, CT, MRI and penile lymphography have all proved unreliable for detecting early nodal metastases.[43],[44],[45],[46] They merely show enlarged nodes, but do not give any idea on whether the nodes are metastatic or not. The role of these investigations has been succinctly summed up by Sehlag.[47] He says that general criteria such as size, shape, structure or texture in variable imaging modalities, are unreliable in diagnosing nodal metastases. He also mentions that while it is still too early to definitely evaluate in this context, - newer imaging modalities such as PET, immunoscintigraphy or contrast-enhanced MRI, the initial results do not provoke enthusiasm.[47]

Fine needle aspiration cytology

FNAC is accurate in detecting metastases in palpable nodes, but is associated with problems of sampling when many nodes are enlarged or when nodes are not palpable.[22] FNAC has been mentioned to be an innocuous minimally invasive excellent alternative to surgical staging for identifying nodal disease.[31],[37]

In an early study, fluoroscopy-guided aspiration cytology was used for pelvic lymph node staging in urologic cancer, including penile cancer after bipedal lymphangiography.[46] The overall diagnostic accuracy was 93%. There were no false positives and there was a 6% false negative rate.[48] It was concluded that aspiration cytology was a safe, well-tolerated, accurate and rapid method of determining the presence of metastatic disease in lymphangiographically visualized pelvic nodes. In another small study by the same authors, in four patients of carcinoma penis, there was no false positive or false negative aspirate report.[49]

Ultrasound-guided FNAC has been evaluated in a recent trial for detecting occult nodal metastases.[50] Forty-three patients with 83 clinically node negative inguinal regions were studied. The results were compared with histology from subsequent dynamic sentinel node biopsy (DSNB) or inguinal lymph node dissection. The sensitivity and specificity of US-guided FNAC were 39% (9/23) and 100% (60/60). The authors concluded that FNAC can be used as the initial investigation in clinically negative or nonpalpable nodes. If tumor is confirmed by FNAC, then therapeutic inguinal lymph node dissection can be done and if negative, it can be followed by DSNB.[50] In a study reported by the current author, it was found that FNAC had a sensitivity of 100% and a specificity of 100% for enlarged nodes.[22]

It appears that nonguided FNAC is mainly useful for palpable nodes. Nonpalpable nodes and pelvic nodes require some form of guided FNAC. A positive FNAC indicates nodal disease, but a negative FNAC does not rule out metastases.

Gallium citrate scanning

The role of Gallium citrate (Ga-67) uptake by metastatic carcinoma has been studied by Abello and Lamki.[51] It was found in six patients with metastatic carcinoma of the penis, that intense radioactive uptake was noted in the metastatic inguinal nodes, which was not influenced by the presence or absence of infection.[51] Although the results suggested the possibility of using Ga-67 in staging nodal disease, no further information is available in the literature relating further experience with this procedure.

Sentinel node mapping

The concept of an orderly and stepwise lymphatic spread of carcinoma penis and the existence of a sentinel node (SN) which would serve as the first filter for nodal metastases, was first proposed by Cabanas in 1977.[38] Cabanas's study showed that the sentinel node was positive in all patients having nodal metastases. When the sentinel lymph node was negative, all other nodes were also negative.[20] Skip metastases beyond the sentinel node was considered to be very rare.[16] However, the Cabanas node cannot be palpated clinically and the reliability of the SN concept has been challenged by many authors.[30],[52],[53],[54],[55] The sentinel node as described by Cabanas, was the superficial femoral lymph node lying superomedial to the saphenofemoral junction and very near the superficial epigastric vein.

In an early study of the value of the Cabanas node in 1984 in 10 patients with carcinoma penis, five of 15 biopsies associated with inguinal lymphadenopathy and two of three biopsies of palpably normal nodes were positive. Additional LN metastases, not identified by SLNB, occurred only in instance. There were no false negatives.[56]

In a study by Bouchot et al ,[48] in 24 patients with clinical stage T1-3, N0, M0 Squamous cell carcinoma of the penis, SLNB was performed bilaterally. Although technically successful, no lymph node metastases were detected.[57] On follow-up of these patients clinically, seven patients (29.1%) developed one or more suspicious ilio-inguinal lymph node after a mean interval of 11.85 8.02 months. In six of these patients who consented to surgery, bilateral block dissection confirmed positive nodes. This paper strongly raised questions on the SLN concept in carcinoma penis.[57]

Dewire and Lepor also felt that from an anatomical perspective, the SLN concept may be useful in the management of superficial carcinoma of the prepuce or the skin of the penis, which drain into the SLN. However, in tumors of the glans, the lymphatics may bypass the superficial nodes to drain into the pelvic nodes directly.[58]

Serial sectioning and immunological and molecular techniques may enhance the sensitivity for micrometastases detection in SLN. However, the clinical significance of these is as yet unclear.[47]

Medial inguinal lymph node biopsy

Clinical observation at our Institute suggested that the first palpable inguinal LN in a patient with metastatic carcinoma of the penis was the most medial inguinal node, lying just lateral to the pubic tubercle[22] and not the SLN of Cabanas which would be below and lateral to the pubic tubercle. Histological positivity of this medial inguinal node was compared to Cabanas's sentinel node in 56 groin dissections in Stage II (n=11) and Stage III (n=16) patients with carcinoma of the penis. The sensitivity, specificity, PPV and NPV of the medial inguinal node was 91, 100, 100 and 94%, respectively, while the corresponding figures for Cabanas's SLN was 78, 100, 100, and 89%, respectively.[22] The SLN was the only node- involved in two groins, while the medial inguinal node was involved with no involvement of the SN in five groins. It appeared therefore, that MILN was more accurate than the SLN for identifying lymphatic metastases.[22] The current practice in our unit is to do a lymph node dissection in patients who have obvious clinical or FNAC- proved nodal disease and a frozen section of the medial inguinal and sentinel node in patients with no obvious nodal disease. If frozen section indicates involvement, an ilio-inguinal node dissection is done. The procedure of medial inguinal node biopsy is recommended only for identifying patients with nodal disease and not for reducing the morbidity of inguinal dissection.

Dynamic sentinel node mapping

While conventional SLN biopsy involved blind biopsy of an anatomically placed lymph node, recent efforts have focused on using radioisotopes or dyes for identifying SLNs. This is called dynamic sentinel node mapping. Since lymphoscintigraphy had been extensively validated for breast cancer and melanoma, it was tried for carcinoma penis.[6] In a study by Valdes Olmos et al , in 74 consecutive patients with clinically N0 status and T2 or greater primary, technetium 99m nano-colloid (mean dose 64.8 MBq) was injected intradermally around the tumor. A dynamic image was performed 20 min later using anterior and lateral images. This was followed by surgery. At surgery, a total of 161 SLNs were identified by handheld gamma probe and removed. Sixteen patients (22%) had a tumor- positive LN and underwent block dissection.[6] During follow-up, two patients with negative SN developed metastases in the mapped basin. They concluded that DSLN mapping is valid for SLN identification.[6]

In another study published the following year, Tanis et al evaluated the value of dynamic sentinel node biopsy for staging carcinoma of the penis.[10] Preoperative lymphoscintigraphy using technetium nano-colloid was combined with intradermal patient blue dye, administered immediately preoperatively.[10] In addition to routine H and E, IHC was used. Two hundred and seventeen SLN were visualized by isotope and 208 by patent blue. The SLN metastases were found in 19 groins in 18 patients and four of eight patients with unilateral N1 disease had tumor-positive SLN in the opposite side. The false negative rate of this procedure was estimated to be 22%.[10] The authors concluded that occult LN metastases in penile cancer can be detected with a sensitivity of about 80% by dynamic SLN biopsy.

Newer investigations

a) lymphotropic nano-particle enhanced MRI (LNMRI)


The procedure of LNMRI using ferumoxtran-10 was used in seven patients with penile carcinoma and correlated with subsequent histology of block dissection specimens.[59] The authors found that LNMRI had a sensitivity of 100%, a specificity of 97%, a PPV of 81.2% and an NPV of 100% in predicting regional LN metastases in carcinoma penis. They concluded that LNMRI is accurate in staging patients for regional lymphadenectomy.[59]

b) Squamous cell carcinoma (SCC) antigen for detecting nodal metastases

Laniado evaluated the use of SCC antigen measurements in identifying nodal metastases in 11 patients with SCC of the penis, after treatment of the primary tumor.[9] He found that an elevated SCC Ag had a sensitivity of 57% and a specificity of 100% for nodal metastases. Levels of SCC Ag increased exponentially in patients who developed nodal metastases after treatment of primary tumor and were elevated before clinical or radiological evidence of nodal disease.[60] They concluded that either the absolute level or rate of rise of SCC Ag may be a useful tool with which to follow patients with N0 nodal status after penectomy.[60]

c) Immunoexpression of p53 protein and proliferating cell nuclear antigen (PCNA)

Martins et al examined p53 protein and PCNA as prognostic factors to the outcome, in 50 patients with SCC of the penis. They concluded that PCNA staining had no prognostic value for disease progression. However, the role of p53 overexpression needed further evaluation.[61]

d) DNA flow cytometry

Studies by Hoofnagle et al suggested that patients with SCC of the penis and a high DNA index, may be at an increased risk of disease progression and therefore, might be candidates for aggressive surgical management. They suggested that DNA flow cytometry might be a reliable prognostic indicator for selecting which patients would benefit most from inguinal lymphadenectomy.[62]


   Conclusion Top


It appears that in spite of numerous tests available for diagnosing metastatic disease in nodes before it becomes clinically apparent, the only test which currently holds promise is dynamic sentinel node mapping using radioisotopes with or without intraoperative colored dye, to identify the draining nodes for sampling. Newer investigations mentioned above are still in the stage of trial. The only other alternative may be to recommend prophylactic node dissection in all T2, T3 or T4 patients or in all patients with Grade 2 or 3 T1 tumors, as stated by Pizzocaro et al .[34]

 
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