Cutaneous Head and Neck Melanoma

TITLE: Cutaneous Head and Neck Melanoma
SOURCE: Grand Rounds Presentation, UTMB, Dept. of Otolaryngology
DATE: July 29, 2009
RESIDENT PHYSICIAN: Michael Briscoe Jr., MD
FACULTY PHYSICIAN: Vicente Resto, MD, PhD
DISCUSSANT: Dr. C. Berlingeri-Ramos, UTMB, Dept. of Dermatology
SERIES EDITORS: Francis B. Quinn, Jr., MD
ARCHIVIST: Melinda Stoner Qui= nn, MS(ICS)

"This material was prepared by resident physicians in partial fulfillment of educational requirements established for the Postgraduate Training Program of the UTMB Department of Otolaryngology/Head= and Neck Surgery and was not intended for clinical use in its present form. It = was prepared for the purpose of stimulating group discussion in a conference setting. No warranties, either express or implied, are made with respect to= its accuracy, completeness, or timeliness. The material does not necessarily reflect the current or past opinions of members of the UTMB faculty and sho= uld not be used for purposes of diagnosis or treatment without consulting appro= priate literature sources and informed professional opinion."

Introduction

Melanoma affects people all over the globe. In the United States, it is the fi= fth leading cancer in men and the sixth leading cancer in women. The incidence of melanoma has stea= dily increased over the past few decades, with an annual increase of up to 7% in certain populations. Melanoma= was generally known as a disease of the old, but there is a recent trend for earlier age at presentation. = This disease is highly curable if found at an early stage, which underscores the importance of patient education and vigilance in physicians when evaluating skin lesions. Melanoma typica= lly occurs in different regions of the body according to sex. In males, the trunk and back, foll= owed by extremities then the head and neck are the predominant patterns. In women, the lower extremities, followed by trunk and back, then the head and neck is the predominant patte= rn. Treating cutaneous melanoma of the= head and neck presents particular problems to the Otolaryngologist because of the complex anatomy of the head and neck, and due to the visual nature of the f= ace, neck and scalp.

Skin anatomy

Melanoma is a disease of the skin or mucosa. Knowledge of skin anatomy is of vi= tal importance in understanding the pathophysiology of this disease. The skin has two components, the epidermis and dermis. The epi= dermal layer can be further broken down into the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale, or basal layer. Keratinocytes located at the basal= layer actively divide and migrate towards the surface of the skin. As they migrate further away from = the basement membrane, they begin to keratinize. Melanocytes are also located in the basal layer, and produce melanosomes which contain melanin which they share with the keratinocytes. Other= cells within the epidermis include merckel cells, langerhans cells, and intraepidermal T-lymphocytes. Immediately below the basement membrane is the dermis. The dermal components are the superficial papillary and deep reticular dermis. The papillary dermis contains grou= nd substance, collagen, elastin, and many cell types including macrophages, fibroblasts, mast cells, and inflammatory cells. The reticular dermis is deep to the papillary dermis and contains more intermediate filaments. Below the dermis is the hypodermis= , or subcutaneous fat layer.

Etiology and Risk factors

There are many factors that are important to the development of melanoma, but the most important is sun exposure. Sun exposure at a young age places= a higher risk of developing melanoma and other skin cancers. The intensity of the sunlight rece= ived also places more risk as evidenced by increased incidence in populations li= ving near the equator. Intermitten= t sun exposure with history of sunburns has a greater affect on the development of melanoma then chronic sun exposure. Despite the common belief that sunblock/sunscreens prevent or decrea= se the risk of melanoma, two studies have proven this wrong. This could be due to increased sun exposure due to the perceived benefit of sunscreen, or inadequate usage of = the sunscreen. (Autier 2007). Other risk factors include Fitzpat= rick types I and II, blue/green eyes, adults with more than 100 freckles or chil= dren with 50 freckles, blonde/red hair, outdoor summer jobs/hobbies. Genetic factors have also been fou= nd to affect the incidence of melanoma. An estimated 5-12% of people with melanoma have a family history of melanoma, and four genes have been found which are associated with increased susceptibility to melanoma. T= hese are inhibitor of cyclin-dependent kinase 4A (CDKN2A) also known as <= i>p16, ARF (ARF) or p14, cyclin-dependent kinase 4 (CDK4), and melanocortin1 receptor (MC1R).&= nbsp; p16 is a tumor suppressor gene and 10-40% of melanoma prone families carry a mutation in this gene.&nb= sp; In addition to familial cases of melanoma, virtually all cases of melanoma have a mutation or inactivation of this gene. The p16 protein is importan= t in cell cycle regulation and plays a central role in the G1 checkpoint by inhibiting phosphorylation of the retinoblastoma protein by CDK4. There is high penetrance with rates ranging from 58-91%. MC1R<= /i> is a transmembrane receptor expressed in melanocytes that mediates melanin production after UV irradiation or stimulation by hormones. There have been multiple allelic variations, and they are associated with red hair and fair skin. There appears to be a lower penetr= ance for this mutation then the others. <= /span>Xeroderma pigmentosa is an autosomal recessive hereditary disorder characterized = by multiple skin malignancies, including melanoma. There is reduced or absent ability= to repair DNA damaged by ultraviolet light.&n= bsp; Giant congenital nevi, nevi that are present at birth and greater th= an 20 mm, impart a greater risk of developing melanoma, with 5-10% of affected individuals developing melanoma.

Types of melanoma

Lentigo maligna is melanoma confined to t= he epidermis, or melanoma in situ. It is seen in chronically sun exposed areas.&= nbsp; In the head and neck, the cheek is the most common location followed= by nose, forehead, ears, and neck. It generally occurs in 60 to 70 year olds, with no gender predilection. They range in size from 0.2 cm to greater the 20 cm. Histologic= ally, there is melanocytic proliferation confined to the basal layer of the epidermis, pleomorphism, effacement and thinning of the epidermis, with prominent solar elastosis, and high nuclear to cytoplasm ratio. There also = is a mononuclear cell infiltrate and fibroplasia of the papillary dermis. Patterns of spread include pagetoid spread, nesting, and lentiginous melanocytic proliferation. In pagetoid spread, there is upward migration of melanocytes in a random fashion, single cells predominate over nests of cells, and cells often reach the granular or cornified layer of the epidermis. Nesting pattern is characterized by variations in size and shape of groups of “nested cells,” which replace large portions of normal epithelium. Lentiginous spread is characterize= d by nesting of melanocytes, and proliferation along adnexal structures. Once the basement membrane is viol= ated, then the lentigo malignant melanoma is the diagnosis.   Usually, there is hypercellu= larity with spindle cells in bundles with adjacent stromal dysplasia and accompani= ed invasion of nerve twigs, neurotropism.&nbs= p;

Nodular melanoma is characterized by a ra= pidly enlarging nodule that is black, blue, or pink. The usual age at presentation rang= es from 30-70 years old, but typically 40-50.= They are 4 mm to 5 centimeters in size with asymmetry and well defin= ed borders. They are unique beca= use they present with a rapid growth phase, two months to four years. Histologically, they are dome-shaped polypoid or sessile tumors with efface= ment of the epidermis, and host response at the base, or tumor infiltrating lymphocytes present.

Desmoplastic-neurotropic melanoma is a ra= re subtype of melanoma with spindle cells and abundant collagen with a propens= ity to infiltrate nerves. This is= a very aggressive form of melanoma which is locally aggressive and infiltrative. A majority of t= hese lesions are amelanotic, and they typically do not have the features characteristic to most cutaneous melanomas, making diagnosis particularly d= ifficult.

Mucosal melanoma is rare and relatively difficult to diagnose at an early stage.&n= bsp; It is clinically distinct from cutaneous head and neck melanoma. Most are diagnosed in patients 60 = to 70 years old, and there is an equal incidence in all racial groups and no gend= er predilection. They range in s= ize from 3 mm to 12 cm and are often greater than 7 mm when first diagnosed. Their color can be black, brown, t= an, gray, pink, white, or blue. Amelanotic lesions do exist, and contribute to the difficulty in diagnosing these cancers. The= y are most commonly found in the nasal cavity (anterior septum>inferior/middle turbinate) or the oral cavity (hard palate and maxillary alveolar ridge). Histologically, they show a thicke= ned stratum corneum, prominent acanthosis (elongated epidermal rete), contiguous lentiginous melanocyte proliferation, variable cytologic atypia, nuclear enlargement, hyperchromatism, and prominent pleomorphism. There is a high incidence of desmoplasia, neurotropism, and angiotropism.

Signs and Symptoms

A comprehensive history should be taken with que= stions directed towards number of lesions, sun exposure, family history of melanom= a or skin cancer, previous skin cancers, history of tanning bed use, history of sunburns, and occupational history. An easy way to remember the signs of a melanoma is the ABCDE pneumonic. Asym= metry, most lesions do not have a regular shape or symmetry. Borders characterize= d by notched or irregular borders. Color characterized by irregular color, variegation of color, or jet black color. Diameter= greater than 6 mm. Evolving= lesion characterized by new onset of bleeding, ulceration or pruritis. These signs only serve as a guide = and are very helpful in diagnosing melanoma, but not all cutaneous melanomas wi= ll fit into these categories. It= is important to recognize skin lesions that may look different from surrounding benign lesions, and biopsies should be taken. Review of systems should be thorou= gh, looking for possible sites of distant metastasis. Constitutional, pulmonary, hepatic, gastrointestinal, musculoskeletal, or neurologic symptoms may warrant furth= er laboratory or radiologic investigation.

Differential Diagnosis

The differential includes processes with melanoc= ytic proliferation including markedly atypical nevi, halo nevi, Spitz tumors, pi= gmented spindle cell tumors. Sun dama= ged skin may also present with actinic keratosis, solar lentigo and solar melanocytic hyperplasia that may be difficult to distinguish from melanoma.= Other lesions on the differential include pigmented sarcomas (Kaposi’s sarcoma, angiosarcoma, and leiomypsarcoma) and metastatic squamous cell carcinoma.

Diagnosis

In order to obtain a diagnosis, tissue must be obtained. Biopsy should be fu= ll thickness and can be excisional with 1-2 mm margins or incisional for larger lesions. Shave biopsy should = be avoided because the depth of the melanoma will not be obtained, and this is important for staging and treatment. Punch biopsy that is full thickness through the lesion is also acceptable. The patient shoul= d have a full body examination by a physician that is familiar with skin lesions a= nd skin cancer. Any other suspic= ious lesions need to be biopsied at the same time. If there is lymph node enlargement= , an FNA of the suspicious lymph node is warranted. Other screening tests such as chest x-rays, CT scans, lactate dehydrogenase, and depend on the stage of disease= , or clinical findings that may warrant their use.

Histologic examination of the specimen should sh= ow proliferation of melanocytes. Other features include cytologic atypia, intraepidermal proliferation with extens= ion down to the papillary dermis, and polypoid morphologies. They have enlarged nuclei and nucl= eoli with pleomorphism present, and a high nuclear to cytoplasm ratio. The cytoplasm has a pink, granular quality with a clear space around the nuclei. Staining with S-100, HMB-45, vimen= tin, and MART1 positivity and cytokeratin negativity help confirm diagnos= is of melanoma when hematoxylin and eosin staining is equivocal.

Staging and Prognostic factors

The most important prognostic factors for locali= zed melanomas are tumor thickness and presence of ulceration. There are two microstaging systems= to assess tumor thickness. These= are the Clark qualitative systems, and the Breslow quantitative system. The Clark system is based on depth= into histological layers of skin, while the Breslow system is based on depth in millimeters. The new AJCC sta= ging system uses the Breslow system because it better predicts outcome, but the = Clark scale is used to differentiate T1a and T1b melanomas.

Clark Quantitative System

<= ![if !supportLists]>&nbs= p;       I.   &nb= sp; In situ; all tumor cells within= the epidermis, superficial to basement membrane

<= ![if !supportLists]>&nbs= p;    II.   &n= bsp; Tumor involves but does not completely fill the papillary dermis

<= ![if !supportLists]>&nbs= p; III.   &= nbsp; Tumor fills the interface betwe= en the papillary and reticular dermis

<= ![if !supportLists]>&nbs= p; IV.      Tumor ce= lls invade the reticular dermis

<= ![if !supportLists]><= span style=3D'mso-list:Ignore'>&nbs= p;    V.   &nb= sp; Tumor involves subcutaneous tissue<= o:p>

Breslow Quantitative System

·        < 0.75 mm<= /span>

·        0.76-1.49 mm<= /span>

·        1.50-3.99 mm<= /span>

·        > 4.0 mm

Low risk lesions are less than 1 mm in thickness= and they have a greater than 90 percent cure rate with wide local excision. Lesions that are between 1.5 mm an= d 3.99 mm are considered intermediate risk and have a greater than 70 to 85 percent cure rate with definitive surgery. For thick lesions, the cure rate falls to 50 to 70 percent. The other prognostic factor for lo= cal melanomas is ulceration. Ulce= ration refers to the microscopic evaluation of the epidermis, not gross ulceration. The presence of ulceration signifies a more aggressive melanoma and up stages that lesion.<= span style=3D'mso-spacerun:yes'> These lesions have no gross nodal = disease, and sentinel lymph node biopsy is negative for micrometastasis. If there is gross nodal disease or micrometastasis is found from sentinel lymph node biopsy, then the patient = has stage III (regional) disease. The most important prognostic factors are number of metastatic nodes, tumor bur= den, and ulceration. For staging, = the total number of metastatic lymph nodes determines N stage, and not the gross lymph node size. N1 disease is confined to one lymph node, N2 is confined to two to three lymph nodes, whi= le N3 has four or more positive lymph nodes or distant nodes. Sentinel lymph n= ode biopsy helps determine the tumor burden and lymph nodes status. Microscopic (occult) metastasis has better prognosis then macroscopic or gross metastatic disease. In addition to the above, lesions = with satellite metastasis or in-transit metastasis are defined as stage IIIB. As with stage I and II disease, the presence of ulceration has a negative impact on survival. Stage IV disease is metastatic disease. The anatomic site of metastasis, and lactate dehydrogenase levels affect prognosis. M1a lesions are confined to the sk= in, subcutaneous tissue and distant lymph nodes, M1b lesions are patients with = lung metastasis, and M1c have visceral organ metastasis or elevated levels of lactate dehydrogenase. Dissem= inated disease has the worst prognosis with survival time of 6 to 8 months. One year survival for metastatic d= isease to the skin or lungs is around 57 percent, this drops to 41 percent if other visceral organs are involved. For distant disease, imaging of the thorax, abdomen, pelvis, and head need to be obtained, as well as lactate dehydrogenase levels.

AJCC 2003 MELANOMA TNM CLASSIFICATION

T Classification=

Thickness

Ulceration Statu= s

T1

≤1.0 mm<= /o:p>

a: without ulcerati= on and level II/III

b: with ulceration = or level IV/V

T2

1.01–2.0 mm

a: without ulcerati= on

b: with ulceration<= o:p>

T3

2.01–4.0 mm

a: without ulcerati= on

b: with ulceration<= o:p>

T4

> 4.0 mm

a: without ulcerati= on

b: with ulceration<= o:p>

N Classification=

No. of Metastati= c Nodes

Nodal Metastatic= Mass

N1

1 node

a: micrometastasis = *

b: macrometastasis = ̶= 4;

N2

2–3 nodes

a: micrometastasis = *

b: macrometastasis = ̶= 4;

c: in transit met(s)/satellite(s) without metastatic nodes

N3

4 or more metastati= c nodes, or matted nodes, or in transit met(s)/satellite(s) with metastatic node(s= )

M Classification=

Site<= /b>

Serum Lactate Dehydrogenase

M1a

Distant skin, subcu= taneous, or nodal mets

Normal

M1b

Lung metastases

Normal

M1c

All other visceral metastases

Normal

Any distant metasta= sis

Elevated=

*

Micrometa= stases are diagnosed after sentinel or elective lymphadenectomy.

†

Macrometastases are def= ined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension.

Pathologic Staging of Cutaneous Melanoma

Treatment

Current treatment guidelines for surgical excisi= on are based on depth of invasion in millimeters for the lesion. For melanoma in situ, a 0.5 millim= eter margin is recommended, but may not be adequate. Margins are taken until they are negative because up to 12% of melanoma in-situ will be upstaged to invasive melanoma on permanent pathology. For lesions less the 1.0 mm, a 1.0 cm margin is recommended. Intermediate lesions are 1.01-2.0 = mm and require a 1.0-2.0 cm margin. Lesions greater than 2.0 mm require a 2.0 cm margin. Non-surgical ablative techniques s= uch as Nd:yag laser, imiquid, and fluorouracil have been tried, but high recurrence rates are problematic. These techniques have no role in the management of melanoma. Moh’s micrographic surgery is another alternative for initial excision.&= nbsp; Wide local excision with adequate margins is usually deferred until permanent pathology results are received.&= nbsp;

There is a 20% rate of occult neck disease in pa= tients with cutaneous melanoma of the head and neck. Because of this, the neck needs to= be evaluated for metastatic disease. Elective neck dissection was carried out for many years, but recent randomized control trials showed no survival benefit of performing elective neck dissection. The morbidity associated with elective neck dissection and performing this procedure in f= our out of five people that did not need it, prompted researchers to look at ot= her means of evaluating lymph nodes. In 1992, Morton used lymphoscintigraphy to map sentinel lymph nodes for cutane= ous melanoma. It was a well estab= lished practice for most sites in the body, but there was concern about using SLNM= in the head and neck due to complex drainage patterns and the number of lymph nodes in the head and neck. <= /p>
Studies performed by Schmalbach and Agnese found= that SLNB in the head and neck was comparable to other sites in the body. There are more lymph nodes in the = head and neck region and more sentinel nodes are found during surgery. Also, there is a 26% rate of findi= ng sentinel lymph nodes in non-predicted sites. Currently, sentinel lymph node bio= psy has supplanted elective neck dissection for staging of the clinically negat= ive neck. Certain criteria must b= e met before performing sentinel lymph node mapping and biopsy. These include Breslow depth equal = to 1 mm in the setting of tumor extension to the deep margin, ulceration, extens= ive regression to 1 mm, young age, high mitotic rate, and Clark level IV. SLN mapping requires preoperative lymphoscintigraphy approximately two to four hours preoperatively. A radioactive colloid is injected = into the dermis surrounding the primary melanoma and a scan is performed. This scan aides the surgeon in foc= using on specific nodal groups during surgery.&n= bsp; Intraoperatively, isosulfan blue dye is injected intradermally around the melanoma. Wide local exci= sion of the primary lesion is performed, followed by using the gamma probe to isolate the sentinel node or nodes. Sentinel node biopsy is complete when the gamma probe demonstrates o= nly minimal background radioactivity. Permanent section is the gold standard for finding micrometastasis, = thus it may be necessary to perform therapeutic neck dissection at a later date.

Treatment of the neck with therapeutic neck diss= ection with or without superficial parotidectomy depends on tumor location, and evidence of gross disease. Sc= alp lesions anterior to the external auditory canal and lesions to the lateral forehead, cheek, and auricle, typically drain to the periparotid lymph nodes and deep cervical lymph nodes.   Therapeutic neck dissection for these lesions involves superficial parotidectomy and modified radical neck dissection. Melanomas on the nose, lips, or ch= in will drain to level I, as well as the deep jugular nodes and require a modi= fied radical dissection of levels I-IV. Posterior and mid scalp lesions generally metastasize to occipital nodes, postauricular nodes, and posterior neck nodes. For these lesions, occipital and l= evel II-V lymphadenectomy is performed without parotidectomy. Lesions of the auricle or ear cana= l may present with extensive local disease prompting auriculectomy with lateral temporal bone resection in addition to the superficial parotidectomy and modified radical neck dissection.

Closure of the resultant defect follows the reconstructive ladder. The fa= ce causes particular concerns because defects may violate the facial units. With undermining, most defects can= be closed primarily with minimal tension.&nbs= p; Skin grafting, local flaps, pedicled flaps, and free flaps may also = be needed. If the facial nerve is involved with melanoma, then static procedures may be necessary as well as nerve grafting.

Patients with disseminated melanoma have a grave prognosis, and surgery only plays a palliative role in their care. Adjuvant treatments for head and n= eck cutaneous melanoma have not yielded improvements in survival. Melanomas are relatively radioresi= stant as well as chemoresistant. Radiation treatments are generally reserved for stage IV disease, and patients with significant negative prognostic factors such as neurotropism, greater than 4 node metastasis, extracapsular spread, or recurrence. The Radiation Oncology group is in= a randomized phase III clinical trial. The only chemotherapeutic option for stage IV disease is Dacarbaz= ine (DTIC). Less than 5% of people experience a complete response, and only 10% to 20% of people have any type of response. Immunotherapeutic a= gents are currently being studied and may be the adjuncts to the treatment of sta= ge III and IV diseases. Currentl= y, interferon alpha-2B is FDA approved for stage IIB and IIC, as well as stage= III disease and has shown improvements in disease free survival but not overall survival. Other immunotherape= utic technologies that are under investigation include vaccinations, cytokines, = and antibodies.

Summary

Cutaneous melanoma of the head and neck accounts= for approximately 25-35% of all melanomas.&nbs= p; This disease has seen an increase in incidence of 3% per year over t= he past year, with those born in 2005 having a 1 in 38 chance of developing melanoma over their lifetime. Traditionally, this was a disease of the elderly, but now melanomas = are found in all age groups. With early detection, wide local excision carries a greater than 90% cure rate. T= umor thickness, the presence of ulceration, nodal status, and distant metastasis= are the most important prognostic factors.&nbs= p; Sentinel lymph node biopsy now plays a major role in detecting micrometastasis and providing information about the necessity of therapeutic neck dissection. Stage IV dis= ease has a grave prognosis with survival measured in months. There are currently many investiga= tional studies looking to improve survival in this group of patients.

DISCUSSANT: Dr. C. Berlingeri-Ramos, Dept. UTMB Dermatology

The question was asked on the difference between UVA and UVB.

UVA penetrates more into the skin, while UVBR= 17;s shorter wavelength penetrates less and its is limited to the dermis and the papillary dermis. It is thoug= ht that UVB is responsible for the mutations involved in causing cancer.

Malignant melanoma does occur in negroes but is = much more common in fair-skinned patients especially those with red hair and blue eyes.

Dr. Quinn remarked that while in Victorian times= , a tanned skin was evidence of an occupation requiring manual work outdoors and therefore a mark of membership in the laboring classes. Today a “heal= thy tan” signifies that the wearer has sufficient leisure and discretiona= ry funds to enjoy days of recreational activity at the seashore, and hence is a claim to enhanced social status and relative affluence.

Dr. Berlingeri-Ramos then remarked that “t= here is no such thing as a healthy tan except for the ones that are sprayed on.<= span style=3D'mso-spacerun:yes'> With respect to tanning salons, Dr. Berlingeri-Ramos believes that in some States, a minor must have a parent’s consent before being admitted for a tanning session.

She was asked about the dimensions of a so-called “giant nevus.” She replied that the usual minimum diameter is considered to be 20 cm. and in these, some 10% become malignant.

Bibli= ography

Agnese DM, Maupin R, = Tilman B et al. Head and neck melanoma= in the sentinel lymph node era. = Arch Otolaryngol Head Neck Surg 2007,133(11):1121-1124

Autier P, Dore JF, Sc= hifflers E, et al. Melanoma and use of sunscreens: an EORTC case-control study in Germany Belgium, and France. Int J Cancer 1995;61:749.

Autier P, Boniol M, Dore JF. Sunscree= n use and increased duration of intentional sun exposure: still a burning issue. = Int J Cancer 2007;121:1–5.

Balch CM et al. New T= NM melanoma staging system: linking biology and natural history to Clinical ou= tcomes. Seminars in Surg. Oncology 2003,21:43-52

Barnhill RL, Mihm MC,= and Elgart G. Malignant Melanoma.= Skin Cancer 1st ed 2008, Nouri K <= /p>

Bottomley A et al. Adjuvant therapy with pegylated interferon alpha-2b versus observation in resected stage III melanomas: a p= hase III randomized control trial of health-related quality of life and symptoms by the European Organisation for Research and Treatment of Melanoma Cancer Group. J Clin Oncol 27:2916-2923

Doting EH, De Vries M= , and Plukker J et al. Does Sentinel Lymph Node Biopsy in cutaneous Head and neck melanoma alter disease outcome. Journal of Surgical Oncology 2006,93:564-570

Easson AM, Rotstein L= E and McReady DR. Lymph node assess= ment in melanoma. Journ of Surg On= cology 2009,99:176-185

Eggermont AMM. Melanoma and Immunotherapy. Hematol Oncol Clin N AM 2009:547-5= 64

Eggermont AMM et al.<= span style=3D'mso-spacerun:yes'> Adjuvant therapy with pegylated interferon alpha-2b versus observation Alone in resected stage III melanoma: final results of EORTC 18991, a randomized phase III trial. The Lancet July 2008,372:117-126

Gillenwater, AM and H= arrison LB ed. Ch 22 Melanoma of the Head and Neck. Head and Neck Cancer: A Multidisciplinary Approach. 3rd edition, 2009

Gomez-Rivera F, Santi= llan A, McMurphey AB et al. Sentinel = lymph node biopsy in patients With cutaneous melanoma of the head and neck: recurrence and survival study. Head And Neck Oct 2008,1284-1293

Lin D, Franc BL, Kashani-Sabet M, amd Singer MI. Lymphatic drainage patterns of head and neck cutaneous melanoma obse= rved on lymphoscintigraphy and sentinel lymph node biopsy. Head and Neck March 2006,249-255

McDermott et al. Double Blind Randomized Phase II s= tudy of the Combination of Sorafenib and Dacarbazine in patients with advanced melanoma/; A report from the 11715 Study Group J Clin Oncol 26:2178-2185

McMasters KM et al. Lessons learned from Sunbelt Melan= oma Trial. Journ of Surg Oncology= 2004,86:212-223.

Tanis PJ, Nieweg OE et al. Dilemma of clinically node-negative head and neck melanoma: Outcome of “watch and wait̶= 1; policy, elective lymph node dissection and sentinel lymph Node biopsy- A Systemic Review. Head and Neck March 2008:380-389

Schmalbach CE, Nussenbaum B, Rees RS et al.<= span style=3D'mso-spacerun:yes'> Reliability of sentinel lym= ph node mapping with biopsy for head and neck cutaneous melanoma. Arch Otolaryngol Head and Neck Sur= gery Jan 2003,129:61-65

Schmalbach CE, Johnso= n TM, and Bradford CR. Ch. 23 The Management of Head and Neck Melanoma. Cummings: Otolaryngology Head and Neck Surgery, 4th ed., 2005

Wolf P, Donawho CK, K= ripke ML. Effect of suncreens on UV radiation-induced enhancement of melanoma growth in mice. J Natl Can= cer Inst 1994;86:99–105.

T Classification=	Thickness	Ulceration Statu= s
T1	≤1.0 mm<= /o:p>	a: without ulcerati= on and level II/III
		b: with ulceration = or level IV/V
T2	1.01–2.0 mm	a: without ulcerati= on
		b: with ulceration<= o:p>
T3	2.01–4.0 mm	a: without ulcerati= on
		b: with ulceration<= o:p>
T4	> 4.0 mm	a: without ulcerati= on
		b: with ulceration<= o:p>
N Classification=	No. of Metastati= c Nodes	Nodal Metastatic= Mass
N1	1 node	a: micrometastasis = *
		b: macrometastasis = ̶= 4;
N2	2–3 nodes	a: micrometastasis = *
		b: macrometastasis = ̶= 4;
		c: in transit met(s)/satellite(s) without metastatic nodes
N3	4 or more metastati= c nodes, or matted nodes, or in transit met(s)/satellite(s) with metastatic node(s= )
M Classification=	Site<= /b>	Serum Lactate Dehydrogenase
M1a	Distant skin, subcu= taneous, or nodal mets	Normal
M1b	Lung metastases	Normal
M1c	All other visceral metastases	Normal
	Any distant metasta= sis	Elevated=

*	Micrometa= stases are diagnosed after sentinel or elective lymphadenectomy.
†	Macrometastases are def= ined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension.