Role of Sentinel Lymph Node Biopsy in Clinically Node Negative Carcinoma Penis — a Prospective Study

Abstract

Nodal metastasis is a strong prognostic indicator in carcinoma penis, with 25% difference in 5-year cancer-specific survival among node negative and node positive patients. This study aims to assess efficacy of SLNB in identifying occult nodal metastasis (seen in 20–25% of cases), thus avoiding morbidity of prophylactic groin dissection in rest. Study was conducted between June 2016 and December 2019 on 42 patients (84 groins). Primary outcomes assessed were sensitivity, specificity, false negative rates, positive predictive value, and negative predictive value of sentinel lymph node biopsy (SLNB) compared to superficial inguinal node dissection (SIND). Secondary outcomes were to know prevalence of nodal metastasis, sensitivity, specificity, false negative rates, positive predictive value (PPV), negative predictive value (NPV) of frozen section study, and ultrasonography (USG) compared to histopathological examination (HPE) and to evaluate false negative results of fine needle aspiration cytology (FNAC). Patients with impalpable inguinal nodes were subjected to USG and FNAC of suspicious nodes. Only those with non-suspicious USG/negative FNAC were included. Patients who were node positive, had prior chemotherapy/radiotherapy/prior groin surgery, or medically unfit for surgery were excluded. Dual-dye technique was used to identify sentinel node. Superficial inguinal dissection was done in all cases and both specimens were subject to frozen section. If ≥ 2 nodes were involved on frozen section, ilioinguinal dissection was done. SLNB had sensitivity, specificity, PPV, NPV, and accuracy of 100%, respectively. There were no false negative results of frozen section study among 168 specimens. Ultrasonography had sensitivity of 50%, specificity of 48.75%, PPV of 4.65%, NPV of 95.12%, and accuracy of 48.81%. We had 2 false negative results of FNAC. Sentinel node biopsy with frozen section study when done in properly selected cases using dual-dye technique in high volume centers by experienced professionals is a very reliable tool in establishing the nodal status, thereby facilitating need directed treatment, thus prevent either over/under treatment.

Introduction

Carcinoma penis is an uncommon malignancy in the West where it affects 0.4% of the males. In India though, its incidence is higher. In urban India, the age adjusted incidence rates vary from 0.7 to 2.3 per 100 000 people in the population-based cancer registries, and in rural India, the rate is three per 100 000 people—more than 6% of all malignant diseases in men [1]. Lymph node metastasis is a strong prognostic indicator in carcinoma of penis. Node negative patients have an excellent survival compared to node positive patients who have worse prognosis [2]. There is a 25% difference in the overall 5-year cancer-specific survival among node negative and node positive patients with invasive carcinoma penis reported in literature [3]. Among the patients who are node negative on clinical examination, approximately 20 to 25% have occult regional lymph node metastasis, thus rendering worse prognosis in these cases [4]. Lymph node dissection helps in prognosticating the patient by accurate staging and aids in improving the survival [5]. The disadvantage of groin dissection is the morbidities it is associated with like flap necrosis, wound infection, wound dehiscence, lymphocele, and lymphedema to name a few. Thus, nearly 80% of the patients who are clinically node negative are over treated with groin dissection. Thus, avoiding prophylactic inguinal dissection based on scientific data not only avoids overtreatment in 80% of patients with cN0 but also avoids treatment-related morbidity in them. Nomograms that predict nodal metastasis that have been proposed have not been validated till date. This study aimed to address the role of sentinel lymph node biopsy (SLNB) in a clinically node negative case of carcinoma penis.

Material and Methods

The study included patients diagnosed having clinically node negative penile cancer. The approvals from Institutional Ethical committee and scientific review board were obtained. A written consent from the patients enrolled in the study was obtained prior to inclusion to the study. We included 84 nodal basins (42 patients) in the study period.

All patients with carcinoma penis (any T stage) who were clinically inguinal node negative were included in the study.

Patients who were clinically node positive, those who received prior chemotherapy or radiotherapy, those who had prior groin surgery, and those who were medically unfit for surgery were excluded from the study.

Primary outcomes were to assess sensitivity, specificity, false negative rates, positive predictive value, and negative predictive value of SLNB compared to superficial inguinal node dissection (SIND).

Secondary outcomes were to know the prevalence of nodal metastasis; to know sensitivity, specificity, false negative rates, positive predictive value, and negative predictive value of frozen section study compared to histopathological examination (HPE); to know sensitivity, specificity, false negative rates, positive predictive value, and negative predictive value of ultrasonography (USG) compared to HPE; and to evaluate false negative results of fine needle aspiration cytology (FNAC).

All patients who were clinically node negative underwent ultrasonography of both the groins and any suspicious nodes were subjected to FNAC. All the patients whose ultrasound examination was normal and/or FNAC negative for malignancy were included in the study. These patients underwent sentinel node biopsy using double-dye technique. Technetium sulfur colloid (1 milli curie) was injected subdermally at the root of the penis 2–4 h prior to the procedure. On table, after draping the surgical site, radioactivity both at the root of penis and sentinel nodes were detected by gamma probe (Fig. 1A and B). The model of the gamma probe used was Europrobe 3.2. Methylene blue (4 ml) was injected at the same site and procedure started after 15 min (Figure 1C). Our preferred incision has always been along the groin crease (Figure 2A) which would give access to both inguinal lymph node dissection and pelvic lymph node dissection (if need arise be). Sentinel nodes were then identified as hot/blue node/suspicious enlarged nodes even if cold or unstained, as the cancer cells might block the afferent channels of the lymph node harboring metastasis, there is a chance of missing these nodes if only staining and radioactivity is used as the criteria to identify sentinel nodes as the dye might be redirected to the “neo” sentinel nodes (Figure 2B and C). Non-sentinel nodes were those nodes in the superficial inguinal group which were not sentinel nodes. The sentinel nodes were sent for frozen section and superficial inguinal node dissection performed which too was subjected for frozen study. If 2 or more nodes were positive for metastases in both specimens put together (sentinel nodes and superficial inguinal node dissection), deep inguinal and pelvic lymphadenectomy was done.

Fig. 1.

Showing technique of SLNB. Panel A — activity of Tc sulfur colloid recorded by handheld gamma probe. Inset showing the radioactivity count on the display module of Europrobe 3.2. Panel B — localizing the sentinel node by gamma probe. Panel C — intra-operative injection of methylene blue at root of penis

Fig. 2.

Showing intra-operative photographs of SLNB demonstrating blue and hot nodes. Panel A — marking the groin crease, on which the incision is placed. Panel B — blue node (marked by arrow head). Panel C — Tc colloid activity in the blue node (activity seen in display module)

Statistical Methods

Inguinal nodes were considered to be involved by the tumor if metastasis was detected on histopathological examination on paraffin embedded tissue of either the sentinel node specimen or the superficial inguinal node dissection specimen. This was considered as the gold standard against which the results of ultrasonography, FNAC, SLNB, and frozen section study were compared to. Thus, sensitivity, specificity, positive predictive values, and negative predictive values were calculated for ultrasonography, frozen section, and SLNB.

Results

Mean age of the patient cohort was 54 years. Sixteen of the 42 patients were smokers (38.1%). All the patients underwent surgery for primary (39 partial penectomy, 2 total penectomy, 1 wide excision) and bilateral sentinel node biopsy and superficial inguinal node dissection. Average sentinel nodes harvested was 2.86. Average nodes harvested in superficial inguinal node dissection were 9.88. Four patients with a positive FNAC of unilateral groin were excluded from the study.

There were 4 instances where the groin harbored occult metastases (negative on USG/FNAC), thus accounting to a prevalence of occult metastasis of 4.76%. All the 4 instances (3 patients) of occult metastasis were detected by sentinel nodes. In two patients, sentinel node was the only positive node in the superficial groin nodal basin. The third had one sentinel and one non-sentinel superficial inguinal node positive for metastasis on one side and sentinel node was the only positive node in the other groin. Among the occult metastases, all were identified by a positive sentinel node. There was no instance of sentinel node not able to identify the occult metastases (non-sentinel node being positive without sentinel node being positive). Thus, in our study, the sensitivity, specificity, and negative predictive value of sentinel nodes biopsy were 100%. Of the 84 ultrasonographies done, 2 had true positive and 2 had false negative result. Forty-one had false positive result and 39 had true negative results. Thus, ultrasonography had a sensitivity of 50%, specificity of 48.75%, positive predictive value of 4.65%, negative predictive value of 95.12%, and accuracy of 48.81%. If the 4 patients excluded from the study were also included in the calculation, ultrasonography had a sensitivity of 62.5%, specificity of 51.19%, positive predictive value of 10.87%, negative predictive value of 93.48%, and accuracy of 52.17%. Among the 62 FNACs, we had 4 cases positive for metastases (excluded from study). Among those included, we had 2 false negative results of FNAC out of the 54 carried out. Thus, among the 62 FNACs, the sensitivity was 66.67%. There were no false negative results of frozen section study among the 168 specimens. After a median follow-up of 28.5 months, 5 patients had disease relapse, 4 of which were relapse confined to the thorax and 1 had a disseminated relapse. Of the 5 relapses, all except one have succumbed to the disease.

Discussion

This study demonstrates the high reliability of sentinel node biopsy done by dual-dye technique in properly selected patients resulting from a stringent protocol. The ultrasonography when assessed in isolation fared poorly in its sensitivity, specificity, positive predictive value, and accuracy which we feel is not how the tool must be looked at. Other studies too have showed poor sensitivity and specificity when ultrasonography alone as a tool to assess the nodal status when compared to the final histopathology report [6]. Instead, if ultrasonography is viewed as a screening tool for ruling out patients having suspicious nodes, it fared very well as seen by the negative predictive value of 95.12% in our study. USG-guided FNAC in our study had a negative predictive value of 96.29%. Thus, it acted as good secondary screening tool in assessing the nodal status of the groin. Kroon et al., in their study on US-guided FNAC, found the sensitivity and specificity of US-guided FNAC were 39% and 100%, respectively [7]. We used dual-dye technique as it has established its supremacy over single-dye technique in SLNB. Lucio et al. published the results of their prospective study on 27 newly diagnosed penile carcinoma patients using only single-dye technique (sodium phytate technetium) and reported a false negative rate of 42.8% [8]. The wonderful results of SLNB in our study should not only be attributed to the use of dual-dye technique but also to stringent adherence to the protocol which was formulated prior to starting of the study at every level, a thorough assessment by the clinician in the outpatient department selecting potential cases, having a single dedicated cytopathologist and uro-histopathologist in all our cases, and having a surgical team well versed with sentinel node biopsy from the commencement of the study. This stringent protocol must be recommended to all patients who are initially deemed to be clinically node negative just on clinical palpation. The protocol aids in avoiding a futile SLNB. The study conducted in Netherlands Cancer Institute also reported improved results after they changed their study protocol few years into the study. On following the modified protocol wherein they added ultrasonography +/− FNAC to all patients, they reduced the false negative rates from 19.2 to 4.8% [9]. By adding USG-guided FNAC to their protocol, Kroon et al. avoided an otherwise futile DSLNB in 11% of the cases [7]. Perdonas et al. in their study too demonstrated a negative predictive value of 100% for SLNB [10]. All the relapses in our study were suggestive of hematogenous route of dissemination further adding credence to the concept of existence of other channels of tumor spread apart from orderly spread along the lymphatic route, thus making a more radical dissection futile when the sentinel nodes are negative.

Conclusions

Sentinel node biopsy with frozen section study when done in properly selected cases using dual-dye technique in high volume centers by experienced professionals can be a very reliable tool in establishing the nodal status, thereby facilitating a need directed treatment and thus prevent either over/under treatment. Strict adherence to the protocol must be followed in selecting candidates for SLNB.

Declarations

Ethics Approval

The content of the article has not been published or submitted for publication elsewhere. The study was approved by the ethics committee of the Basavatarakam Indo American Cancer Hospital and Research Institute and conformed to the provisions of the Declaration of Helsinki in 1995.

Consent to Participate

Informed consent was obtained from the subject, and patients’ anonymity is preserved.

Conflict of Interest

The authors declare no competing interests.