European Journal of Plastic Surgery

, Volume 41, Issue 2, pp 183–188 | Cite as

Importance of sentinel lymphatic node biopsy in patients with low-risk and high-risk cutaneous squamous cell carcinoma

  • Donatas Samsanavicius
  • Vygintas Kaikaris
  • Jurgita Makstiene
  • Adas Cepas
  • Rytis Rimdeika
Original Paper
  • 33 Downloads

Abstract

Background

Cutaneous squamous cell carcinoma (CSCC) is the second most common non-melanoma skin cancer type. The purpose of our study was to compare the diagnosis of CSCC micrometastases using sentinel lymphatic node biopsy (SLNB) in sentinel lymphatic nodes (SLN) in patients with high-risk and low-risk CSCC.

Methods

A prospective clinical study was carried out. Patients with clinically diagnosed and histologically confirmed CSCC were included in the study if no metastases were observed preoperatively. Patients were divided into low-risk (n = 42) and high-risk (n = 46) groups according to the risk factors. Patients underwent a one-stage operation, tumor excision, and SLNB. Primary tumor characteristics and metastases rates were compared between the groups. Statistical analysis was performed using SPSS 21.0 software. A significance level of 0.05 was chosen.

Results

Micrometastases were found in three high-risk group patients (6.54%). However, the rate of micrometastases in the low-risk group was 0%. The mean size of primary tumors in the low-risk group was 0.97 cm ± 0.44 and was 2.25 cm ± 1.74 in the high-risk group (p < 0.001). The distribution of ulcerated and non-ulcerated tumors differed between the risk groups (p = 0.035). The mean Breslow thickness of CSCC was higher in the high-risk group (2.97 mm ± 1.49 versus 1.39 mm ± 0.51 in the low-risk group, p < 0.001).

Conclusions

According to the results of our study, SLNB should be performed for high-risk CSCC patients only. Primary tumor size, depth, and fact of ulceration correlate with the rate of micrometastases, which is 6.54% for high-risk CSCC patients.

Level of Evidence: Level II, risk/prognostic study.

Keywords

Cutaneous squamous cell carcinoma Micrometastases Sentinel lymphatic node biopsy SLNB 

Introduction

Cutaneous squamous cell carcinoma (CSCC) is a malignant tumor of the epidermis that grows from skin squamous cells [1, 2]. CSCC is the second most common non-melanoma skin cancer type. The highest number of cases of CSCC is diagnosed in Australia, New Zealand, and southern states of USA. More than 200,000 new CSCC cases are diagnosed in the USA annually [1, 2, 3, 4, 5, 6, 7, 8, 9]. The highest morbidity of CSCC in Europe is in Sweden (34.4/100000 population) and Switzerland (28.9⁄100,000 population). In other northern European countries (Norway, Finland, Denmark), morbidity is significantly lower (around 10/100000 population). The most frequent cause of CSCC is skin exposure to ultraviolet (UV) rays. Epidemiological investigations have found a correlation between occurrence of CSCC and previous severe sunburns [5, 10, 11, 12, 13, 14, 15, 16]. In North and South America, Australia, and Germany, people who immigrated to regions of high sun activity as adults suffer from CSCC less than those who arrived in their childhood. People working outdoors in sunlit zones are more likely to be affected than those who work indoors where sun exposure is lower [11]. The impact of UV sun rays on skin accumulates with age, and therefore, CSCC occurs in people of older ages. A study performed in Scandinavia revealed that people who travel to countries that are south of 45° latitude are at higher risk of CSCC and other skin cancer types. Ultraviolet-B rays (290–320 nm) are the most carcinogenic and ultraviolet-A rays (320–400 nm) are less carcinogenic [12, 13, 14, 15, 16, 17, 18, 19, 20, 21]. CSCC occurs in the most sun exposed parts of the body (face, neck, hands, and calves). However, CSCC can be caused by iatrogenic radiation such as radiotherapy. Patients after kidney or other organs transplantation and patients with HIV are at 18–36 times higher risk of CSCC than the general population, since immunosuppression is a high-risk factor for CSCC occurrence. Scars and chronic wounds are another high-risk factor for CSCC occurrence [13, 22, 23]. Diseases such as xeroderma pigmentosum, systemic lupus erythematosus, and actinic keratosis accompanied with UV sunrays may cause CSCC even in younger people [11, 13, 17, 24]. People with freckles, light and red hair, light eyes, those who tend to get severe sun burns (skin type I–II according to Fitzpatrick), and those who hardly get sun burns are at higher risk of CSCC [1, 2, 4, 5, 6, 17]. CSCC risk determination is important for tumor prognosis evaluation. High-risk CSCC has higher metastases and recurrence frequency. Presently, CSCC is diagnosed when increased regional lymphatic nodes are found clinically and/or distant metastases are determined by noninvasive investigation methods. Clinically diagnosed metastases are a sign of advanced and spread CSCC. Using sentinel lymphatic node biopsy (SLNB) has been suggested in the medical world for more exact evaluation of CSCC [25, 26, 27, 28, 29, 30]. The purpose of our study was to compare the diagnosis of CSCC micrometastases in sentinel lymphatic nodes (SLN) using SLNB in patients with high-risk and low-risk cutaneous squamous cell carcinoma.

Methods

A prospective clinical study was carried out from July 2012 to January 2015 at the Clinic of Plastic and Reconstructive Surgery Hospital of Lithuanian University of Health Sciences (LUHS). The purpose of this study was to evaluate the frequency of micrometastases in sentinel lymph nodes in patients with low-risk and high-risk CSSC. The study was approved by the Ethics Committee of Kaunas Regional Biomedical Research.

Before hospitalization in the Clinic of Plastic and Reconstructive Surgery in the LUHS Hospital, all the patients were examined in the Clinic of Skin and Venereal Disease. Patients with suspected CSCC and a general physician referral arrived for a dermatologist’s consultation. Dermatoscopic examination following a punch biopsy was performed and sent for pathological CSCC verification. After histological tumor verification, patients were further examined for CSCC metastases. If no distant or regional lymph node metastases were found during noninvasive examination (panoramic radiography of the chest and ultrasonography of upper abdominal floor and regional lymph nodes) and CSCC deeper than in situ was determined, patients were included in the study upon their consent. Then, further surgical treatment was scheduled.

Patient grouping to low-risk and high-risk

The patients included in the study were grouped to low-risk and high-risk CSCC groups according to the guidelines of the National Comprehensive Cancer Network (NCCN) [31]. Grouping criteria are summarized in Table 1. If at least one high-risk criterion of CSCC was present together with low-risk CSCC criterion, the patient was included in the group of high-risk CSCC. SLNB was performed for both study groups.
Table 1

Selection criteria of patients into groups of low-risk and high-risk cutaneous squamous cell carcinoma

Group of high-risk cutaneous squamous cell cancer

Group of low-risk cutaneous squamous cell cancer

Tumor diameter is ≥2 cm on the anatomical locations of the torso, arms, and legs, ≥1 cm on the cheeks, forehead, scalp, and neck, and ≥0.6 cm on the ears, lips, genitals, hands, and feet.

Tumor diameter is <2 cm on the anatomical locations of the torso, arms, and legs, <1 cm on the cheeks, forehead, scalp, and neck, and <0.6 cm on the ears, lips, genitals, hands, and feet.

Tumor thickness according to Breslow ≥2 mm or Clark IV, V.

Tumor thickness according to Breslow <2 mm or Clark I, II, III.

Histologically poorly differentiated (G3) or undifferentiated (G4) tumor.

Differentiated (G1) or moderately differentiated (G2) CSCC.

Histologically confirmed perineural and perivascular spread.

Tumor lesion of the entire dermis layer or subcutaneous fat, tumor penetration into the muscles, cartilages, and bones.

Lesion of part of the dermis thickness.

Skin SCC recurrence.

Operative hospitalization period of patients with skin SCC

On the hospitalization day, the patients included in the study underwent radionuclide lymphoscintigraphy at the Department of Nuclear Medicine of the LUHS Hospital. Radiopharmaceutical preparation (RF) nanocolloid (Nanocoll®, 99mTc-albumin 0.1–0.2 mL, Amersham Health, Milan, Italy) was subcutaneously injected and evenly distributed around the primary tumor (50–250 MBq in total). Then, a planar gamma camera (Siemens e.cam®, Siemens Medical Solutions, Illinois, USA) was used to perform a dynamic lymphoscintigram in order to determine lymph leakage from the tumor and the greatest RF accumulation in a sentinel lymph node. Static lymphoscintigrams were performed 20 min after an RF injection. Surgery was initiated either 4 h after an RF injection before remote lymph nodes were filled with radionuclide or after 16–24 h when the radioactive colloid already retreated from remote lymph nodes. All the patients had an excision of CSCC and SLNB performed. Excision margins of 4 mm for tumors less than 2 cm in diameter and 6 mm for tumors larger than 2 cm were chosen. In a few cases, sentinel lymph nodes were detected very close to the tumor. A sound signal from a radiometer (Neoprobe Neo2000®, Neoprobe Corporation, Dublin, Ireland) emanating from locations around the primary tumor where radioactive materials accumulated hindered the detection of sentinel lymph nodes; therefore, the tumor was removed first and then the sentinel lymph node biopsy was performed. The excised tumor and sentinel lymph nodes were sent for histological examination.

Histological examination of CSCC and sentinel lymph nodes

The fragments of skin and the subcutaneous layer and lymph nodes excised during the operation were fixed in a 10% solution of formaldehyde and were sent by scheduled order on the same day to the Clinic of Pathological Anatomy of the LUHS Hospital, where macroscopic and microscopic examinations of the material were performed. Histological preparations were hematoxylin-eosin stained. Additional staining for immunohistochemical reagent cytokeratin 5 was performed. Staining of histological samples using two methods was applied in order to minimize the risk of a false negative SLN. The Breslow thickness of CSCC was evaluated.

Statistical analysis

Statistical data analysis was conducted using the IBM Statistical Package for the Social Sciences Statistics 23.0. Quantitative variables were described by providing means and standard deviations. The hypotheses about the differences of the means in the compared independent groups were tested using a parametric Student’s t test or nonparametric Mann-Whitney U test. Associations between qualitative variables were analyzed using the independent chi-square (χ 2) criterion or the Fisher’s exact test. A significance level of 0.05 was chosen.

Results

A total of 88 patients were included in the study and were separated into the low-risk group (42 patients) and high-risk group (46 patients). The risk groups were homogenous in terms of age, gender, and tumor localization [Table 2; Table 3]. The mean diameters of CSCC were significantly different between the low-risk group (0.97 cm ± 0.44) and the high-risk group (2.25 cm ± 1.74) (p < 0.001), [Fig. 1]. There were 30 patients (65.2%) with ulcerated CSCC in the high-risk group and 18 patients (42.9%) in the low-risk group. The distribution of ulcerated and non-ulcerated tumors differed between the risk groups (p = 0.035), [Table 4]. The mean Breslow thickness of CSCC was higher in the high-risk group (2.97 mm ± 1.49) than in the low-risk group (1.39 mm ± 0.51) (p < 0.001), [Fig. 2]. The assessment results of CSCC origin demonstrated that tumors appeared in healthy skin in the majority of cases (65%). In 27% of cases, CSCC appeared from earlier diagnosed actinic keratosis, skin warts, or other benign skin formations. Scars and chronic ulcers, as a causal factor, accounted for 8% of all CSCC [Fig. 3].
Table 2

Demographics of the patients

Factor

Low-risk group

High-risk group

p value

Age (mean years ± SD)

73.38 ± 12.36

75.98 ± 8.92

0.52

Gender

 Male

 Female

13 (31%)

29 (69%)

20 (43.48%)

26 (56.52%)

0.24

Table 3

CSCC localization according to risk group

Regions

Low-risk group n (%)

High-risk group n (%)

Head and neck

23 (54.76%)

35 (76.09%)

Torso

4 (9.52%)

2 (4.35%)

Arms

6 (14.29%)

6 (13.04%)

Legs

9 (21.43%)

3 (6.52%)

Overall

42 (100%)

46 (100%)

p = 0.11

Fig. 1

The mean size of CSCC according to the risk group

Table 4

The rate of ulcered and non-ulcered CSCC according to the risk group

 

Low-risk group n (%)

High-risk group n (%)

Ulcered CSCC

18 (42.86%)

30 (65.22%)

Non-ulcered CSCC

24 (57.14%)

16 (34.78%)

Overall

42 (100%)

46 (100%)

p = 0.03

Fig. 2

The mean depth of CSCC among the risk groups

Fig. 3

The origin of CSCC in the study population

During our research, 153 sentinel lymph nodes (87 in the high-risk group and 66 in the low-risk group) were found and excised in the patients with CSCC. Their histological preparations were stained using two methods: hematoxylin-eosin and immunohistochemical staining for cytokeratin 5. Both staining methods confirmed micrometastases in five sentinel lymph nodes of three high-risk group patients (6.54%) with CSCC on the anatomical locations of the head, arm, and foot. No micrometastases were found in the low-risk group patients. The patients with micrometastases in SLN underwent radical lymphadenectomy. Following this treatment, there was no recurrence of CSCC during the study period.

The results of both staining methods demonstrated that micrometastases were detected in the same five sentinel lymph nodes. No new micrometastases were additionally found with immunohistochemical marker cytokeratin 5.

Discussion

Cutaneous squamous cell carcinoma is prone to metastasize via the lymphatic pathway to regional lymph nodes [17, 25, 26]. Instrumental investigation of cancer expansion is effective only if the spread of the tumor is advanced, the regional or distant lymph node/nodes are infiltrated by tumor cells, or tumor metastases are detected. Instrumental investigation does not allow for evaluating spread of tumor in the early stage when there are no morphological modifications of the SLN. The importance of SLNB in early diagnostics of CSCC spread has been discussed worldwide for 2 decades which should help to avoid unnecessary complete lymph node dissection and ensure early detection of metastasis [32, 33]. It is believed that early detection of micrometastases in SLN and timely adequate treatment would decrease patient mortality from CSCC significantly. Meanwhile, there are no studies with a large sample size performed that reliably evaluate the importance of SLNB in the early diagnostics of CSCC. Application of efficient treatment methods, long-term recurrence-free survival after diagnosing micrometastases and indications for SLNB are still not defined. Mullen et al. found no micrometastases in patients with CSCC and reported a metastatic rate of 0% [34]. However, the sample size of this study was small (n < 14) and the results were not accurate. In 2014, Fukushima et al. reviewed and obtained clinical data from 54 patients with a rate of 7.4% positive SLNB. Limiting the cases to those of ≥ pT2, the positive rate became 12.9% and there were no patients who showed positive SLNB with pT1 [30]. In our study, micrometastases were detected in patients with ≥ pT2. The general rate of micrometastases in CSCC patients was 2.64% (low-risk group—0%, high-risk group—6.52%). In their systematic review of 73 patients, Ahmed et al. stated that ten (13.7%) had a positive SLN in the head and neck region and the tumor diameter was not associated with positive SLNB; however, the mean size of the tumor in their study was 3.09 cm [33]. According to our data, micrometastases in SLN were detected in high-risk CSCC patients with a mean tumor size of 2.25 cm ± 1.74. On the basis of our investigation, in all cases when positive SLN was detected, the primary tumor was ulcerated. This confirmed the higher risk of spread, and the ulceration of CSCC should be defined as one of the indications for using SLNB. In their retrospective data analysis, Jensen et al. claim that one of the most important features of metastases is the depth of the tumor [35], and the results of our study confirm their findings. The average tumor depth according to Breslow in the high-risk group (2.97 mm ± 1.49) with micrometastases in SLN was significantly higher compared to the low-risk group (1.39 mm ± 0.51) with no micrometastases.

Further treatment after positive SLNB should be discussed. One study suggests that the period of time that lymphadenectomy can prevent the spread of tumors is relatively short [33]. In our investigation, all patients with positive SLNB underwent lymphadenectomy. Following this treatment, no recurrence occurred during the study (average recurrence-free survival follow-up period—18.76 ± 10.88 months). We believe that SLNB should only be performed in high-risk CSCC patients and not in low-risk CSCC patients. However, large sample size, multicenter prospective studies should be conducted in the future to confirm our results.

Notes

Compliance with ethical standards

Conflict of interest

Donatas Samsanavicius, Vygintas Kaikaris, Jurgita Makstiene, Adas Cepas, and Rytis Rimdeika declare that they have no conflict of interest.

Ethical approval

All procedures involving human participants were performed in accordance with the ethical standards of the Ethics Committee of Kaunas Regional Biomedical Research and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Funding

None

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Donatas Samsanavicius
    • 1
    • 2
  • Vygintas Kaikaris
    • 1
    • 2
  • Jurgita Makstiene
    • 1
    • 3
  • Adas Cepas
    • 1
    • 4
  • Rytis Rimdeika
    • 1
    • 2
  1. 1.Hospital Kauno KlinikosLithuanian University of Health SciencesKaunasLithuania
  2. 2.Plastic and Reconstructive Surgery DepartmentHospital of Lithuanian University of Health Sciences Kauno KlinikosKaunasLithuania
  3. 3.Department of PathologyHospital of Lithuanian University of Health Sciences Kauno KlinikosKaunasLithuania
  4. 4.Medical facultyLithuanian University of Health SciencesKaunasLithuania

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