Meghana Anika Varde
Meghana Anika Varde received her medical degree from the University of Frankfurt am Main, Germany, and did her residency in ophthalmology at the Universities of Tübingen, Erlangen and Kiel. She completed a fellowship in Oculoplastics and Trauma at SankaraNethralaya Eye Hospital in Chennai, India.
Dr. Varde has been working as a consultant at the KlinikumNordstadt in Hannover, Germany, for the past 6 years. Her main interests are Oculoplastics as well as Traumatology and globe reconstruction.
She is a full member of the European Society of Ophthalmic Plastic and Reconstructive Surgery and teaches Oculoplastic Surgery at Acha Eye Hospital in Cameroon. She is also examiner for the European Board of Ophthalmology.
Melanoma
Malignant melanoma (MM) is a potentially life-threatening tumour. Cutaneous melanomas account for about 7 % of skin malignancies but are responsible for 90 % of skin cancer-related deaths according to the National Cancer Institute in the USA [1]. The prognosis is mainly dependent on the size of the tumour at presentation, so that timely diagnosis is of utmost importance. The growth rate of melanomas is variable, but about a third of cutaneous melanomas can exhibit a fairly fast growth of 0.5 mm per month or more [2]. These tumours have to be treated on an emergent basis (Fig. 47.1).
Fig. 47.1
Growth of a lid melanoma in 6 weeks
Malignant melanomas of the eyelid may involve the skin as well as the conjunctiva and in many cases a combination of the two. When examining a case of eyelid melanoma, it is essential to evert the lids and rule out any involvement of the palpebral or bulbar conjunctiva.
Cutaneous Eyelid Melanoma
Introduction and Epidemiology
Cutaneous melanoma of the eyelid is a rare tumour representing less than 1 % of all eyelid malignancies [3, 4]. The incidence is significantly lower in darker-skinned individuals with persons of African origin rarely affected. Eyelid melanoma is a disease of the older population and shows a peak incidence in the sixth and seventh decades of life.
Eyelid skin melanoma can occur as primary lesion, as metastasis from cutaneous melanoma at another site or by extension of a conjunctival melanoma. The clinical features, histopathology, treatment and prognosis are comparable to that of cutaneous malignant melanoma elsewhere [5].
Aetiology and Pathogenesis
Cutaneous melanoma may arise de novo most likely to ultraviolet (UV) radiation-induced skin damage or appear as malignant transformation of a precursor lesion.
There are four major types of cutaneous melanomas in the periocular region:
Lentigo maligna melanoma (LMM)
Nodular melanoma (NM)
Superficial spreading melanoma (SSM)
Desmoplastic melanoma (DM)
Lentigo maligna (LM, Hutchinson’s freckle) represents a melanoma in situ. It presents as a flat, non-palpable pigmented macule, which is found mostly in elderly white-skinned individuals on sun-exposed skin. The lesions exhibit irregular pigmentation and margins. Some areas may show spontaneous involution (Fig. 47.2). An invasive melanoma commonly presents as a firm nodule of variable pigmentation within the lesion (Fig. 47.3).
Fig. 47.2
Spontaneous regression of lentigo maligna over the course of 2.5 years. (a) 09/2011, (b) 03/2012, (c) 03/2014
Fig. 47.3
Lentigo maligna melanoma with conjunctival involvement in a 98-year-old patient
About 61 % of eyelid cutaneous melanomas arise from LM [3].
Nodular melanomas represent about 15–30 % of eyelid melanomas. They tend to show early vertical growth with little horizontal spread and arise de novo without a precursor lesion.
Superficial spreading melanomas often arise from pre-existing dysplastic naevi. In the eyelid, this type of melanoma is the least common [3].
Desmoplastic melanomas are rare. They present as firm, indurated, nonpigmented mass with ill-defined borders, can resemble a scar and any benign or malignant lesion [6] and are associated with perineural invasion.
Clinical Presentation
Eyelid melanomas occur most frequently in the lower lid [7]. The pigmentation can vary from dark black to amelanotic. Melanomas of the lid often involve the lid margin. If associated with a conjunctival component, it may be difficult to distinguish the origin of the melanoma. These tumours seem to have a worse prognosis because of possible late detection of the conjunctival growth [8].
The rare desmoplastic variant of melanoma is often a tumour of the deeper structures and can thus appear as subcutaneous nodule or even as a chalazion.
Differential Diagnosis
Naevocellular naevi can involve the skin as well as the lid margin. Another entity found in the eyelid is the Spitz naevus. It arises before the fourth decade of life and can exhibit morphological features similar to melanoma although it is commonly perceived as a benign lesion. It might be considered as potential precursor for a melanoma, similar to dysplastic naevi [9].
Another important differential diagnosis is seborrhoeic keratosis (SK). Basal cell carcinoma (BCC) may be pigmented, especially in individuals with increased skin pigmentation (Fig. 47.4) and can be mistaken for nodular melanoma.
Fig. 47.4
Pigmented BCC of the left lower lid in an Indian patient
Histopathology
Cutaneous melanomas normally arise from the junctional area between the dermis and epidermis. Cell pleomorphism and a high mitosis rate might help in the differential diagnosis to a compound naevus [10]. The tumour may sometimes show ulceration. Melanoma cells are mainly of two morphologic types: epithelioid and spindle cells. Epithelioid cells are round and large with prominent nuclei, large nucleoli and a broad rim of eosinophilic cytoplasm. Spindle cells on the other hand are narrow, spindle-shaped with less cytoplasm (Fig. 47.5). Desmoplastic melanomas present a challenge also on histologic and immunohistochemical analysis.
Fig. 47.5
Haematoxylin and eosin staining of lid melanoma with areas of epithelioid cells (large cells with abundant nuclei and pleomorphism, arrow pointing to a mitosis) and spindle cells (elongated cells with scarce cytoplasm). The tumour exhibits few areas of pigmentation
Three histologic characteristics correlate strongly with the outcome of the disease and thus should be reported for adequate staging [11]:
Breslow’s depth of invasion: In the histological slide, the maximum vertical extent of the tumour is measured in millimetres.
Presence or absence of histological ulceration (tumour-induced full-thickness loss of the epidermis) [12].
Mitotic rate: measured as number of dermal mitoses per square millimetre [13].
Special immunohistochemical (IHC) staining is done for confirmation of diagnosis. Among the antibodies most commonly used are:
S100 with a very high sensitivity (97–100 %) for the detection of cells from melanocytic origin but with a low specificity (75–87 %), staining nucleus and cytoplasm [14].
HMB45, MART–1/Melan–A or Tyrosinase with lower sensitivities (69–93 %, 75–92 %, 84–94 %, respectively) but very high specificities for melanocytes (near 100 %, 95–100 %, 97–100 %, respectively) [14].
Ki–67 as marker of tumour cell proliferation. In naevi, less than 5 % of cell nuclei are stained; in Spitz and dysplastic naevi, it can be up to 15 %. In general, the stained cells will be seen mainly in the apical regions of the tumour, whereas in melanoma, about 13–30 % stain positive, and they may be located also in the deeper parts of the lesion. This marker can be used to distinguish melanoma from benign lesions of melanocytic origin, such as naevi [14, 15].
Classification and Staging
The TNM (tumour, node, metastasis) staging system is used for cutaneous melanomas (Tables 47.1, 47.2, and 47.3).
pT | Meaning |
|---|---|
pTX | Primary tumour cannot be assessed |
pT0 | No evidence of primary tumour |
pTis | Melanoma in situ |
pT1 | ≤1.0 mm thickness (a without ulceration, mitotic rate <1/mm2; b with ulceration or mitotic rate ≥1/mm2) |
pT2 | 1.01–2.0 mm thickness (a or b) |
pT3 | 2.01–4.0 mm thickness (a or b) |
pT4 | >4.0 mm thickness (a or b) |
N | Meaning |
|---|---|
NX | Regional lymph nodes cannot be assessed |
N0 | No regional lymph node metastasis |
N1 | 1 node involved (a microscopic metastasis, b macroscopic metastasis, c in-transit metastasis without lymph node involvement) |
N2 | 2–3 nodes involved |
N3 | ≥4 nodes involved or matted LN or satellites or in-transit metastasis with LN involvement |
According to the American Joined Committee on Cancer (AJCC), the tumours are grouped by their TNM status into groups that define the treatment or enrolment into clinical studies (Table 47.4).
Group | pT | N | M |
|---|---|---|---|
0 | In situ | 0 | 0 |
IA | ≤1 mm, no ulceration | 0 | 0 |
IB | ≤1 mm with ulceration or MR ≥1/mm2 1.01–2 mm, no ulceration | 0 | 0 |
IIA | 1.01–2 mm with ulceration 2.01–4 mm, no ulceration | 0 | 0 |
IIB | 2.01–4 mm with ulceration >4 mm, no ulceration | 0 | 0 |
IIC | >4 mm with ulceration | 0 | 0 |
IIIA | Any Ta (without ulceration) | Microscopic mets≤ 3 LN | 0 |
IIIB | Any Tb (with ulceration) Any Ta Any Ta | Microscopic mets≤ 3 LN Macroscopic mets≤ 3 LN No LN involvement, but satellites or in-transit mets | 0 |
IIIC | Any Tb Any T a or b | Macroscopic mets≤ 3 LN or satellites or in-transit mets without LN involvement Macroscopic mets≥ 4 LN or matted LN or satellites or in-transit mets with LN involvement | 0 |
IV | 1 |
Staging procedures for cutaneous melanoma are designed to help detect treatable locoregional or distant metastasis. Staging procedures should be tailored to the stage of the disease and the possibility of correct identification of prognostically relevant systemic involvement.
The staging procedures in tumours clinically not suspicious for metastatic disease up to Stage IIB involve:
Detailed local examination (e.g. involvement of the lid margin, bulbar or palpebral conjunctiva, motility, globe integrity, dilated fundus examination, any other skin lesion such as lentigo maligna, in-transit lesions (subcutaneous nodules in the path between primary tumour and regional lymph nodes), seborrhoeic keratosis, and BCC)
Palpation of regional lymph nodes (i.e. preauricular, parotid, submandibular, cervical) as well as drainage channels to rule out in-transit metastasis
General skin examination to rule out metastatic disease to the lids
Sonography of the regional lymphatic basins from Stage IB onwards
Serum S100 as tumour marker
Wide local excision with histopathological confirmation of diagnosis (type of melanoma, Breslow’s depth, presence of ulceration and mitotic level)
Sentinel lymph node biopsy (SLNB) for tumours thicker than 1 mm or thicker than 0.75 mm in patients with higher risk of metastatic disease (age <40, ulceration, high mitotic rate)
In Stage IIC and III melanomas, additional staging procedures are recommended:
Cranial MRI
Cross–sectional imaging (PET/CT, CT or MRI of the whole body, wherein PET/CT has superior diagnostic accuracy)
Serum lactate dehydrogenase (LDH ) as tumour marker
In Stage IV melanomas, recommendations for staging are as follows:
Cranial MRI
Cross–sectional imaging (PET/CT, CT or MRI of the whole body)
Serum LDH as tumour marker
Abdominal sonography
Lymph node sonography
Skeletal scintigraphy
Serum S100 and serum LDH as tumour markers
Treatment
Surgical Treatment
Primary Excision
Stage 0, I and II melanomas are local tumours without lymphatic spread and thus considered primarily resectable.
In periocular tumours, wide local excision as recommended for cutaneous melanomas elsewhere is associated with significant morbidity and the necessity to excise structurally important tissue. According to recent studies analysing the target excision margin for periocular skin melanomas, a 3 mm surgical margin (2 mm histologic margin) for the excision of melanomas less than 1 mm Breslow thickness and 5 mm in thicker melanomas is recommended. The excision should include the full thickness of the lid in tumours thicker than 1 mm [16, 17].
The current AJCC guidelines suggest micrographically controlled surgery for lesions in these regions. In lentigo maligna melanoma, there is marked subclinical extension, so modified Mohs procedure (mapped serial excision) was able to show unpredictability of margin clearance of the disease requiring multiple excisions. A 3 % recurrence rate [18] as compared to previously published recurrence rates of 9–10 % [19, 20] was reported.
Exenteration for cutaneous melanoma of the lid is very rare. Most of the exenterations associated with melanomas are conjunctival or orbital in origin [21].
If the initial tumour resection yields R1 (microscopic) or R2 (macroscopic remnants) status on permanent histological sections, re-excision is recommended if possible until histological clearance is achieved.
Lymph Node Dissection
Stage III disease displays lymph node involvement but no distant metastases. The theory of metastasis development in melanoma is that primary metastasis occurs into the sentinel lymph node (SLN), from there into the regional lymphatic basin and only after a delay via further lymphatic and haematogenous spread to the rest of the body. Thus, in early stages of melanoma without distant micrometastasis, cure could possibly be achieved by targeting the SLN or regional lymph nodes before further spread occurs. If anatomically possible, complete excision should be done for satellite lesions, in-transit and lymph node metastases.
In cases of positive sentinel lymph node biopsy, completion regional lymph node dissection (CLND) is recommended to achieve R0 state. Elective therapeutic lymph node dissection (TLND) is not recommended.
Excision of Distant Metastases
Patients with Stage IV disease (distant metastasis) need to be individually assessed by an interdisciplinary team regarding the indication for surgical intervention. Excision of distant metastases can be considered if R0 excision is possible and morbidity associated with surgery is acceptable, the number of metastases limited, disease-free interval long and other therapeutic modalities have been unsuccessful or less promising [22].
Medical Treatment
Primary Medical Treatment
The primary treatment of cutaneous melanomas is surgical excision.
The lifetime risk for the development of LMM in a 45-year-old patient diagnosed with LM is approximated to 5 % [23]. LM in the periocular region can be of considerable size thus causing significant morbidity if excised. In biopsy-proven LM when surgical treatment is not feasible or refused by the patient, immune response therapy with imiquimod 5 % cream can be started. Application is once or twice daily for 6 weeks to 3 months. The response rate is excellent with complete remission reported in 93 [24] – 100 % [25]. Because of the inflammatory response, periocular use may be limited by ocular irritation and chemical conjunctivitis [26]. Imiquimod can also be used as adjunctive treatment prior to micrographically controlled excision [27]. Development of amelanotic melanomas within the lesion has to be kept in mind when using conservative treatment in these patients, and they have to be closely followed. Radiotherapy is another option for the treatment of LM [28].
Adjuvant and Palliative Medical Treatment
Adjuvant or palliative medical treatment is recommended for Stage III and Stage IV melanomas.
Radiotherapy is administered to the lymphatic basin after lymph node dissection in certain conditions [29–31].
Adjuvant radiotherapy may be an option to enhance local control of resected desmoplastic melanoma in the head and neck region [32].
Radiotherapy can be administered to non-resectable metastases of the bone and brain especially for palliation [33, 34].
Interferon α–2b is an immunomodulatory as well as antiproliferative agent used mainly in viral hepatitis. Trials show a small but significant benefit for overall disease-free survival. Interferon can be given as high-dose, low-dose or pegylated therapy. The main limiting factors are the side effects causing discontinuation of treatment [35, 36]. Adjuvant interferon therapy is recommended for melanomas at high risk of metastasis, ulcerated melanomas as well as those with micrometastases.
Interleukin–2 is an immunomodulatory agent targeting natural killer cells. High-dose therapy has been shown to benefit some patients with Stage IV melanoma. Overall response rates vary from 8 % to 16 %. Toxicity is high.
Dacarbazine is the standard chemotherapeutic agent for non-resectable and metastasized melanomas. It acts via DNA alkylation. Polychemotherapy is also available and can be used in progressive disease [22].
Certain mutations in activating oncogenes of melanomas can be targeted with new medications. These are mainly the BRAF mutation (36–57 % of cutaneous melanomas [37, 38]), the NRAS mutation in 11–15 % [37, 38] and the c–KIT mutation mainly in acral and mucosal melanomas [39].
In cutaneous melanomas of the lid, mainly BRAF and NRAS mutations can be targeted with specific medications. BRAF and KIT mutations have been found in some conjunctival melanomas [40].
Vemurafenib is a specific inhibitor of BRAF (V600E) kinase, and treatment in conjunction with clinical trials is recommended in case the molecular testing is positive for the mutation [31, 41]. The response rate in melanomas showing the respective mutation is almost complete. Main side effects include the development of secondary neoplasms. The main problem encountered is resistance to the drug after several months [42].
There is no specific inhibitor for NRAS-mutated oncogenes. MEK inhibitors (MAP kinase pathway inhibitors), specifically trametinib, show effects on affected cells and can be used to treat metastatic melanoma positive for NRAS mutations [43].
Imatinib mesylate, an orally available c-KIT inhibitor, has shown some effect in treating metastatic melanoma with the respective mutation with good tumour regression rates of 42 % [40, 44].
Ipilimumab is a novel immunomodulator targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), a suppressor for T lymphocyte activity. Treatment with this agent has been promising for some patients with Stage III or IV melanoma. The response rate is relatively limited (10–15 %), but responders treated over a short period of time were able to exhibit significant survival of up to 10 years [45].
Recent advances in the development of drugs targeting melanoma cells give hope in the treatment of Stage III and IV melanomas. Adjuvant treatment with radiotherapy in Stage III and recurrent melanoma is recommended. Adjuvant treatment with targeted immunotherapy is recommended in BRAF-positive Stage III and IV disease. Ipilimumab is promising in BRAF-negative tumours, especially as combination therapy with radiation or with targeted immunotherapy.
Therapy in these advanced stages has to be done in a dermato-oncological setting especially in regard to the option of enrolling the patient into current trials.
Prognosis and Follow-Up
The prognosis for cutaneous melanoma is generally dependent on the stage of the disease.
In localised disease (Stages I and II), the prognosis is generally favourable. Small T1a tumours as in Stage I show 10-year survival rates of 93 %. T4b tumours as in Stage II disease, although localised, have less favourable 5-year/10-year survival rates of 53/39 %, respectively [46]. Tumours located in the lower lid had a higher risk of recurrence in one study [16]. Negative prognostic factors regarding the lid are lid margin and conjunctival involvement [47]. Desmoplastic melanoma seems to have lower risk for developing metastatic disease, albeit a higher risk for local recurrence [48, 49].
In Stage III disease, 5-year survival rates were 70 % for N1a nodal involvement and 39 % for N3 nodal involvement, putting emphasis on the prognostic importance of micrometastastatic disease, low tumour burden, and absence of in-transit metastases [46].
Stage IV melanoma has a generally poor prognosis with 5-year survival rates reported less than 10 % and mean survival of 6 months [50].
Risk-adapted follow-up of the patients has been recommended for 10 years from diagnosis [31].
Newer adjuvant treatment are promising in terms of prolonging life, but metastatic cutaneous melanoma remains an incurable cancer nevertheless, and the goal has to be early recognition and complete micrographically controlled excision with adequate reconstruction in the periocular area wherever possible.
Eyelid Conjunctival Melanoma
Introduction and Epidemiology
Conjunctival melanomas comprise about 5 % of all periocular and ocular melanomas. They are predominantly seen in Whites older than 60 years and rarely in Blacks, although the White-to-Black (WBR) ratio of conjunctival melanoma seems to be less pronounced (2:1) than that of cutaneous (about 16:1) or uveal (18:1) melanoma [51].
Conjunctival melanoma can occur as primary lesion, as metastasis from cutaneous melanoma or by extension from a cutaneous melanoma of the lid. Uveal melanomas, which are by far more common, can appear as pigmented subconjunctival mass if extrascleral extension is present.
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