Basal Cell Carcinoma
Location/Morphology: Predilection for lower eyelid, nodular or ulcerative type.
Color: Often accompanied by melanin pigmentation.
Metastasis: Low-grade malignancy that does not metastasize distantly.
Sentinel Lymph Node Biopsy for Periorbital Malignant Tumors
Key Points at a Glance
Section titled “Key Points at a Glance”1. Sentinel Lymph Node Biopsy for Periocular Malignancies
Section titled “1. Sentinel Lymph Node Biopsy for Periocular Malignancies”Sentinel lymph node biopsy is a procedure to confirm the presence of malignant cells in draining lymph nodes and identify potential systemic micrometastases.
History
Section titled “History”The concept of sentinel lymph node biopsy has evolved in stages.
- 1960: The concept of the “sentinel node” was first proposed for parotid tumors.
- 1970s: The concept of lymphatic mapping using lymphoscintigraphy was introduced.
- 1990s: Intraoperative mapping using isosulfan blue dye for cutaneous melanoma was published, marking the beginning of the modern sentinel lymph node biopsy era.
- 2000: The concept of sentinel lymph node biopsy for patients with conjunctival melanoma was introduced.
- 2001: The first case of sentinel lymph node biopsy in conjunctival melanoma was reported.
Epidemiology (Frequency of Metastasis)
Section titled “Epidemiology (Frequency of Metastasis)”All malignant tumors of the ocular adnexa except basal cell carcinoma have a tendency to metastasize to regional lymph nodes. The frequency of regional lymph node metastasis by tumor type is as follows:
- Conjunctival melanoma: Regional lymph node metastasis 15–41%, lymph node metastasis approximately 25–52% (varies by report) 1)
- Eyelid melanoma: 29%
- Sebaceous carcinoma: 7–20%
- Eyelid squamous cell carcinoma: 1.3–24.3%
- Eyelid Merkel cell carcinoma: 21% in the largest single study, range 30–66% in reports
A large Indian study (536 cases) reported a tumor composition significantly different from Western countries: sebaceous carcinoma 53%, basal cell carcinoma 24%, squamous cell carcinoma 18%. Sebaceous carcinoma had a recurrence rate of 21%, regional lymph node metastasis 16%, systemic metastasis 13%, and metastasis-related death 9% 2).
Clinical Significance
Section titled “Clinical Significance”A positive sentinel lymph node indicates micrometastatic disease, influences AJCC TNM staging, and directly affects prognosis and treatment strategy. The status of the sentinel lymph node is considered the most important prognostic factor for survival and recurrence in patients with cutaneous melanoma.
Q
Why is sentinel lymph node biopsy not indicated for basal cell carcinoma?
A
Basal cell carcinoma is a low-grade tumor that rarely metastasizes distantly, and the likelihood of lymphatic spread is extremely low. Therefore, performing sentinel lymph node biopsy is considered to provide no clinical benefit.
2. Main Symptoms and Clinical Findings
Section titled “2. Main Symptoms and Clinical Findings”
Wendy J Li et al. Emerging Techniques in the Treatment of Conjunctival Melanoma. Current Ophthalmology Reports. 2025 Jun 13; 13(1):7. Figure 1. PMCID: PMC12162382. License: CC BY.
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Subjective Symptoms
Section titled “Subjective Symptoms”- Eyelid and periorbital mass formation: A painless to painful mass appears on the eyelid or around the orbit.
- “Masking syndrome” of sebaceous carcinoma: A nodular lesion easily mistaken for a chalazion repeatedly recurs and enlarges after incision.
- Merkel cell carcinoma: Appears as a rapidly growing red nodule with a fast growth rate.
Clinical Findings
Section titled “Clinical Findings”Characteristic clinical findings by tumor type are shown below.
Sebaceous Carcinoma
Location: Predilection for upper eyelid. Originates from Meibomian glands, Zeis glands, or sebaceous glands of the caruncle.
Morphology: Yellowish nodular tumor.
Features: May exhibit pagetoid spread (sheet-like proliferation of tumor cells within the conjunctival epithelium of the eyelid and eyeball).
Squamous cell carcinoma
Location: Commonly occurs on the conjunctival surface.
Morphology: Flat reddish tumor with fireworks-like tumor vessels, whitish due to keratinization.
Merkel cell carcinoma
Morphology: Dome-shaped red nodule on the eyelid skin, with dilated tumor vessels and smooth surface.
Features: Rapid growth and high tendency for metastasis.
Positive sentinel lymph node indicates micrometastasis, often without clinically evident enlarged lymph nodes. Conjunctival melanoma is highly invasive and may have micrometastasis at diagnosis.
3. Causes and Risk Factors
Section titled “3. Causes and Risk Factors”Lymphatic metastasis of ocular adnexal tumors: All malignant ocular adnexal tumors except basal cell carcinoma have a tendency for lymph node metastasis.
Risk factors for sentinel lymph node biopsy indication by tumor type are shown below.
| Tumor type | Indication criteria/risk factors for sentinel lymph node biopsy |
|---|---|
| Conjunctival/eyelid melanoma | Thickness ≥1 mm, or histological ulceration |
| Cutaneous melanoma | Thickness ≥1 mm, or ulceration/mitotic figures >1/mm², Clark level IV or higher |
| Sebaceous carcinoma | Width ≥10 mm (T2b or higher); size >15 mm increases metastasis risk |
| Squamous cell carcinoma | Width >20 mm, local recurrence, perineural invasion |
| Merkel cell carcinoma | Any size carries risk of metastasis |
| Basal cell carcinoma | Not indicated due to low metastatic potential |
- Poor prognostic factors for conjunctival melanoma: thickness ≥2 mm, ulceration, non-limbal location, local recurrence. Recurrence rate 33–61%, 5-year disease-specific mortality approximately 27%1)
- Characteristics in Asian populations: The proportion of sebaceous carcinoma is higher in Asians than in Western populations (in India, sebaceous carcinoma 53% vs. basal cell carcinoma 80–95% in Western countries). Sebaceous carcinoma has a worse prognosis than other eyelid malignancies2)
- Host immune status: Metastasis rate also varies depending on the host immune system
Q
At what size does sebaceous carcinoma of the eyelid increase the risk of metastasis?
A
Tumor size exceeding 15 mm is associated with an increased risk of regional lymph node metastasis. A width of ≥10 mm (stage T2b or higher) is considered an indication for SLNB.
4. Diagnosis and Examination Methods
Section titled “4. Diagnosis and Examination Methods”Before performing sentinel lymph node biopsy, imaging studies such as ultrasound or CT must be negative. Patients with confirmed disseminated disease are not candidates for sentinel lymph node biopsy.
Preoperative Lymphoscintigraphy
Section titled “Preoperative Lymphoscintigraphy”- Technetium-99m tin colloid is injected into the primary tumor bed (intradermal for eyelid lesions, subconjunctival for conjunctival lesions).
- Injection by an ophthalmologist experienced in handling radioactive tracers is recommended.
- Serial scintigraphic images are taken with a gamma camera every 15 minutes, then every 30 minutes, to track tracer drainage.
- SPECT/CT is also being considered for more accurate identification of sentinel lymph nodes.
Intraoperative Sentinel Lymph Node Biopsy Technique
Section titled “Intraoperative Sentinel Lymph Node Biopsy Technique”- Approximately 1.5 hours before surgery, 0.3–0.4 mCi of filtered technetium-99m tin colloid dissolved in 0.2 mL saline is injected into 3–4 sites around the lesion.
- A handheld percutaneous gamma probe is used intraoperatively to re-identify the sentinel lymph node.
- Sentinel lymph node: defined as a lymph node with counts at least twice the background radioactivity.
Histological Examination
Section titled “Histological Examination”The excised sentinel lymph node is sectioned into 1–2 mm slices using the bread-loaf method.
- Hematoxylin and eosin staining: Evaluation of malignant cells
- Immunohistochemistry: Use appropriate markers according to tumor type
Immunohistochemistry markers used by tumor type are shown below.
| Tumor type | Immunohistochemistry markers |
|---|---|
| Melanoma | S100, HMB45, etc. |
| Sebaceous carcinoma | Adipophilin, etc. |
| Squamous cell carcinoma | Pan-cytokeratin, etc. |
| Merkel cell carcinoma | Cytokeratin 20, etc. |
In preoperative evaluation of sebaceous carcinoma, it is necessary to check for metastatic lesions in advance using head and neck CT or MRI.
Q
What is the false-negative rate of sentinel lymph node biopsy?
A
The American Academy of Ophthalmology Consensus Paper (2020) reported a false-negative rate of 4.6% based on a review of 27 studies. The false-negative rate is inversely correlated with the surgeon’s experience and is showing an improving trend. One institution has reported a false-negative rate of zero over the past 15 years.
5. Standard Treatment
Section titled “5. Standard Treatment”Indications for Sentinel Lymph Node Biopsy
Section titled “Indications for Sentinel Lymph Node Biopsy”The indications for sentinel lymph node biopsy vary depending on tumor type and stage (see “Causes and Risk Factors” for details).
Surgical Treatment of Primary Tumor
Section titled “Surgical Treatment of Primary Tumor”- Basal cell carcinoma: Nodular type can be completely excised with a safety margin of 1-2 mm. Ulcerative type has unclear borders and deep invasion, requiring a deep margin.
- Sebaceous carcinoma: Resection with a safety margin of 3 mm or more. Confirm the presence or absence of tumor cells at the margin with frozen section pathology. If the tarsal plate defect is one-third or less, simple closure is possible.
- Squamous cell carcinoma: Complete excision including the tarsal plate, followed by 2-3 sets of cryocoagulation to the resection surface.
- Merkel cell carcinoma: Full-thickness eyelid resection and reconstruction. Since it is highly radiosensitive, radiation therapy is also an option if radical resection is not tolerated.
Treatment Strategy Based on Sentinel Lymph Node Biopsy Results
Section titled “Treatment Strategy Based on Sentinel Lymph Node Biopsy Results”- If positive: More extensive lymph node dissection is performed, and adjuvant therapy is considered.
- If negative: The likelihood of other lymph node involvement or distant metastasis is low, and unnecessary radical lymph node dissection can be avoided.
Management of Pagetoid Spread (Sebaceous Carcinoma)
Section titled “Management of Pagetoid Spread (Sebaceous Carcinoma)”For pagetoid spread (tumor extension into the conjunctival epithelium), topical antineoplastic eye drops are used. All are off-label uses.
- Mitomycin C 0.04% eye drops: 4 times daily, 1 week on, 1 week off, for 2-3 cycles.
- 5-Fluorouracil 1% eye drops: 4 times daily, 2–4 days on, 1 month off, for 2–6 cycles
Q
If the sentinel lymph node biopsy is positive, what additional treatment is performed?
A
If a positive sentinel lymph node is confirmed, a more extensive lymph node dissection (radical lymphadenectomy) is performed. Additionally, adjuvant therapy (radiotherapy, chemotherapy, immunotherapy, etc.) is considered. The specific treatment plan depends on the tumor type and stage.
6. Pathophysiology and Detailed Mechanisms
Section titled “6. Pathophysiology and Detailed Mechanisms”Principles of Lymphatic Metastasis
Section titled “Principles of Lymphatic Metastasis”Certain malignant tumors preferentially and sequentially metastasize via the lymphatic system before hematogenous spread. The sentinel lymph node is the first lymph node to receive lymphatic drainage from the primary tumor, reflecting the earliest presence of metastasis.
Periocular Lymphatic Drainage Patterns
Section titled “Periocular Lymphatic Drainage Patterns”Periocular lymphatic drainage varies by region and shows significant individual differences.
- Entire upper eyelid, medial canthus, lateral lower eyelid → Parotid and preauricular lymph nodes
- Medial and central lower eyelid → Submandibular lymph nodes
- Lateral half of conjunctiva → Preauricular lymph nodes; Medial half of conjunctiva → Submandibular and deep cervical lymph nodes
- Temporal conjunctival melanoma → Preauricular lymph nodes; Nasal side → Submandibular lymph nodes
- Drainage patterns vary among individuals, and preoperative mapping with lymphoscintigraphy is essential.
Metastatic characteristics of each tumor
Section titled “Metastatic characteristics of each tumor”In a retrospective study of 536 cases in India by Kaliki et al. (2019), sebaceous carcinoma had a 5-year estimated regional lymph node metastasis rate of 42.55%, a 5-year systemic metastasis rate of 35.74%, and a 5-year metastasis-related mortality rate of 24.88%. Compared with basal cell carcinoma and squamous cell carcinoma, sebaceous carcinoma had significantly higher rates of local invasion (13%), regional lymph node metastasis (16%), and systemic metastasis (13%) 2).
In a review article on conjunctival malignant melanoma by Mirzayev et al. (2024), distant metastasis to the liver, lungs, and brain was reported in 11–42% of cases. Sentinel lymph node biopsy is considered particularly useful for tumors with thickness >2 mm and diameter >10 mm 1).
7. Latest research and future perspectives (research-stage reports)
Section titled “7. Latest research and future perspectives (research-stage reports)”Research on improving the accuracy of sentinel lymph node biopsy
Section titled “Research on improving the accuracy of sentinel lymph node biopsy”In the largest study by Esmaeli et al. (2017), 51 patients with ocular adnexal melanoma were evaluated. The sentinel lymph node biopsy positivity rate was 20%, with eyelid margin/eyelid skin melanoma (30%) higher than conjunctival tumors (13%). Three false-negative cases were reported.
In the American Academy of Ophthalmology consensus paper (2020), a review of 27 studies reported a mean sentinel lymph node positivity rate of 16.8% and a false-negative rate of 4.6%. The false-negative rate was inversely correlated with surgeon experience, and one institution reported a zero false-negative rate over the past 15 years.
Use of SPECT/CT
Section titled “Use of SPECT/CT”More accurate identification of sentinel lymph nodes using SPECT/CT is being studied. Compared with conventional lymphoscintigraphy, it may allow more precise anatomical localization of sentinel lymph nodes.
Indocyanine green-guided sentinel lymph node biopsy
Section titled “Indocyanine green-guided sentinel lymph node biopsy”As an alternative to technetium-99m, indocyanine green-guided sentinel lymph node biopsy has been investigated in a few studies. Currently, technetium-99m remains the standard tracer.
Molecular targeted therapy and immunotherapy for conjunctival melanoma
Section titled “Molecular targeted therapy and immunotherapy for conjunctival melanoma”In a review by Mirzayev et al. (2024), anti-BRAF/anti-MEK/anti-PD-L1 therapy is considered promising for conjunctival melanoma, but the data available at present are limited 1).
8. References
Section titled “8. References”- Mirzayev I, et al. Conjunctival melanoma: current understanding and future directions. Cancers. 2024;16:3121.
- Kaliki S, Bothra N, Bejjanki KM, Nayak A, Ramappa G, Mohamed A, Dave TV, Ali MJ, Naik MN. Malignant eyelid tumors in India: a study of 536 Asian Indian patients. Ocul Oncol Pathol. 2019;5(3):210-219.