For the detection of sentinel lymph nodes, specific tracers are injected intradermally close to the tumor to trace the characteristic drainage pattern for each patient. In general, radioactive isotopes are used (technetium [Tc]) in the form of colloidal particles that may or may not be associated with vital dyes.

After the administration of tracer, increased interstitial pressure drives the particles through the vessels to the draining nodes, where they remain (in what is the sentinel lymph node). Appropriate imaging techniques are then used to detect the tracers.

According to the size of the colloid used to vehiculize the Tc (between 2nm and 400nm), the rate of transport to and residence time in the lymph node will vary. The most widely used radiomarkers include 99mTc-albumin nanocolloid, filtered 99mTc-sulfur colloid, and 99mTc-amonium sulfide. It should be noted that none of these colloidal systems have a uniform particle diameter but rather a range of diameters distributed around a mean value. The most widely used are intermediate colloids, between 5 and 80nm. These include nanocolloidal albumin, colloidal sulfide, and colloidal rhenium sulfide, which all have the advantage of lower systemic penetration and sharply outline the draining nodes.

Preoperative detection is performed in the following ways:

• 1.

  Dynamic scintigraphy, which allows the direction and number of outflow paths to be visualized.

• 2.

  Static scintigraphy, which visualizes the final site of the tracer, marking a “hot spot” with dye in the skin.

In recent years, studies have been performed with new tracer systems such as the following2–6:

• 1.

  Imaging of indocyanine green (Dianogreen) fluorescence with infrared cameras. A fluorescent tracer is used that can be visualized with cameras set up to detect the wavelength emitted. This is a real-time system.The advantages of this method are that a) it does not depend on γ-ray counters or radioisotope detectors; b) lymph node detection is easier than with radiotracers; c) it is more useful for detecting nodes close to the tumor; and d) neither the patients nor the operators are exposed to ionizing radiation.

  The disadvantages of this method are that a) it only detects lymph nodes up to 2cm deep and b) quantitative study of tissue fluorescence is difficult, and so there is a risk of missing sentinel lymph nodes when other larger ones are resected.

• 2.

  Gold nanocages detected by photoacoustic systems. These nanocages are readily conjugated to antibodies for specific receptors.4

Although the studies performed to date have included low numbers of patients, most suggest that this technique could be useful in high-risk squamous cell carcinoma. Patients with positive sentinel lymph node biopsy can be given more aggressive treatments and follow-up protocols, which could translate into longer survival.

Morbidity would be decreased in patients with negative sentinel lymph node biopsy as more aggressive and unnecessary treatments would be avoided.

The main difficulty comes when establishing the indication, that is, when we have to define what constitutes high risk, given the different criteria used in the studies. The study by Brantsch et al25 could be used as a starting point, with subsequent studies designed with unified criteria.

With the data currently available, sentinel lymph node biopsy seems appropriate in squamous cell carcinoma with a risk of metastasis of greater than 5%, which in the studies reviewed is when the squamous cell carcinoma has a depth greater than 6mm.

We also believe that it is important not to lose sight of the life context of our patients. They are usually very old, and performing these types of techniques would not make sense in terms of risk-benefit.

Likewise, we should take into account the erratic nature of lymphatic drainage in the head (a common site for squamous cell carcinoma of the skin), and this could also limit the usefulness of the technique.

No staging system has been universally accepted; in fact, until 2009, 5 different staging systems were being used to describe Merkel cell carcinoma. For this reason, the American Joint Committee on Cancer established a new staging system based on consensus38 (Table 1).

Clinical staging is considered the most important factor; thus, survival at 5 years is 81% for stage Ia, 67% for stage Ib, 52% for stage II, and 11% at 2 years for stage III.39

Recurrence rates between 40% and 45% have been reported, and can be as high as 77% when tumors are located on the head and neck. The mean time to recurrence is 8 months, and 90% recur within 2 years.40

Patients with Merkel cell carcinoma should undergo detailed study that includes a search for satellite skin lesions, lymph node palpation, and computed tomography, although Sheela et al41 concluded in their review that computed tomography has poor sensitivity for detecting lymph node involvement and a high specificity for detecting distant metastases.

In fact, when tumor involvement is visible in computed tomography, the chance of curative treatment vanishes. However, several recent studies discuss the use of positron emission tomography combined with computed tomography in the follow-up and subsequent management of patients with this diagnosis.42

Lesion size greater than 2cm and the presence of local recurrence or distant metastases are considered factors for poor prognosis. Some authors have also found that histology showing small or intermediate cells with a high mitotic index can also be considered as predictors of poor prognosis. Other authors, however, have found no prognostic value in histologic type (solid, trabecular, or diffuse) or in cell size (small, medium, or large).43,44 The most important prognostic factor at present is the presence of lymph node involvement, making sentinel lymph node biopsy a valuable diagnostic technique.45

The presence of lymph node involvement and the presence of distant metastases are the prognostic factors associated with the poorest survival rates in Merkel cell carcinoma. The need for prophylactic regional lymphadenectomy is being debated in view of the associated morbidity and the lack of improvement in survival.

Complete lymph node dissection has been proposed for large tumors, those on the head and neck, those with a small-cell histology, and those with lymphovascular invasion.36

Performing sentinel lymph node biopsy is an attractive alternative to elective complete lymphadenectomy in that it allows more appropriate selection of candidates and also early detection of lymph node involvement.The contribution of sentinel lymph node biopsy in Merkel cell carcinoma is generally accepted.46–49Table 2 summarizes the studies conducted on this topic to date.37,45–64

Several authors have reached the conclusion that the risk of recurrence and metastatic disease is greater if a sentinel lymph node biopsy is positive, while a negative biopsy is predictive of better short-term survival.36

It is important to note that Merkel cell carcinoma is a rare condition, and so experience with sentinel lymph node biopsy in this setting is necessarily limited. Gupta et al36 described their experience in 61 patients with Merkel cell carcinoma. Thirty of these underwent sentinel lymph node biopsy and they also performed a metaanalysis of a further 92 case reports of patients diagnosed with Merkel cell carcinoma who underwent sentinel lymph node biopsy. Overall, then, 122 patients with Merkel cell carcinoma with no clinical evidence of lymph node spread were studied. Sentinel lymph node biopsy was performed, and found to be positive, in 39 (32%). The authors also found that the incidence of positive sentinel lymph node biopsy increased with increasing primary tumor size such that in patients with Merkel cell carcinoma larger than 2cm, 52% had a positive sentinel lymph node biopsy compared to 29% of patients with a tumor size less than 2cm (although the differences were not statistically significant, P=.23). At 3 years, the recurrence rate in patients with a positive sentinel lymph node biopsy (32%) was 60%, 3 times higher than the rate in patients with a negative sentinel lymph node biopsy (20%). This study demonstrates the high rate of positive sentinel lymph node biopsies in patients with no clinical or radiologic evidence of involvement of lymphatic territories; from a prognostic point of view, the authors found survival benefit in association with a positive lymph node biopsy when patients underwent early lymphadenectomy compared to those who did not undergo the procedure. The authors concluded that sentinel lymph node biopsy should be performed in patients with N0 Merkel cell carcinoma to establish prognosis and determine treatment.

In the largest series published to date, 251 patients were included. The authors reported a 5-year survival of 97% in patients without lymph node involvement, compared to a survival of 52% in those with lymph node involvement.40

By way of conclusion, and according to the 2010 NCCN guidelines, when there is no clinical or radiologic evidence of lymph node involvement in most patients with Merkel cell carcinoma, sentinel lymph node biopsy should be performed as part of the routine management of the tumor (regardless of size), unless the procedure is contraindicated for other medical reasons.

One exception would be Merkel cell carcinoma located on the head and neck. In this case, the rate of false negatives is very high and so the technique is not routinely recommended, even though it may provide prognostic information.

Extramammary Paget disease is a term for a type of rare tumor usually located on the genitals, although it has been reported at many other sites. Clinically, it presents as a hypo- or hyperpigmented erythematous plaque with poorly defined edges. The rate of local recurrence is high. Generally, prognosis is good, as the tumor cells tend to remain in the epidermis and rarely metastasize. Nevertheless, lymph node metastasis rates of up to 26% have been reported for invasive primary tumors.65

Management of patients with extramammary Paget disease, with no clinical evidence of lymph node involvement, is subject to debate. In patients with an invasive primary tumor with no clinical evidence of lymph node involvement, elective lymphadenectomy is recommended. Sentinel lymph node biopsy might be a useful approach in these patients.

In 2008, Hatta et al66,67 published a series of 76 patients, 24 of whom had undergone sentinel lymph node biopsy. The biopsy was positive in 12, and these patients underwent complete lymph node dissection. Among the parameters analyzed in this study was degree of tumor invasion. Tumors were thus divided into tumors that were wholly within the epidermis, those with microinvasion of the papillary dermis, and those with invasion of the reticular dermis and subcutaneous cell tissue. The authors found that 43 of the 76 patients studied (57%) had intraepidermal tumors, 22 (29%) had tumors with microinvasion of the papillary dermis, and 22 (14%) had tumors with invasion of the reticular dermis and subcutaneous cell tissue.

The authors’ univariate analysis found that patients with tumors showing invasion of the reticular dermis and subcutaneous cell tissue had a higher risk of mortality than those with intraepidermal tumors or those with tumors showing microinvasion of the papillary dermis (P=.01). They concluded that sentinel lymph node biopsy would be indicated in this study and in another conducted in 13 patients, all with invasive extramammary Paget disease, as the frequency of lymph node involvement, even when not clinically evident, is greater than in noninvasive disease.

The technique normally used for detection in sentinel lymph node biopsy is less sensitive for detecting lymph nodes located close to the tumor in extramammary Paget disease, as the radiotracer signal for the node overlaps with that of the primary tumor. In these cases, some authors have suggested that fluorescence with indocyanine green, detected with an infrared camera, could be useful.6

Adenocarcinomas of sweat glands form a heterogeneous group of tumors derived from eccrine or apocrine sweat glands. Given the low incidence of these tumors, randomized controlled trials are difficult to perform. Several studies have reported that these tumors, and aggressive digital papillary adenocarcinoma and the hidradenocarcinomas in particular, often spread to regional lymph nodes. In general, adnexal adenocarcinomas do not share a typical clinical presentation. The tumor grows rapidly, and bleeding and ulceration are common. Biopsy is usually required for diagnosis.

Little has been reported in the literature about sentinel lymph node biopsy in these patients.68–70 The largest study in which the procedure was used included 6 patients with sweat gland adenocarcinomas (3 hidradenocarcinomas, 2 eccrine duct cell carcinomas, and a porocarcinoma).71 Sentinel lymph node biopsy was positive in 4 patients, 2 of whom underwent regional lymphadenectomy while the other 2 did not undergo the procedure for medical reasons. All patients were alive and free of disease at the end of follow-up, which ranged from 2 to 19 months, with a mean of 12 months.

The authors indicated that although sentinel lymph node biopsy could be useful for staging in these patients, the prognostic value or usefulness for guiding treatment decisions would need studies with larger numbers of patients.

Sebaceous gland carcinoma is an uncommon tumor that arises in the adnexal epithelium of sebaceous glands. It is most frequently located in the palpebral region (75%), although nonocular sites have also been reported. Clinical diagnosis is difficult and the tumor can easily be mistaken for other skin tumors or chronic inflammatory disease. The most frequent ocular presentation is in the form of a solitary, small, firm, raised nodule of yellow-orange color.

Nonocular tumors are usually on the head and neck, and their appearance is that of a yellow-orange nodule.

The tumor is aggressive and associated with high mortality and metastasis rates. Mortality rates range from 9% to 50%, but it seems that with early diagnosis these rates are declining.72

The mortality rates for ocular sebaceous carcinoma range from 11% to 30%, with distant metastases in 3% to 25%. In principle, it was thought that nonocular sebaceous carcinoma had a better prognosis than its ocular counterpart, but in a study of 91 patients with nonocular sebaceous carcinoma, a recurrence rate of 29% was reported with a metastasis rate of 21%.73

Several articles report studies of sentinel lymph node biopsy in ocular sebaceous carcinomas, suggesting that the technique is safe and simple, and that it could be useful for better staging and clinical management.

When the authors performed sentinel lymph node biopsy on 10 patients with sebaceous carcinoma on the eyelid (primary tumor in 4 and recurrent tumor in 6), the sentinal node was negative in all, but lymph node metastasis was detected in 2 of the 10 patients during follow-up. Despite these findings, the authors concluded that sentinel lymph node biopsy is a safe technique and that it should be considered in sebaceous carcinomas with a high risk of metastasis (recurrent, large size, or those involving postseptal structures).74,75

Nijhawan et al76 studied 6 patients with sebaceous carcinoma of the eyelid with clinically negative lymph nodes, and 5 of them underwent sentinel lymph node biopsy. This was negative in all cases, although the authors concluded that the technique could be useful given the high rate of lymph node involvement reported for such patients.

By way of conclusion, we could say that the data currently available do not support the usefulness of this technique in sebaceous carcinoma.

Sentinel lymph node biopsy could play an important part in staging of primary cutaneous lymphomas. Several authors point out that, in their experience, lymph node involvement is the first stage of extracutaneous spread.

Very little has been published on the topic, however, and so larger, robustly designed studies would be needed to substantiate the theories put forward by these authors.63,77–79 Our literature review did not find any study that concluded that sentinel lymph node biopsy can determine whether lymph node involvement is primary or an extension of a cutaneous lymphoma, only whether there is lymph node involvement or not.