KARSINOMA SEL BASAL

PENDAHULUAN
Pada dekade ini, banyak terjadi peningkatan kasus kanker kulit oleh karena adanya eksposure karsinogen berupa peningkatan radiasi Ultra violet (UV) terutama UVB akibat adanya lubang ozon di atmosfer.Adanya eksposure ini menyebabkan terjadinya kerusakan DNA, sehingga sistem apoptosis gagal mengantisipasinya, yang pada akhirnya menyebabkan timbulnya kanker tersebut. Kondisi ini menyebabkan mulai didapatkannya perubahan prekanker pada usia yang lebih muda.Kanker kulit secara umum digolongkan menjadi kanker kulit Melanoma dan kanker kulit Non Melanoma (Karsinoma Sel Basal dan Karsinoma Sel Skuamosa). Karsinoma Sel Basal merupakan tumor ganas lokal yang destruktif, biasanya tidak bermetastase dan merupakan tumor ganas kulit yang terbanyak tumbuh sebagai benjolan kecil yang selanjutnya mengalami ulserasi sentral (ulkus rodens) dengan pinggir yang menonjol.Sering mengenai orang-orang yang terpapar sinar matahari serta timbul pada usia pertengahan hingga tua. Lokasi biasanya mengenai kepala dan leher.Pada paper ini akan difokuskan lebih mendalam mengenai karsinoma sel basal.1,2,3,4

DEFENISI
Karsinoma Sel Basal adalah suatu tumor kulit yang bersifat ganas, berasal dari sel pluripotensial di lapisan dasar epidermis, atau dari selubung akar folikel rambut. Beberapa sinonim dari karsinoma sel basal dikenal antara lain : Basal cell epithelioma (BCE),Basalioma,Ulkus rodens,Ulkus jacob,Dan Tumor Komprecher.1,2,3

PATOFISIOLOGI
Tumor ini disangka berasal dari sel epidermal pluripotensial atau dari lapisan sel basal dari kulit. Pajanan UV terutama spectrum UVB (290-320 nm) yang menginduksi mutasi gen tumor supresor menyebabkan kerusakan dari DNA dan menyebabkan mutagenesis dari sel tumor yang baru. Sel. mutasi yang terutama diinduksi sinar UV pada tumor suppressor gene TP53. Gen ini terletak di kromosom 17 lengan pendek (17p). Bisa juga terjadi karena mutasi gen pada pita 9q22. KSB diakibatkan kelainan inhibisi gen yang mengkode protein untuk kaskade proses pertumbuhan sel dan adneksanya sejak fetus. Homolog gen ini ialah Sonic Hedgehog (SHH), Patched (PTCH), dan Smoothened (SMO), tiga ini yang paling banyak pada manusia. Pada sebagian besar KSB terdapat abnormalitas gen PTCH atau SMO.1,2,4,5,6

ETIOLOGI
Insiden karsinoma sel basal berbanding lurus dengan usia pasien dan berbanding terbalik dengan jumlah pigmen melanin pada epidermis. Ada juga korelasi langsung keadaan ini dengan lama total pajanan terhadap sinar matahari seumur hidup pasien.Sekitar 80% dari kanker sel basal terjadi pada daerah terbuka yang biasanya terpapar sinar matahari seperti wajah,kepala dan leher. Spektrum sinar matahari yang bersifat karsinogenik adalah sinar yang panjang gelombangnya berkisar antara 280-320 nm , spektrum inilah yang membakar dan membuat kulit menjadi coklat. Penyebab lain karsinoma sel basal adalah riwayat pengobatan radiologi sebelumnya untuk menyembuhkan penyakit kulit lain,kontak dengan arsen,dan gangguan genetik yang jarang

(xeroderma pigmentosum dan sindrom karsinoma sek basal nevoid).Sinar ultravioled panjang (UVA) yang dipancarkan oleh alat untuk membuat kulit kecoklatan seperti terbakar sinar matahari juga merusak epidermis dan dianggap sebagai karsinogenik.2,3

GEJALA KLINIS
Tumor ini umumnya ditemukan didaerah berambut ,bersifat infasif ,jarang mempunyai metastasis.Dapat merusak jaringan di sekitarnya serta cenderung untuk residif . Bentuk klinis yang banyak ditemukan ialah : 1.Bentuk Nodulus Bentuk ini paling sering ditemukan . Pada tahap permulaan sangat sulit ditentukan malah dapat berwarna seperti kulit normal atau menyerupai kutil.Gambaran klinis yang khas berupa gambaran keganasan dini seperti : Tidak berambut,bewarna coklat hitam ,tidak berkilat.Bila sudah berdiameter 0,5 cm sering ditemukan pada bagian pinggir berbentuk papular ,meninggi ,anular ,di bagian tengah cekung.Pada perabaan terasa keras dan berbatas tegas .Dapat melekat didasarnya bila berkembang lebih lanjut . Dengan trauma ringan atau bila krustanya diangkat mudah terjadi perdarahan. 2.Bentuk Kista Bentuk ini agak jarang ditemukan ,Permukaanya licin ,menonjol di permukaan kulit berupa nodus atau nodulus Pada perabaan keras dan mudah digerakkan dari dasarnya.Telangiektasis dapat ditemukan pada tepi tumor.

3.Bentuk superfisial Bentuk ini menyerupai penyakit bowen,lupus eritematosus,psoriasis atau dermatomikosis.Ditemukan dibadan serta umumnya multipel.Biasanya terdapat faktor-faktor etiologi berupa faktor arsen atau sindrom nevoid basal sel karsinoma.Ukuranya dapat berupa plakat dengan eritema,skuamasi halus dengan pinggir yang agak keras seperti kawat dan agak meninggi.Warnanya dapat hitam berbintik-bintik atau hematogen yang kadang-kadang menyerupai melanoma maligna. 4.Bentuk morfea Secara klinis menyerupai morfea akan tetapi ditemukan tanda-tanda berupa kelainan yang datar ,berbatas tegas tumbuh nya lambat berwarna kekuningan ,pada perabaan pinggirnya keras. Karsinoma sel basal umumnya tumbuh lambat ,kadang-kadang dapat berkembang cepat.Jaringan yang paling banyak rusak ialah pada bagian permukaann .Ulserasi dapat dapat terjadi yang menjalar kearah samping maupun kearah dasar meliputi otot.1,2,3,4,5,6

DIAGNOSA
Diagnosis seringkali bisa ditegakkan melalui gejala-gejalanya. Sebagai prosedur standar untuk memperkuat diagnosis biasanya dilakukan biopsi kulit. Karakteristik sel KSB ialah memiliki nukleus besar, oval, uniform, serta nonanaplastik dengan sitoplasma yang sedikit. Nukleus ini terlihat mirip sel-sel basal epidermis (besar-besar dan oval) namun sel-sel KSB memiliki lebih banyak jembatan intersel. Stroma jaringan penujang yang mengelilingi pulau-pulau tumor tersusun secara paralel dan sering memperlihatkan fibroblas muda di sela-sela sel tumor. Stroma pulau-pulau tumor tersebut sering terlihat retraksi secara artifisial, serta kadang-kadang terlihat berlendir. Secara histologis, KSB dibagi menjadi dua kategori; dengan diferensiasi dan tanpa diferensiasi. KSB dengan diferensiasi yang rendah atau tidak ada diferensiasi sama sekali akan muncul sebagai

tipe klinis KSB superfisial, pigmentasi, superfisial, sklerosis, serta infiltratif (subtipe histologis). KSB dengan diferensiasi secara histologis agak sulit dibedakan dengan adneksa kulit yang normal, misalnya KSB keratotik mirip dengan rambut, KSB dengan diferensiasi sebasea mirip dengan kelenjar sebasea yang normal saja, atau KSB adenoid mirip dengan kelenjar-kelenjar tubular, yang paling sering kita temui, yakni KSB nodular, di bawah mikroskop akan terlihat sebagai tipe yang berdiferensiasi. Secara ringkas, hubungan tipe klinis dan tipe histologis KSB yakni KSB noduloulseratif (ulkus roden) terdiri dari pulau-pulau tumor yang bulat atau oval dalam dermis, kadang sampai ke perlekatan epidermal dan memperlihatkan retraksi artifisial stroma. KSB mikronodular mirip dengan noduloulseratif namun ukuran pulau-pulau tumornya relatif lebih kecil daripada tipe noduloulseratif (<15 sel per lapang pandang). KSB pigmentasi terdiri dari pulau-pulau tumor yang besar, bulat, atau oval berisi melanin dalam jumlah banyak di dalam melanosit dan melanofag. KSB kista secara histologis akan memperlihatkan pulau-pulau tumor yang besar, bulat, atau oval di dalam dermis disertai musin di bagian tengah pulau tersebut. KSB morfeaform atau sklerosis terdiri dari jejaring sel tumor basaloid yang memanjang, mengakibatkan jaringan stroma akan terlihat bertumpuk-tumpuk. KSB superfisial terdiri dari tunas-tunas sel basofilik di dalam papil dan sering terlihat superfisial di dermis, namun mereka melekat ke epidermis.2,3,5,6,7

DIAGNOSA BANDING
1.Keratosis aktinik 2.Penyakit Bowen 3.Papul fibrosa pada wajah 4.Keratocanthoma 5.Nevi (melanocytic) 6.Hiperplasia sebasea 7.Keratosis seboroik

PENATALAKSANAAN
Penatalaksanaan KSB dapat digolongkan kedalam 2 kelompok : 1.Pembedahan : eksisi dengan bedah skalpel , diangkat melalui pengorekan lalu dibakar dengan jarum listrik( kuretase dan elektrodesikasi) Terapi yang menjadi primadona tentunya ialah dioperasi saja agar lesi lekas hilang, pasien tidak terlalu repot, dan kekambuhannya relatif sangat rendah. Modalitas operasi ini ialah electrodesiccation dan curettage, bedah eksisi, bedah mikro kimiawi (Mohs) terkontrol, serta bedah beku. Ada satu lagi, yakni radiasi ionisasi, meskipun bukan prosedur bedah, namun termasuk dalam pertimbangan tindakan yang interventif. Elektrodesikasi dan kuret dilakukan di bawah prosedur anestesia lokal, awalnya tumor dikuret, kemudian tepi dan dasar lesi dibersihkan dengan elektrodesikasi, diulang-ulang selama dua kali. Prosedur ini relatif ringkas, praktis, dan cepat serta berbuah kesembuhan hingga 95% untuk KSB nodular dan superfisial. Namun kerugiannya, prosedur ini sangat tergantung pada operator dan sering meninggalkan bekas berupa jaringan parut. Karenanya, sebaiknya prosedur ini tidak dilakukan untuk daerah hidung dan untuk tumor di bawah daerah pilosebasea. Prosedur ini juga tidak terlalu cocok untuk KSB infiltratif, mikronodular, morefeaform, dan KSB yang rekuren. Sebenarnya bisa juga dilakukan kuret tanpa elektrodesikasi, hasilnya akan lebih baik secara kosmetik, namun lebih sering menimbulkan jaringan parut berwarna putih. Kalau ingin lebih kosmetis lagi, bisa juga kuret saja namun ditambah laser YAG (erbium) yang bertujuan membuat tepi bekas lesi akan mengalami ablasi. Sayangnya, dua prosedur yang terdengar menarik itu tidak digunakan luas oleh para ahli.

Satu cara konservatif namun tetap dipakai sampai sekarang ialah bedah skalpel. Dengan ukuran nomor 15 atau 10, skalpel digunakan untuk insisi hingga ke subkutis. Nah, umumnya karena invasi tumor sering tidak terlihat sama dengan tepi lesi dari permukaan, sebaiknya bedah ini dilebihkan 3-4 mm dari tepi lesi agar yakin bahwa seluruh isi tumor bisa terbuang. Keuntungan prosedur ini ialah tingkat kesembuhan yang tinggi serta perbaikan kosmetis yang sangat baik. Sayangnya, harus dikerjakan oleh tenaga yang memang sangat ahli, selain itu tidak terlalu cocok untuk tumor dengan tepi lesi yang benar-benar tidak jelas, misalnya pada KSB infiltratif, mikronodular, dan morfeaform. Lebih-lebih tidak efektif lagi untuk KSB yang berulang. Untuk lesi-lesi sulit yang tersebut di atas, misalnya KSB infiltratif, mikronodular, morfeaform, dan yang berulang, pilihan prosedur bedah yang tepat ialah bedah Mohs. Sebenarnya prosedur bedah ini relatif sama dengan kuret dan elektrodesikasi, namun sesudah dilakukan kuretase dan elektrodesikasi, sebagian jaringan epidermis diambil lagi setebal kirakira 1mm untuk diperiksa di bawah mikroskop, kemudian jika masih ada tumornya, tentu akan dikuret dan desikasi lagi sampai tuntas. Kedengaran sangat komprehensif, namun pada kenyataannya prosedur ini sangat makan waktu, cepat membuat lelah, sangat butuh ketelitian tinggi, dan anestesi pun mau tak mau harus diberikan secara lebih kepada pasien. Wajar saja kalau tarifnya pun berbeda dengan prosedur biasa. Bedah beku dilakukan untuk tumor yang memang sudah jelas-jelas timbul di permukaan kulit. Prosedur ini sangat praktis, namun tetap membutuhkan keahlian tersendiri, terutama untuk membasmi sel-sel tumor di tepi lesi dan infiltrasinya di dalam kulit. Seperti biasa, N2 disemprotkan pada lesi hingga temperatur mencapai -600C dan lesi tumor akan mati perlahanlahan. Tidak perlu anestesi, namun akan sedikit membuat rasa sakit pada pasien. Terakhir, kalau memang keadaan benar-benar tidak memungkinkan untuk operasi di daerah lesi, misalnya ada tumor di wajah, dapat dilakukan radiasi ionisasi dengan sinar X 4Gy (400rad), hanya tumor di wajah yang bisa dilakukan prosedur seperti ini. Prinsipnya sama seperti radiasi ionisasi secara umum, yakni membelokkan energi elektron sel. Sayangnya, sama juga dengan terapi radiasi lainnya, mau tak mau pasien harus bolak-balik ke rumah sakit untuk mendapat terapi. 2.Tanpa pembedahan : radioterapi, imiquimod atau 5-Fluoro Urasil Topikal. Meski hampir semua KSB akan sembuh dengan mudah melalui prosedur operatif, kadang kita memerlukan terapi topikal untuk kasus yang berulang, multipel, atau untuk penelitian jangka panjang. 5-fluorourasil dioleskan dua kali sehari selama dua hingga dua belas pekan untuk KSB yang bersifat superfisial. Pasalnya, obat ini memang tidak mampu menembus hingga ke lapisan dermis secara efektif, bahkan jika dioleskan banyak-banyak di lesi, tetap saja tidak mampu penetrasi dalam, malah hanya membuat kulit menjadi iritasi dan tidak nyaman. Ada juga krim Imiquimod tiga kali perminggu atau interferon alfa-2b 1,5 juta IU intralesi tiga kali seminggu selama tiga pekan yang kini sedang tren digunakan untuk KSB. Keduanya mampu mengobati KSB tipe superfisial bahkan tipe nodular .2,3,4,5,6,7 Dari beberapa, cara pengobatan, eksisi dengan bedah skalpel memberikan hasil paling baik secara kosmetik.

PROGNOSIS
Prognosis cukup baik, bila diobati dengan baik (angka kesembuhan 97%). Pengobatan pada KSB primer biasanya memberikan angka kesembuhan sekitar 95%; sedangkan pada KSB rekuren sekitar 92%. Dijumpai angka kekambuhan 5 tahun pada metode kuretase dan elektrodesikasi sebesar 7,7%; bedah mosh 1%.

Background
Cutaneous squamous cell carcinoma (SCC) is the second most common form of nonmelanoma skin cancer (basal cell carcinoma [BCC] is the most common skin cancer) and accounts for 20% of cutaneous malignancies[1, 2] and 90% of all head and neck cancers. Unlike most BCCs, SCCs of the skin are associated with a risk of metastasis. A malignant tumor of epithelial origin, SCC has a regional distribution involved in the biologic activity of the neoplasm. The behavior of SCC depends on its site of origin. Each anatomic site has its own particular spread pattern and prognosis. SCC frequently arises on the sun-exposed skin of middle-aged and elderly individuals (see the image below). Most SCCs are readily identified and removed in the physician's office as a minor surgical procedure. Larger and more invasive lesions may require aggressive surgical management, radiation therapy, or both. High-risk SCC carries a significant risk of metastasis and, as such, requires careful evaluation and treatment. An estimated 8000 cases of nodal metastasis and 3000 deaths occur in the United States annually, almost wholly attributable to aggressive or high-risk SCC.[3, 4]
Large, sun-induced squamous cell carcinoma on the forehead/temple with superficial erosion. Image courtesy of Glenn Goldman, MD.

Historical information Evidence of head and neck carcinomas has been found in ancient skulls. The oldest known tumor is contained in a fossil found in East Africa by Louis Leakey that dates back more than 500,000 years. Some historians speculate that a high incidence of nasopharyngeal cancer may have been present in some ancient populations because of the inhalation of wood smoke in poorly ventilated huts. In approximately 400 BC, Hippocrates described a common chronic ulcer at the edge of the tongue that he attributed to the presence of sharp teeth rubbing against the tongue. The ancient Indian physician Sushruta described the removal of tumors and developed great skill in plastic surgery, partly from defects created by frequent amputations of the nose and ears for punishment. Modern Western medicine received its foundation from early Roman medical writings. Little medical advancement was made for head and neck cancers until the advent of anesthesia and surgical excision in the 11th century.

In 1893, President Grover Cleveland was found to have a SCC of the hard palate that required surgical excision. The operation was performed secretly on a yacht so that he could manage the "financial panic of 1893." Cleveland was known for his heavy cigar smoking and social drinking. See the following for more information: Sentinel Lymph Node Biopsy for Squamous Cell Carcinoma Urogenital Squamous Cell Carcinoma Imaging of Nasopharyngeal and Laryngeal Squamous Cell Carcinoma Cell Biology of Head and Neck Squamous Cell Carcinoma Targeted Molecular Therapy in Head and Neck Squamous Cell Carcinoma. Mohs Micrographic Surgery Mohs Surgery

Anatomy
Squamous cell carcinoma (SCC) of the head and neck possesses unusual features not universally found in carcinomas in other anatomic sites. SCC is a field-defect phenomenon. Although this is also true of transitional-cell carcinoma of the urinary bladder, it is not the rule for malignant degeneration in all body sites. Simply defined, field defect means that, if dysplastic changes occur in 1 location of an organ or body site, other locations in the same organ are likely to have dysplastic changes. The implications of this phenomenon can be profound. For instance, mild dysplasia in 1 region of the buccal mucosa may be associated with frankly invasive carcinoma only millimeters away. An invasive carcinoma of the soft palate may be completely excised, in that the margins are free of morphologically recognizable neoplasm. However, the patient may present 1 year later with a carcinoma of the hard palate. This occurrence does not indicate that the margins were misread but that field-defect lesions are associated with skip lesions. In this context, the clinician must realize that the pathologist's evaluation of the margins (eg, "free of malignancy or significant dysplasia" or "malignancy completely excised") means that the surgeon did not cut across dysplastic tissue. A premalignant lesion may be still in the patient only 2 mm away from the excisional margin. This knowledge becomes important given the complex nature of the anatomic structures in the head and neck. Wide margins are not always an option. Although a skin lesion of the shoulder may justify 2-cm margins, a "generous" margin of the maxillary sinus may lead to an orbital exenteration.

A parotid tumor may require a decision between close margins or loss of the facial nerve. Dr Charles Vaughan in Boston inculcates his otolaryngology and pathology residents with the knowledge that "SCC of the head and neck is a disease of millimeters." This statement is undeniably true, and a field-defect phenomenon that occurs where a structure must be conscientiously preserved makes oncologic therapy in this area notoriously hazardous. Another consideration with regard to SCC of the head and neck is that this relatively small region has numerous subdivisions, which authors define in different ways. Some divide them by gross anatomic features, some by histologic barriers, and some by embryologic origins. These divisions are valid for empirical reasons. Each area has its own peculiarities with regard to etiology, likelihood of malignancy, surgical approach, other therapeutic options, and prognosis. To consider each one individually would be exhaustive, and the literature in the general domain covers these in sufficient detail. In this article, subdivisions are considered only when the nuances of that region illustrate an important teaching point. Mucosa For purposes of discussing the head and neck, mucosa, a widely used term, refers to the membranous lining protecting the oral cavity, oropharynx, nasopharynx, larynx, and laryngopharynx. The lining is composed of the epithelium covering the surface and the underlying stroma, and (where appropriate), the muscularis mucosae. The critical anatomic barrier is the basement membrane. This is the layer of collagen and glycoproteins directly beneath the inferior layer of the epithelium and the connective tissue stroma. A breach in this structure by dysplastic epithelial cells is the sine qua non for invasive carcinoma. Epithelium Epithelial cells line the surfaces of the body. Categorization is based on the number of layers and on the morphology of the most superficial cells. Squamous epithelium usually consists of 5-7 cell layers. The basal cell layers are elongated cells arranged so that the long axis of the cell is perpendicular to the basement membrane. In normal epithelium, the basal cell layer, and perhaps the one directly above it, are the only layers engaged in active division and proliferation. For this reason, mitotic figures are the norm in the basal and parabasal layers. Mitotic figures above this level are of increasing concern given their proximity to the surface layers. As one proceeds upward toward the surface layer, the cells take on an increasingly ovoid to round shape. By midway, the cells are

approximately round. Ascending above the midway portion, one sees that the cells begin to assume an elongated shape. This time, however, the long axis of the cell is parallel to the basement membrane, which means it is also parallel to the surface. Finally, at the surface, the epithelium is completely flattened and therefore the ideal shape for complete coverage of the body. One must understand that epithelium is avascular. Therefore, nonirritated, nontraumatized epithelium should not bleed. This is true for SCC in situ as well. By definition, carcinoma in situ (CIS) does not break through the basement membrane; therefore, blood vessels are not exposed. This being the case, a previously dysplastic lesion that begins to bleed is a cause for concern. Stroma The stroma underlying the squamous or respiratory epithelium of the head and neck varies by anatomic site. In some areas, voluntary (striated) muscle (eg, tongue, true vocal cord) is present. In others, no striated muscle but abundant mucous glands (eg, false cord) is present. With some exception of the cartilaginous tissues, all locations have lymphatic channels, blood vessels, proteoglycans, and neural elements in common. The vascular channels, lymphatic and blood vessels, and nerves allow for rapid and widespread dissemination as soon as these structures are invaded. Furthermore, the stromal matrix offers little resistance to the spread of the tumor into these structures. The stroma of the Waldeyer ring is markedly different from that of any other in the body, including stroma in other head-and-neck sites. The Waldeyer ring can be envisaged as including the base of tongue, palatine tonsils, soft palate, and pharyngeal tonsils (adenoids). Here, the epithelium does not have a clear basement membrane, and the epithelial cells intermingle with the dense lymphoid tissue in these areas. The stroma does have blood vessels, nerves, or lymphatic, but the abundance of lymphoid tissue largely obscures these structures on routine histologic examination. Invasion of these structures happens early, as no natural barrier exists between the epithelium and stroma. That is, no basement membrane is present. See Definitions and Clinical Terminology for other specific language used in discussions of SCC. Oral cavity The oral cavity is defined as the area extending from the vermilion border of the lips to a plane between the junction of the hard and soft palate superiorly and the circumvallate papillae of the tongue inferiorly. This region includes the buccal mucosa, upper and lower

alveolar ridges, floor of the mouth, retromolar trigone, hard palate, and anterior two thirds of the tongue. The lips are the most common site of malignancy in the oral cavity and account for 12% of all head and neck cancers, excluding nonmelanoma skin cancers. SCC is the most common histologic type, with 98% involving the lower lip. This predilection to the lower lip has been attributed to sun exposure. Next most common sites in order of frequency are the tongue, floor of the mouth, mandibular gingiva, buccal mucosa, hard palate, and maxillary gingiva. The tumor site and lymphatic drainage of the oral cavity are as follows: Anterior tongue to subdigastric, submaxillary, or midjugular nodes Floor of mouth to subdigastric, submaxillary, or midjugular nodes Gingival to jugulodigastric, submaxillary, or midjugular nodes Buccal mucosa to submaxillary, preparotid, or jugular nodes Hard palate to submaxillary or jugulodigastric nodes The pharynx consists of the oropharynx, nasopharynx, and hypopharynx. The most common sites of cancer in the oropharynx are the tonsillar fossa, soft palate, and base of tongue, followed by the pharyngeal wall. The nasopharynx is the part of the pharynx bounded superiorly by the skull base and sphenoid bone, inferiorly by a horizontal plane at the level of the palate, laterally by the superior constrictor muscles, anteriorly by the nasal cavity through the choanae, and posteriorly bounded by the prevertebral fascia. The hypopharynx is divided into the pyriform sinus (most common site of tumor involvement), posterior pharyngeal wall, and postcricoid region. In nasopharyngeal carcinoma, the most frequent site of origin is the fossa of Rosenmller. This is a structure anterior and superior to the entrance of the eustachian tube. It is basically an outpouching of nasopharyngeal mucosa between the skull base and the muscular layers of the nasopharynx. Invasion of the cartilage framework of the larynx and mobility of the vocal cords influence the treatment of primary tumors of the hypopharynx and larynx. The Ohngren line is an imaginary line drawn from the medial canthus to the angle of the mandible that divides the paranasal sinuses into an infrastructure and suprastructure. Sinus tumors that involve the infrastructure have a more favorable prognosis than tumors of the suprastructure.

Pathophysiology
Malignant transformation of normal epidermal keratinocytes is the hallmark of cutaneous squamous cell carcinoma (SCC). Some cases of SCC occur de novo (ie, in the absence of a precursor lesion); however, some SCCs arise from sun-induced precancerous lesions known as actinic keratoses, as well as leukoplakia, radiation

keratosis or dermatitis, scars, chronic ulcers, or chronic sinusitis. People with actinic keratosis have atypical squamous cells in one third to one half of the epidermis, and those with multiple actinic keratoses are at increased risk for developing SCC. [5] Those with Bowen disease (see the following image), or SCC in situ, have atypical keratinocytes in the entire epidermis. SCC is capable of locally infiltrative growth, spread to regional lymph nodes, and distant metastasis, most often to the lungs. Invasive SCC involves the epidermis and invades the dermis.
Squamous cell carcinoma in situ (Bowen disease). Courtesy of Hon Pak, MD.

One critical pathogenic event is the development of apoptotic resistance through functional loss of TP53, a well-studied tumor suppressor gene. Ultraviolet (UV) B-induced photocarcinogenesis appears to work by suppressing the immune system in several ways. The UVB spectrum inhibits antigen presentation, induces the release of immunosuppressive cytokines, and elicits DNA damage, specifically the generation of pyrimidine dimers in keratinocyte DNA that is a molecular trigger of UV-mediated immunosuppression. [6] This process is known to result in genetic mutation of TP53. TP53 mutations are seen in over 90% of skin cancers diagnosed in the United States, as well as most precursor skin lesions, suggesting that loss of TP53 is an early event in the development of cutaneous SCC.[7, 8] Upon subsequent UV radiation exposure, keratinocytes undergo clonal expansion, acquiring further genetic defects, and ultimately leading to invasive cutaneous SCC. Other tumor suppressor genes found to be mutated in SCC include P16 (INK4a) and P14 (ARF).[9] Many other genetic abnormalities are believed to contribute to the pathogenesis of cutaneous SCC, including mutations of BCL2 and RAS. Likewise, alterations in intracellular signal transduction pathways, including epidermal growth factor receptor (EGFR) and cyclooxygenase (COX), have been shown to play a role in the development of cutaneous SCC. Salehi et al noted that translational control is critical for the proper regulation of the cell cycle, tissue induction, and growth.[2] The eukaryotic initiation factor 4E (eIF4E) is important for these processes and may play an important role in SCC. [2] Although typically observed in elderly patients, SCC may be seen in younger patients with a history of radiotherapy or in patients with human immunodeficiency virus (HIV) infection (see the image below). Human papillomavirus (HPV) infection or TP53 overexpression may play a role in development of SCC in patients who are infected with HIV.[10, 11] Multiple infectious agents likely play a role in the development of SCC of the conjunctiva via the actions of infectious oncogenes and chronic antigenic stimulation.[12]

A 35-year-old man who is positive with human immunodeficiency virus (HIV) infection presented with a 2-year history of a slowly enlarging, left lower eyelid lesion; incisional biopsy revealed squamous cell carcinoma.

Occupations with considerable exposure to oils or tar may be associated with increased incidence of SCC of eyelids. In patients with xeroderma pigmentosum, defective DNA repair causes predisposition for development of malignant epithelial lesions, including SCC.

Etiology
The etiology of cancer is a difficult, ill-defined, and incomplete concept. Etiology is not synonymous with cause. Cause implies a condition that is necessary and sufficient to produce a certain result, whereas etiology is literally the study of causes. As such, etiology implies a complex interaction of entities, their introduction, and their interaction with a host to produce a malignancy. This is an important point, because it underscores the reality that few etiologic agents are necessary or sufficient to produce a particular type of malignancy. Therefore, a number of etiologic agents are associated with various degrees of risk in the development of squamous cell carcinoma (SCC) of the head and neck. Exposure to cancer-promoting stressors and the response of the body to those exposures (host response) combine to determine the risk of developing cutaneous SCC. These risk factors include exposure to ultraviolet (UV) radiation; immunosuppression; use of tobacco or alcohol; age; familial or genetic predisposition; nutritional status; chronic irritation; and exposure to industrial products or heavy metals, viruses, or ionizing radiation. Some of these risk factors are discussed in more detail below. These etiologic agents, as determined on the basis of demographic and statistical data, are of limited predictive value in any given individual. UV radiation exposure The primary risk factor of most SCC is cumulative lifetime sun exposure; that is, SCC can develop even if the history of sun exposure occurred decades before development of the skin lesion. [13] The frequency of SCC is increased at lower latitudes, correlating with an increased intensity of ambient light. The component of sunlight believed to be most important in cutaneous carcinogenesis is UVB (290-320 nm), which is both an initiator and a promoter of carcinogenesis. In animal models, UV-induced photocarcinogenesis appears to involve the UVB and UVA-2 spectral ranges. [14] UV light treatments used for psoriasis (and other recalcitrant dermatoses) also predispose to the development of SCC. Psoralen and UVA (PUVA) therapy is particularly phototoxic and mutations in both TP53 and the oncogene Ha-Ras are present in a large proportion of PUVA-associated SCC.[7] In addition to being mutagenic, UVA in conjunction with UVB is a potent suppressor of

the cutaneous immune system, which likely contributes to its role in cutaneous carcinogenesis. Fair complexion Persons with fair complexion, albinism, hazel or blue or gray eyes, and light-colored hair (blond or red) and those who burn easily when exposed to the sun are at higher risk for cutaneous SCC than those with other physical characteristics. Individuals with skin types I and II account for most of the patients who develop SCC; patients with oculocutaneous albinism are also at risk, and SCCs account for the most common type of cutaneous malignancy in this group. Such individuals lack natural protection from UV-induced carcinogenesis, owing to reduced levels of the photoprotective pigment, melanin. [15] DNA repair failure Healthy human skin is constantly repairing UV-induced damage through DNA repair mechanisms. Patients with xeroderma pigmentosum have a deficiency in an enzyme essential for normal DNA repair and are thus prone to the development of innumerable SCCs, and, less commonly, other cutaneous tumors. [16] Iatrogenic immunosuppression Immunosuppression is also increasingly recognized as a risk factor for the development of skin cancer. The use of immunosuppressive medications to prevent rejection in organ transplant recipients is associated with a 65- to 250-fold increased risk of developing SCC compared with the general population.[17] This correlates with the intensity of immunosuppression (ie, number and/or dosage of medications) typically required to prevent rejection in these patient populations, so that heart transplant recipients have 3 times the risk of SCC compared with kidney transplant recipients. Thus, although the proportion of heart transplant recipients developing new tumors is greater than in kidney transplant recipients, the mean number of tumors per patient is higher in kidney transplant recipients. This may be due to a longer duration of immunosuppression in patients who are younger at transplantation.[18] For organ transplant recipients on chronic immunosuppression agents, skin cancers account for 90% of all diagnosed malignancies. In this group of patients, cutaneous SCC is more common than other keratinocyte-derived neoplasms, including basal cell carcinomas (BCC). Additionally, organ transplant recipients have a high risk of developing further SCCs, with 66% developing a second SCC within 5 years of their first SCC diagnosis.[19] The primary risk factor in organ transplant patients is cumulative lifetime UV exposure in combination with having Fitzpatrick skin type I or II. This risk also increases with the number of years posttransplantation, presumably because of the cumulative effects of prolonged immunosuppressive therapy. In fact, not only is SCC a

more frequent occurrence in organ transplant recipients, the tumors can be very aggressive clinically. In a study of cardiothoracic transplant recipients (heart or heart-lung transplants), 4% of patients developed aggressive cutaneous SCC within 10 years of transplantation.[20] The majority (15 of 18) of the lesions were poorly differentiated, and two thirds of the patients with aggressive lesions had distant-organ metastases or died of their disease. Pretransplantation end-organ disease may also impact the development of post-transplant SCC. For example, among renal transplant recipients, the highest prevalence of skin cancer was observed in patients with polycystic kidney disease, whereas the lowest incidence was seen in those with diabetic nephropathy. Similarly, cholestatic liver disease was associated with a greater post-transplantation risk of skin cancer compared with other causes of liver failure. Patients immunosuppressed secondary to human immunodeficiency virus (HIV) infection have a more modestly elevated risk of developing a nonmelanoma skin cancer, 3-5 times that of the general population, but do not have the altered SCC-to-BCC ratio typical of transplant recipients. Regardless of etiology, cutaneous SCC that arises in the setting of immunosuppression exhibits a more aggressive course, with a higher rate of local recurrence, metastasis, and death. Noniatrogenic immunosuppression In addition to iatrogenic immunosuppression, defects in cellmediated immunity related to lymphoproliferative disorders (eg, chronic lymphocytic leukemia) predispose to the development of aggressive SCC. The specific mechanisms by which immunosuppression leads to SCC development are poorly understood, but diminished immunosurveillance is thought to be critical. CD8+ T cells specific for the tumor suppressor gene TP53 have been observed in patients with SCC, suggesting that a functional immune system may target keratinocytes expressing mutated TP53.[21] Suppression of the immune system would presumably abrogate this response and might be expected to facilitate the development of SCC. Tobacco use The medical and epidemiologic literature contains numerous reports of the association between carcinomas of the head and neck and use of tobacco, including tobacco inhaled as smoke and the smokeless products, such as snuff and chewing tobacco. Although the association is strong and dose related, the issue is more complex than is usually assumed. Factors that make assessing the role of tobacco in cancer causation difficult are problems with self-reporting, variations in responses to tobacco and tobacco products among individuals, the complex

chemical nature of tobacco and its products, and the presence of confounding risk factors or causes. Self-reporting is notoriously unreliable; therefore, dose dependency is not as reliable as it may seem at first. Moreover, the fact that some individuals have an impressive tobacco exposure history but never develop malignancy highlights the complex relationship of putative etiologic agents. Conversely, some people develop head and neck cancers but have relatively limited tobacco exposure or none at all. Both smoked and smokeless forms of tobacco contain considerable numbers of putative carcinogens. Therefore, pinpointing the mechanism of tobacco-induced carcinogenesis is exceedingly difficult and largely speculative. Finally, smokers are likely to have other risk factors or etiologic agents in addition to their tobacco use. Factors such as poor dentition, ethanol use, and poor nutrition are associated with tobacco use. Even more difficult to remove from consideration is the person's age, which is inextricably linked with the years of tobacco use. Age may be one of the most important risk factors for many malignancies. Alcohol use An association between alcohol use and human cancer has been observed since 1910, when it was noted in Paris that 80% of patients with esophageal carcinomas were heavy drinkers. Even then, confounders were similar to those noted for tobacco. The fact that absinthe, a fermentation product of wormwood (Artemisia absinthium) accounted for much of the alcohol consumed at that time in Paris suggests a possibility that other substances may have contributed to this association. Nevertheless, the incidence of head and neck carcinoma is undoubtedly associated with the use of ethanol. In 1998, the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO) concluded that the evidence was sufficient to show that alcoholic beverages are carcinogenic in humans. SCC of the head and neck is most commonly associated with the use of alcohol and tobacco. Both case-control and cohort studies have shown an association between alcohol and carcinomas of the oral cavity, oropharynx, and larynx. The risk for oral cancer is additive and is up to 40 times greater than in those who neither smoke nor drink. In some studies, the use of both ethanol and tobacco increased the risk of head and neck cancer 100-fold. In SCC, mutations in the TP53 gene correlate with drinking and smoking habits.

The results of one study confirmed that tobacco and alcohol use are the main risk factors for the development of head and neck SCC and affect overall patient survival. However, comparable disease outcomes were found in patients who either did or did not use these substances.[22] Age Head and neck cancers have age-related patterns similar to those of many epithelial malignancies, with rising rates of occurrence closely linked to increasing age. In the United States, the median age at which patients present with oral cancers is 63 years. Although data show that men and women as young as 25 years can die from oral and/or pharyngeal cancer, the mortality rate steadily increases in subsequent decades. Familial and genetic predisposition Genetic profiles are associated with an increased, albeit slight susceptibility for oral carcinoma. Patients with xeroderma pigmentosum, polydysplastic epidermolysis bullosa, or Bloom syndrome are certainly at increased risk for oral cancer. These conditions are fairly uncommon and not major public health issues; however, to the individual and family, they are rightfully of paramount concern. Familial associations of head and neck cancers have been investigated. Studies have demonstrated many cases of head and neck cancers, and a case report describes identical twins with oral carcinoma. However, the familial cases highlight the problem of assigning a role to genetics versus environmental factors to the development of SCC. The genetics of nasopharyngeal carcinoma have been studied in some detail. The histocompatibility locus human leukocyte antigen (HLA)-A2 may be a marker for susceptibility to this tumor. Other loci also being considered include HLA-B17 and HLA-Bw46. Nutritional status The role of a single factor such as nutritional status is difficult to ascribe with certainty. Diet is often associated with numerous confounders, such as tobacco exposure, lifestyle-related viral exposure, alcohol use, and oral hygiene. However, despite this difficulty, some conclusions are fairly cogent. For example, vitamin A deficiency and iron deficiency associated with Plummer-Vinson syndrome have been linked to oral and pharyngeal cancers. Nitrosamine-rich fish is a large part of the diet in many regions where nasopharyngeal carcinoma is prevalent. This diet is by no means universal, it does not seem to explain the sexual distribution of the disease, and it is not as compelling as the association of Epstein-Barr virus (EBV) with this malignancy. Malignant epithelial

cells harboring EBV have been demonstrated on in situ hybridization (ISH), polymerase chain reaction (PCR) tests, immunohistochemical analysis, and ultrastructural studies. Vitamins A, D, and E have all been suggested for the prevention or treatment of carcinomas. In addition, increased fruit consumption has shown an effect in preventing malignancy. The role of fruits in the diet may be related to more than simply their vitamin content. To date no significant, prospective, and comprehensive study has been conducted to evaluate the combined and perhaps synergistic effects of diet, tobacco use, and ethanol consumption. Concern over the use of alcohol-containing mouthwash in recent years should be addressed. This is a fascinating issue, and some reports suggest that the frequency and duration of the use of such mouthwash may be associated with an increased risk of oral SCC. This finding certainly deserves further study. Exposure to industrial products and heavy metals Numerous studies have been undertaken to ascertain the risks of head and neck cancer associated with various occupations and exposures. Studies have demonstrated that individuals working in the heavy-metal, textile, or electronic industry or those exposed to paint fumes, plastic byproducts, asbestos, wood dusts, and gasoline fumes have increased cancer risks. However, these studies were often small surveys, and, in some cases, subsequent studies did not show increased risks. Exposure to arsenic is a well-established cause of cutaneous SCC and internal cancers.[23] In the present day, the main source of arsenic is contaminated well water, although arsenic may also be found in traditional Chinese medicines. Other carcinogens associated with SCC include polycyclic aromatic hydrocarbons such as tar, soot, and pitch. Chronic inflammation or irritation Likewise, the Marjolin ulcer variant of SCC may develop in patients with a chronic scarring condition such as dystrophic epidermolysis bullosa. In fact, the leading cause of death in patients with dystrophic epidermolysis bullosa is metastatic cutaneous SCC, [24] with an 80% mortality rate within 5 years of diagnosis of SCC [25] and with two thirds of patients dying from metastatic disease. [26] In recent years, evidence suggests that patients with junctional epidermolysis bullosa may also be at increased risk for developing SCC.[27] The underlying pathogenesis of such lesions is not understood, but mutations in the TP53 and P16 tumor suppressor genes have been described in dystrophic epidermolysis bullosa associated SCC.[28]

Precisely defining the role of poor oral hygiene in SCC of the oral cavity is difficult; however, they are associated. Poor dentition increases the risk of oral carcinoma, with the use of tobacco and ethanol. Some studies have demonstrated an association with illfitting dentures with oral cancer. However, other investigations have not revealed a similar association. Overall, the consensus among oral-cancer investigators is that poor dentition and poor oral hygiene appear to increase the risk of oral SCC. Gastroesophageal reflux disease is now thought to be a significant risk factor for cancer of the larynx and especially the anterior two thirds of the vocal cords. Viruses One of the most exciting developments in oncology within the last 20 years is the investigation of viral oncogenesis. The explosion of research into this topic was the result of 3 major events occurring in a short span: (1) the invention of the PCR in 1983, followed by tens of thousands of reports of this technology used in its first 20 years; (2) the observation of unusual tumor types in association with newly identified and unusual viruses (eg, Kaposi sarcoma and HIV, nasopharyngeal carcinoma, and EBV, and hepatitis virus and hepatocellular carcinoma [HCC]); and (3) improved better understanding of the molecular biology of cancer. Some 15% of patients with SCC have a viral etiology. In the arena of head and neck cancer, EBV and human papilloma virus (HPV) are both prominent. EBV is a DNA-containing herpes virus that has been implicated in at least 5 distinct malignancies: endemic Burkitt lymphoma, NPC, Hodgkin disease, T-cell lymphoma, and immunoblastic lymphoma. High antibody titers to EBV capsid antigen are observed in more than 80% of patients with nasopharyngeal carcinoma. The geographic distribution of EBV and nasopharyngeal carcinoma in those regions impressively overlap with a high prevalence of EBV infection that corresponds to high incidence of nasopharyngeal carcinoma. HPV has been demonstrated to be a cause of uterine cervical SCC. Increasing evidence suggests a similar role for HPV in the development of head and neck SCC,[29] as well as in the carcinogenesis of upper aerodigestive tract tumors. In particular, HPV-16 can be isolated in up to 72% of oropharyngeal cancers. In recent years, the increase in cancer of the tongue and tonsils in developed countries, particularly in patients younger than 45 years, has been linked to HPV infection.[30] Studies of patients without the commonly assumed risk factors for lung SCC (ie, tobacco use, radiation or asbestos exposure) have revealed a previous history of laryngeal papillomatosis and the same type of HPV present in both the laryngeal papillomata and the lung malignancy.

PCR and ISH have been used to ascertain the role of the various types of HPV in development of SCC of the head and neck. Nearly 100 types of HPV have been identified, and these have been classified as high or low risk with respect to their potential to cause malignancy. Original investigations of this DNA virus and cancer focused on uterine cervical cancer and, to a lesser degree, cutaneous and genital carcinomas. The International Agency for Research on Cancer (IARC) determined that current evidence only supports HPV types 5 and 8 as possible carcinogens[31] ; these have been associated with cutaneous SCC in the setting of epidermodysplasia verruciformis and some solid organ transplant patients.[32] However, HPV-6 and -11 have been associated with Buschke-Lowenstein tumors, whereas HPV-16 has been frequently identified in both genital and periungual SCC, suggesting the possibility of genital-digital spread. [33, 34] Evidence now suggests that high- or low-risk HPV in 1 anatomic location may not neatly fit the same category in other anatomic locations. As an example, verrucous carcinomas are associated with HPVs in 30-60% of cases examined, depending on the study. When these are found in the larynx, HPV-6 and -11 are frequently identified, whereas in the uterine cervix, these viruses are infrequently found and classified as low risk. HIV infection and acquired immunodeficiency syndrome (AIDS) are not definitively associated with high-risk SCC; however, an increased incidence of anal and penile SCC associated with HPV has been reported in HIV patients. A high risk of recurrence has been reported after desiccation and curettage in HIV patients,[35] and a small series reported cases of aggressive cutaneous a 50% mortality rate at 7 years in these patients.[36] Exposure to ionizing radiation External-beam radiation has been used to treat a variety of diseases, such as tonsillar hypertrophy, acne, thyroid disease, and laryngeal papillomatosis. Laryngeal cancers have been statistically associated with previous radiation. Patients treated with radiation for laryngeal carcinoma are well known to develop metachronous carcinomas years later. Therapeutic ionizing radiation is typically associated with the later development of BCCs, but the risk of developing SCCs is also increased.[37] Most patients with radiationinduced tumors have a remote history of x-ray therapy for acne vulgaris, although patients developing SCC in radiation ports for Hodgkin disease or thyroid cancer treatment is not uncommon. The incidence of metastasis from cutaneous SCC has been found to be 0.23-2.4% of cases; however, tumors arising from areas of previous radiation therapy may have an incidence of metastasis as high as 20%.[38, 39]

Summary of risk factors that predispose to SCC development General risk factors associated with the development of SCC are as follows[40, 41, 23, 42, 43, 36, 24, 44] : Age older than 50 years Male sex Tobacco and/or alcohol use Geography (closer to the equator) History of previous nonmelanoma skin cancer The following are exposure-related risk factors in the development of cutaneous SCC: UV radiation exposure (high cumulative dose of sunshine, tanning beds, or medical UV treatments) Immunosuppression (eg, HIV), including iatrogenic immunosuppression (eg, transplant recipients) Ionizing radiation (eg, medical treatments, occupational or accidental radiation exposure) Infections (eg, HPV, osteomyelitis, acne conglobata, hidradenitis suppurativa, dissecting cellulitis of scalp, lupus vulgaris, lymphogranuloma venereum, granuloma inguinale, and chronic deep fungal infection) Chemical carcinogens (eg, arsenic, tar, polyaromatic hydrocarbons) Host responses that influence cutaneous SCC development include the following: Genetic susceptibility and dermatoses (eg, xeroderma pigmentosum, dystrophic epidermolysis bullosa, epidermodysplasia verruciformis, xeroderma pigmentosum, oculocutaneous albinism, dyskeratosis congenita, porokeratosis [Mibelli type, disseminated superficial actinic type, linear type], nevus sebaceous, and KID syndrome [keratitis, ichthyosis, deafness]) Susceptibility to UV radiation (eg, fair skin [Fitzpatrick skin types I and II], blond or red hair, light-colored eyes) Chronic inflammation, such as nonhealing burns or scars (eg, Marjolin ulcer, burn scar or thermal injury, venous ulcer, lymphedema, discoid lupus erythematosus,[45] erosive oral lichen planus, lichen sclerosis et atrophicus, mutilating keratoderma, and necrobiotic lipoidica)

Epidemiology
Skin cancers are the most frequently diagnosed cancers in the United States. More than 1 million estimated new nonmelanoma skin cancers were diagnosed in the United States in 2005, a number that was nearly equivalent to the number of all other cancers diagnosed in the US the same year. Of these cases, approximately 80% are basal cell carcinoma (BCC) and 20% are squamous cell carcinoma (SCC), making cutaneous SCC the second most common skin cancer and one of the most common cancers overall in the US.

On initial presentation, more than 90% of cancers of the head and neck are SCCs. In the US, head and neck carcinomas account for approximately 5% of all malignancies in adults. The percentage is slightly lower than this in women and slightly higher in men. Nevertheless, the low percentage belies the fact that SCC is a major public health problem. The 2004 report by the American Cancer Society illustrates this point dramatically, as shown in Table 1 below. Table 1. Estimated Number of New Cancer Cases and Deaths in Both Sexes in the United States in 2004 (Open Table in a new window)
Cancer New Cases Oral cavity and pharynx 28,260 Tongue 7320 Mouth 10,080 Pharynx 8250 Other oral cavity 2160 Larynx 10,270 Source: American Cancer Society, 2004.[46] Deaths 7230 1700 1890 2070 1570 3830

Note: The US Census Bureau estimated that the US population was approximately 282,000,000.

Despite increased knowledge and public education regarding the causes of skin cancer and modes of prevention, the incidence of cutaneous SCC continues to rise worldwide. This increasing incidence is likely multifactorial. Speculated causes for the increased incidence of skin cancer include an aging population, improved detection, an increased use of tanning beds, and environmental factors such as depletion of the ozone layer. Additionally, the number of patients on immunosuppressive therapy, used in solid organ transplantation and various rheumatologic and dermatologic conditions, is increasing. As noted previously, SCC formation has been associated with immunosuppressive drug therapy in solid organ transplantation patients, who have a markedly elevated risk of SCC formation. Metastasis may also be more common in this group.
[47]

Patients who live close to the equator tend to present at a younger age than patients who live more distant from the equator. The incidence of the disease varies geographically, 0.03-3.5 cases per 100,000 people per year. United States statistics Determining the true incidence of SCC is difficult, because health registries exclude nonmelanoma skin cancer (including SCC) from their databases owing to the high number of cases and limited resources to collect data and due to the varying rate of SCC based on geographic locale. SCC of the head and neck comprises about 4% of all malignancies. This corresponds to an estimated 17 per 100,000 persons with newly

diagnosed SCC of the head and neck per year. Male-to-female incidence rates are greater than 3:1; this discrepancy in the male-tofemale ratio is even more pronounced in laryngeal tumors, in which carcinoma is 4-5 times more common in men. This ratio has declined in the last 20 years, possibly reflecting the increased number of women using tobacco products during this period.[48] Nasopharyngeal carcinoma most frequently affects individuals aged 40-60 years. In black individuals, the disease peaks in those aged 10-20 years. Studies also confirm a dramatic increase in the incidence of cutaneous SCC over the past several decades. For example, in Rochester, Minnesota, the annual age-adjusted incidence rates of SCC per 100,000 women rose from 47 cases from 1984-1986 to 100 cases from 1990-1992.[49] The corresponding rates for men increased from 126 cases to 191 cases per 100,000 population. [49] SCC is the most common conjunctival malignancy in the United States and accounts for 4-29% of all oculo-orbital tumors. [50] Although eyelid SCC is not nearly as common as BCC of the eyelids, previous studies have found this condition to be the second or third most common eyelid malignancy, accounting for approximately 5% of all eyelid neoplasms.[51] Certain benign and malignant epithelial tumors may simulate SCC both clinically and histopathologically [52, 53] ; earlier studies may have overestimated the frequency of SCC. [54] Kwitko found that of 115 tumors originally diagnosed as SCC at the Armed Forces Institute of Pathology, only 12 were diagnosed correctly after reevaluation.[51, 52] International statistics Prevalence rates of SCC vary in different countries. The highest incidence occurs in Australia, where nonmelanoma skin cancer incidences as high as 1.17 per 100 have been reported, a rate 5 times greater than all other cancers combined. The age-adjusted incidence has been calculated to be 1332 cases per 100,000 population for men and 755 cases per 100,000 population for women. Again, this is likely due to large numbers of light-skinned people in this region who have had extensive sun exposure. [55] Laryngeal cancer generally is a disease of the elderly, with a peak incidence in the 50s and 60s. In certain parts of India and Southeast Asia, the practice of mixing cured tobacco with betel nuts has been associated with head and neck cancers. More than 200 million persons are thought to engage in this practice worldwide. A resultant 2.8 times higher relative risk of cancer exists for these individuals, and this increases to more than 10 times when smoking is also practiced. In these areas, the incidence of oral cancer alone is greater than 25 cases per 100,000 persons. [56]

In some African populations, nasopharyngeal carcinoma is responsible for approximately 15% of childhood malignancies. In fact, in Sudan, nasopharyngeal carcinoma is the most common malignancy of children, and it affects males more frequently than females at a ratio of roughly 3:1. Racial differences in incidence SCC is the second leading cause of skin cancer in white individuals. [1] Persons of Irish or Scottish ancestry have the highest prevalence in the US. SCC is relatively rare in people of African and Asian descent, although it is the most common form of skin cancer in these groups. SCC in black persons carries a higher mortality rate, perhaps due to delayed diagnosis, because tumors are more likely to occur in sun-protected areas, including the scalp and sites of previous injury and scarring.[57] SCC of the conjunctiva is most common in white individuals. The incidence of nasopharyngeal is increased in China, especially Southeast China (about 30 per 200,000 population), as well as in Taiwan, Hong Kong, and Singapore. Northern Canadian and Greenland indigenous peoples also have an incidence of nasopharyngeal carcinoma that is higher than that of the general population. The incidence of this carcinoma among Western people of Caucasian descent is approximately 1 per 200,000 population; the incidence is also higher in parts of Central Africa than in areas of Europe, South America, North America, and Australia. These areas in Africa correspond to areas where the prevalence of EBV infection is high. Sex- and age-related differences in incidence SCC occurs in men 2-3 times more frequently than it does in women, most likely as a result of greater cumulative lifetime UV exposure, which may be due to certain occupations that entail more significant exposure to sunlight or other occupational hazards such as soot, oils, or tars. The typical age at presentation for SCC is approximately 70 years; however, this varies widely, and, in certain high-risk groups (eg, organ transplant recipients, patients with epidermolysis bullosa), SCC often manifests at a much younger age. Patients with SCC of the conjunctiva tend to be elderly, with an average age of 60 years, whereas immunocompromised individuals develop SCC at a younger age. In a study of cutaneous SCC, the mean age of patients infected with HIV was 49 years, whereas the mean age of patients who were not immunocompromised was 75 years.[10, 11] In addition, Patients with acquired immunodeficiency syndrome (AIDS) have a 13-fold increased risk of developing conjunctival epithelial malignancies; these patients also present at a younger age.

Prognosis
Although patients infrequently die from cutaneous squamous cell carcinoma (SCC), these tumors can cause significant morbidity. Most cutaneous SCCs are located in the head and neck region, where surgery for advance stage disease can be disfiguring. Furthermore, the cost of treatment has been shown to pose a significant public health burden. In a study of the Medicare population, the treatment of nonmelanoma skin cancers ranked fifth among the most expensive cancers to treat. Like many cancers, cutaneous SCC is classified according to the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) "tumor, node, metastasis" (TNM) staging system.[58] This anatomy-based staging system is designed to stratify patients into general prognostic cohorts based on the size and extent of disease (see SCC Staging and Classification). Although TNM staging is useful for estimating the outcome for a group of patients with cutaneous SCC who have similar tumor characteristics, it cannot estimate the risk for an individual patient. Palme et al have argued that the staging system for SCC of the head and neck is too simple and should account for the many variables involved in a metastatic SCC of the head and neck to be useful in informing treatment.[59] It does not take into consideration other tumor and patient factors, such as ultraviolet (UV) radiation exposure, age, and comorbidity, that may also affect prognosis. Therefore, current methods for estimating the outcome of a patient with head and neck cutaneous SCC depend heavily on the experience of the treating physician and can vary significantly between surgeons. Despite the inherent limitations of TNM staging, the outcomes of patients with head and neck cutaneous SCC follow a predictable pattern. In general, most patients with early-stage tumors fare well (overall 5-yr survival rate >90%) when the tumors are adequately treated. Most patients present with early-stage tumors, and the prognosis is reasonably good for completely excised lesions. Various mortality rates have been reported, with some rates as high as 48%. By adhering to a policy of complete excision of all lesions, the recurrence rate should be 10% or less. The outcome of patients with advanced-stage cutaneous SCC is considerably worse. For patients with lymph node metastases, the 5-year survival is even lower, estimated at 25-45%. Most large series in the literature have reported the risk of nodal or distant metastasis for primary tumors to be 2-6%. High-risk SCC A subset of SCC carries an elevated risk of local recurrence, nodal, or distant metastasis (usually to the lungs), and death. Tumors in this subset are termed high-risk SCC. However, prognostic models do not exist for SCC. Because many of the risk factors discussed below

occur concurrently in single tumors and patients, determining which risk factors have the greatest prognostic significance is difficult. In the absence of prognostic models that take the presence of multiple risk factors into account, estimating risk for individual patients is based on very limited data and gestalt. Due to the lack of data, evidence-based decision making is often not possible. Subsequently, current management of high-risk SCC varies widely.[60] In one case series, the 3-year disease-specific survival rate for SCC was estimated to be 85%. Survival rates approached 100% for lesions with no high-risk factors, but the disease-specific death rate was 30% for patients with at least 1 risk factor. [61] These estimates derived from a case series may not be reflective of the risk for SCC in general and may overestimate risk. However, the data highlight that a subset of SCC do poorly. When SCC does metastasize, it is usually occurs within 5 years from the time of diagnosis and involves the primary (ie, first echelon) draining lymph nodes. In general, metastasis from SCC of the forehead, temples, eyelids, cheeks, and ears is to the parotid nodes; metastasis from SCC of the lips and perioral region is primarily to the submental and submaxillary (upper cervical) nodes. Once nodal metastasis of cutaneous SCC has occurred, the overall 5year survival rate is low, as discussed earlier. Patients with a compromised immune system, those with metastasis to multiple lymph nodes, or those with cervical lymph nodes larger than 3 cm in diameter have an extremely poor prognosis. Nevertheless, data from one study showed that the combined use of surgery and adjuvant radiotherapy for patients with nodal metastasis increased the 5-year disease-specific survival rate to 73%.[62] Metastasis to distant organs remains incurable (eg, lung metastasis). Thus, close surveillance and early detection of nodal metastasis can be life saving and is of paramount importance. SCC can be characterized as high-risk by virtue of tumor-related factors (intrinsic factors), patient-related factors (extrinsic factors), or a combination of both. Tumor-related factors in high-risk SCC Tumor-related factors include the following[3] : Tumor location (ie, lips, ears, anogenital region, within a scar or chronic wound) Tumor size greater than 2 cm (or 1.5 cm on ear or lip) Invasion to subcutaneous fat (or deeper) Poorly differentiated tumor cells Recurrent tumor Perineural involvement (except, perhaps, for tumors with smallcaliber nerve invasion and no other risk factors [63] )

Additionally, a prospective study of 210 patients with a diverse range of SCCs showed tumor-related factors were associated with adverse disease-specific survival using univariate analyses. [61] Specifically, these factors were: Local recurrence at presentation Invasion beyond subcutaneous tissue Depth in general Perineural invasion Size of 4 cm or larger Detailed information on tumor-related factors such as location, diameter, depth, cellular differentiation, recurrent tumors, perineural invasion are reviewed below. Location Foremost among the factors influencing metastatic risk are the size and location of the tumor and, to a lesser extent, a rapid growth rate. Rapidly growing lesions on the eyelid or ear metastasize in up to one third of cases. Unlike basal cell carcinoma (BCC) of the eyelid, SCC of the eyelid can be an aggressive tumor that has potential to invade the orbit, metastasize to lymph nodes and distant sites, and cause death.[64, 65, 66, 54, 67, 68] The morbidity from conjunctival SCC relates to the ocular side effects of the disease and its treatment, as well as regional orbital sequelae, periorbital spread, periorbital sinus involvement, and intracranial involvement (see the following image). Rarely ocular penetration can occur, particularly with the mucoepidermoid type. Death may result from distant or regional metastases, as well as intracranial spread.
Extensive conjunctival squamous cell carcinoma of the left eye. The patient has limbal and corneal involvement temporally, as well as scleral invasion with intraocular spread. A malignant cellular reaction in the anterior chamber was present. The patient was treated with a lid-sparing exenteration.

Metastatic rates are particularly high for the ear (11%) and lip (13.7%), and the 5-year survival rate after metastasis from these primary sites ranges from 25% to 40%.[3] Other sites associated with a higher risk of metastasis are the scalp, forehead, temple, eyelid, nose, mucous membranes, hands (dorsal surface), penis, scrotum, and anus.

Primary SCCs on the trunk and limbs have been associated with a metastatic rate of 4.9% in a series that may be biased toward larger lesions. SCCs that arise in injured or chronically diseased skin are associated with a risk of metastasis that approaches 40%. Numerous studies have demonstrated that the Marjolin ulcer subtype of SCC behaves aggressively, with metastatic rates of up to 35%, [69, 70] and a mortality rate of 33%.[71] Marjolin ulcer most frequently refers to

an SCC that arises from chronically scarred or inflamed skin; however, malignant transformation to a BCC, melanoma, or sarcoma may also occur.[72] Similarly, invasive SCC of the anogenital region carries a greater risk of metastasis. The poor prognosis of both the Marjolin ulcer and anogenital subtypes is likely related to delayed diagnosis. Diameter Lesions of invasive SCC measuring smaller than 2 cm in diameter have been associated with a 9.1% rate of metastasis, whereas those larger than 2 cm in diameter have a metastatic rate of up to 30.3%, which is 3 times that of smaller lesions. Lesions deeper than 4 mm behave similarly. A prospective study reported a 3-year diseasespecific survival rate of 67% for lesions larger than 4 cm, compared with 93% for tumors smaller than 4 cm.[61] Depth Depth of infiltration is predictive of prognosis. Increased depth of invasion of SCC is strongly associated with local recurrence, metastasis, and death. That is, with increasing depth of invasion of the primary tumor, the risk of nodal metastasis increases and survival decreases. Lesions with a depth of less than 2 mm rarely metastasize; those with a depth of invasion of 2-4 mm have a historical recurrence rate of 5.3% and a metastasis rate of 6.7%. A 2008 prospective cohort study found a rate of metastasis of 4% for tumors of 2-6 mm thickness.[4] For tumors thicker than 6 mm, the risk increased to 16%. The depth of the lesion associated with the percentage survival rate has been reported as follows: Less than 2 mm 95% survival rate From 2-9 mm 80% survival rate Larger than 9 mm 65% survival rate Cellular differentiation More poorly differentiated tumors have a worse prognosis in SCC, with reported recurrence rates of 33-54%.[3] The actual value of histologic grading alone, however, is less clear, because poorly differentiated tumors that metastasize or recur also usually have other primary risk factors (eg, large diameter, deep invasion). Nonetheless, poorly differentiated lesions are generally considered to behave more aggressively. Recurrent tumors Local recurrence rates following extirpation of a recurrent SCC range from 10% to 23%. Reported rates of metastasis are as high as 2545%, but these figures may overestimate the risk in recurrences that are caught early.

Perineural invasion Perineural invasion has been estimated to occur in up to 7% of persons with cutaneous SCC. The prognosis in such cases is worse, with historical rates of metastasis reported to be as high as 47%. Much lower rates of metastasis (8%) have been reported using Mohs micrographic surgery.[3] The degree of nerve involvement likely has a large impact on prognosis. Involvement of major (ie, named) nerve branches carries a very high risk of recurrence, metastasis, and death. The risks are substantially decreased when tumor-free margins are painstakingly obtained by removal of the involved nerve. However, the prognosis is still guarded. One study showed the diameter of involved nerves to significantly impact outcomes, with no disease-specific deaths occurring in those with involvement of nerves less than 0.1 mm in diameter, compared with 32% of patients dying from disease when nerves 0.1 mm or larger were involved.[73] Patient-related factors and conditions associated with aggressive SCC General patient-related factors are (1) organ transplant recipient, (2) hematologic malignancy (eg, chronic lymphocytic leukemia), (3) long-term immunosuppressive therapy, and (4) human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) (see Etiology). SCC arising in patients with chronic lymphocytic leukemia and small lymphocytic lymphoma carries a worse prognosis. For example, in patients with chronic lymphocytic leukemia, the SCC recurrence rate in those treated with Mohs micrographic surgery was 7-fold higher at 5 years compared with patients without chronic lymphocytic leukemia.[43] Another study found that SCC in chronic lymphocytic leukemia and small lymphocytic lymphoma patients are often multiple (67%), high grade (56%), and have a high risk of recurrence and metastasis (25%) and death from disease (41%). [74] The risk of aggressive SCC in patients with bullous disease is markedly elevated. The risk of death is particularly high in those with epidermolysis bullosa, with an 80% mortality rate 5 years after diagnosis of the first primary SCC. In addition, arsenic exposure [75] and psoralen plus UVA (PUVA) light exposure are associated with aggressive disease.

Patient Education
Patients should be counseled to avoid excessive ultraviolet (UV) radiation by limiting outdoor activity to early morning and late afternoon, using protective clothing, and wearing a broad-brimmed hat to shade the head and the neck area. Patients should seek prompt evaluation of suspicious eye lesions, even chronic red eyes, to rule out early ocular surface malignancies. Educating people who

live in tropical areas and in regions with a high degree of solar exposure is particularly important. Use of artificial tanning devices should be strongly discouraged, because this has been associated with a 2.5-fold increase in the risk of developing squamous cell carcinoma (SCC). Daily application of a broad-spectrum sunscreen with a sun protection factor (SPF) of at least 15 should also be encouraged. Recurrences of lesions are possible even years after excision, so patients should have routine examinations. In addition, counsel patients regarding treatment of areas of chronic skin inflammation or trauma to prevent the future development of SCC at those sites. These measures are critically important for patients who are immunosuppressed, and they should be an integral part of the educational program for patients who have recently undergone organ transplantation. For patient education information, see the Cancer and Tumors Center, as well as Skin Cancer and Skin Biopsy. For information on cancer risk, prevention, and screening in organ transplant patients, see the AT-RISC Alliance and the International Transplant Skin Cancer Collaborative. For more information about MMS, see the American College of Mohs Surgery. Proceed to Clinical Presentation

History
A detailed patient history often reveals the presence of one or more risk factors for squamous cell carcinoma (SCC) (see Etiology). The clinician should be obtain at least the following information: Existing medical conditions such as xeroderma pigmentosum, or previous history of cutaneous malignancies (basal cell carcinoma [BCC], SCC, sebaceous cell carcinoma, malignant melanoma) Immunocompetency of patient (risk factors for human immunodeficiency virus [HIV] infection or acquired immunodeficiency syndrome [AIDS], history of organ transplant, current chemotherapy, immunosuppression, hematologic malignancy [chronic lymphocytic leukemia]) History of significant sun exposure, occupational exposures (oils, tars, soot) Previous history of skin insult or trauma (eg, scars from old burns [Marjolin ulcer][72] or vaccinations) Family history of skin cancer Previous history of benign lesions (eg, actinic keratosis, chalazion); recurrence after treatment of lesion Duration for which lesion has been present

Change in size, contour, or color of lesion - An assessment of the rate of tumor growth is important, as this often reflects the aggressiveness of the lesion. The initial presentation of cutaneous SCC typically includes a history of a nonhealing ulcer or abnormal growth in a sun-exposed area (see the image below). Similarly, many precancerous lesions (eg, actinic keratosis, Bowen dermatosis) also appear to be related to ultraviolet light exposure. SCC can develop even if the history of sun exposure occurred decades before development of the skin lesion. [13]
Large, sun-induced squamous cell carcinoma on the forehead/temple with superficial erosion. Image courtesy of Glenn Goldman, MD.

Approximately 70% of all cutaneous SCCs occur on the head and neck, most frequently involving the lower lip, external ear, and periauricular region or the forehead and scalp, with an additional 15% found on the upper extremities (see the following image). Frequently, the presentation is preceded by the presence of actinic keratosis. These precancerous lesions appear as scaly plaques or papules, often with an erythematous base. Actinic keratosis is usually only several millimeters in size and ranges from normal skin color to pink or brown; patients with this condition have an estimated 6-10% lifetime risk of developing skin cancer.
Squamous cell carcinoma of the dorsal wrist. Courtesy of Hon Pak, MD.

The most common head and neck sites for SCC are the floor of the mouth, the tongue, the soft palate, the anterior tonsillar pillar, and the retromolar trigone. Although most patients with SCC are asymptomatic, symptoms such as bleeding, weeping, pain, or tenderness may be noted, especially with larger tumors. When lesions become palpable masses, symptoms such as a vague persistent sore throat or ear infection occur. Numbness, tingling, or muscle weakness may reflect underlying perineural involvement, and this history finding is important to elicit, because it adversely influences prognosis.[76] Irritation and/or chronic conjunctivitis may accompany conjunctival SCC, such as in chronic wearers of contact lenses[77] ; patients may notice a conjunctival mass, which may be enlarging. Ocular symptoms such as decreased vision, diplopia, increasing proptosis, or ocular surface irritation may be associated with eyelid SCC. Occult nasopharyngeal carcinoma may present long before the tumor is locally detected. In fact, patients rarely present with this mass and usually present with a cervical neck mass due to lymph node metastasis from the tumor. Other signs or symptoms that may call attention to a neoplasm in the nasopharynx are unilateral serous otitis media, nasal obstruction, epistaxis, hearing loss, headache, and involvement of the cranial nerves. Patients with Marjolin ulcer may report a change in the skin (eg, induration, elevation, ulceration, weeping) at the site of a preexisting scar or ulcer. The

average latency period is 35 years[78] ; therefore, the diagnosis requires a high index of clinical suspicion. Virally induced SCC most commonly manifests as a new or enlarging warty growth on the penis, vulva, perianal area, or periungual region. Patients often present with a history of "warts" that have been refractory to various treatment modalities in the past. A history of previously documented genital human papillomavirus (HPV) infection may be elicited. The location of papillary SCC determines the symptoms. The size of the lesions ranges from smaller than 1 cm to larger than 5 cm. At any site, this exophytic, fungiform mass usually causes mechanical interference, which brings the lesion to attention of the patient or clinician. For example, a large lesion in the oral cavity may interfere with mastication, it may bleed because of trauma, or it may simply annoy the patient. In the larynx, hoarseness is by far the most common first indication of the neoplasm.

Physical Examination
Every patient with suspected squamous cell carcinoma (SCC) should undergo a comprehensive head and neck examination, including the following: Location of lesion (eg, eyelid SCC is more common on the lower eyelid) Size of lesion Character of lesion (smooth/nodular, vascularity, color) SCC may appear as plaques or nodules with variable degrees of scale, crust, or ulceration Presence of ulceration Evaluation of subcutaneous tissues (depth of lesion, bony involvement) Palpation of preauricular, submandibular, and cervical lymph nodes In all patients with SCC or suspected SCC, the draining nodal basins should be palpated. If nodes are palpable, a biopsy should be performed using fine-needle aspiration (FNA) or excision. If lymph nodes are clinically negative but the tumor meets high-risk criteria, there are few data available to guide what should be done next. Subsequently, management currently varies with regard to further staging.[60] General appearance of lesion The overall appearance of any skin lesion must be detailed. Of course, the presenting appearance of each cutaneous SCC varies according to the site and extent of disease. In addition to clinical notes, use photography to document the appearance of the lesion(s).
External photograph of a large, ulcerated, invasive squamous cell carcinoma of

the left lower eyelid. This patient also had perineural invasion of the infraorbital nerve extending into the cranial base.

The classic presentation of an SCC is that of a shallow ulcer with heaped-up edges, often covered by a plaque. These lesions are termed erythroplasia (see Definitions and Clinical Terminology) and deserve biopsy. One third of lesions are pure white; they are known as leukoplakia, but only 10% of them are carcinoma in situ or invasive carcinoma. Surface changes of typical SCC may include scaling, ulceration, crusting, or the presence of a cutaneous horn. Less commonly, the lesion may manifest as a pink cutaneous nodule without overlying surface changes. The absence of surface changes should raise suspicion of a metastatic focus from another skin or nonskin primary site or a different and potentially more lethal tumor such as Merkel cell carcinoma. A background of severely sun-damaged skin, including solar elastosis, mottled dyspigmentation, telangiectasia, and multiple actinic keratoses, is often noted. Clinically, lesions of SCC in situ (SCCIS) range from a scaly pink patch to a thin keratotic papule or plaque similar to an actinic keratosis. Bowen disease is a subtype of SCCIS characterized by a sharply demarcated pink plaque arising on nonsun-exposed skin (see the first image below). Erythroplasia of Queyrat refers to Bowen disease of the glans penis, which manifests as one or more velvety red plaques (see the second image below).
Squamous cell carcinoma in situ (Bowen disease). Courtesy of Hon Pak, MD. cell carcinoma of the penis. Courtesy of Hon Pak, MD.

SCC of the lip usually arises on the vermillion border of the lower lip. It is sometimes predated by a precursor lesion, actinic cheilitis, which manifests as xerosis, fissuring, atrophy, and dyspigmentation. Actinic cheilitis is analogous to actinic keratosis of the skin. SCC on the lip manifests as a new papule, erosion, or focus of erythema/induration. Intraoral SCC typically manifests as a white plaque (leukoplakia) with or without reddish reticulation (erythroplakia). Common locations include the anterior floor of the mouth, the lateral tongue, and the buccal vestibule (see the images below).
This image depicts reddening of the soft palate, perhaps with scattered areas of white and velvet red patches; tobacco-induced squamous cell carcinoma involving the tongue base and/or supraglottis; and a firm, mobile mass that is palpable at the left carotid bifurcation. This image shows scattered red and white patches, some of which are thick, with inflammation of the underlying mucosa.

Periungual SCC typically mimics a verruca and is frequently misdiagnosed for years as a wart before biopsy. Less commonly, the lesions may resemble chronic paronychia with swelling, erythema,

and tenderness of the nail fold; onychodystrophy also may be noted. Periungual SCC is frequently associated with human papillomavirus (HPV).[79] Marjolin ulcer appears as a new area of induration, elevation, or ulceration at the site of a preexisting scar or ulcer. The diagnosis of Marjolin ulcer should be considered in any ulcer that fails to heal with standard therapy. SCC in the anogenital region may manifest as a moist, red plaque on the glans penis; indurated or ulcerated lesions may be seen on the vulva, external anus, or scrotum. Verrucous carcinoma is a subtype of SCC that can be locally destructive but rarely metastasizes. Lesions appear as exophytic, fungating, verrucous nodules or plaques, which may be described as cauliflowerlike. Verrucous carcinoma is further subdivided based on its location in the anogenital region (Buschke-Lwenstein tumor), the oral cavity (oral florid papillomatosis), and the plantar foot (epithelioma cuniculatum). Invasive SCC involves the epidermis and invades the dermis. The tumors initially appear as skin patches, plaques, and nodules that enlarge and develop central areas of inflammation, induration, and, subsequently, necrosis and oozing. Size and location of lesion In addition to the general appearance of the lesion, the size and location of the SCC should be recorded, as both have prognostic and therapeutic importance. For instance, lesions larger than 2 cm and those located on the external ear and lip have been shown to have a higher rate of metastatic spread (see the image below). Additionally, tumor size and location affect the cosmetic and functional outcome of surgical excision. Therefore, reconstructive options should be carefully considered in the assessment of every head and neck cutaneous SCC. Lesions located near critical areas, such as around the eyes, may require additional evaluation by a dedicated reconstructive surgeon before excision.
External photograph of a large, ulcerated, invasive squamous cell carcinoma of the left lower eyelid. This patient also had perineural invasion of the infraorbital nerve extending into the cranial base.

Up to 14% of cutaneous SCCs exhibit perineural invasion. Evidence of cranial nerve dysfunction on examination should raise concern of significant perineural invasion. The most frequently involved cranial nerves are the facial and trigeminal nerves, underscoring the importance of assessment of facial movement and sensation. Therefore, every patient with head and neck cutaneous SCC should undergo systematic evaluation of cranial nerve function. Finally, regional lymphatics should be assessed for metastatic spread. Regional metastasis of cutaneous SCC occurs in 2-6% of

cases. The risk of metastasis correlates roughly with tumor size and differentiation. The most frequently involved lymphatics include those located within the parotid gland and upper cervical lymph node levels. Investigate regional spread by palpating for enlarged lymph nodes in the head and neck region. Rarely, cutaneous SCC presents as a parotid or neck mass because of lymphatic spread from an occult cutaneous lesion or remotely treated skin cancer (see image below). The median time from initial treatment to presentation with a parotid or neck mass ranges from 10 to 13 months. Fine-needle aspiration (FNA) biopsy can be of assistance in the evaluation of any mass suspected to represent occult metastasis.
Preauricular and helical scars (black arrows) from previous excisions are noted in a patient who presented with cervical metastases (white arrow) from an occult cutaneous squamous cell carcinoma (cSCC).

Distinguishing conjunctival SCC from conjunctival intraepithelial neoplasia is difficult on clinical examination alone[80] ; conjunctival SCC represents a type of conjunctival intraepithelial neoplasia that has either broken through the basement membrane to involve the subepithelial tissue or has metastasized. Epithelial tumors of the conjunctiva are similar to conjunctival intraepithelial neoplasia. [81,
82, 83]

Most SCCs involving the conjunctiva manifest as chronic, unilateral, localized patches of redness or more diffuse conjunctivitis; they can also present as a mass in the interpalpebral fissure at the nasal or temporal limbus with a gelatinous and velvety, papilliform, or leukoplakic appearance. Prominent feeder vessels may be seen. The corneoscleral limbus is the most common location, although the palpebral conjunctiva or cornea may be involved, particularly in the interpalpebral region. Given its variable appearance, conjunctival SCC may pose a diagnostic challenge as a masquerade syndrome. Patients with an atypical pterygium may have a conjunctival tumor. These patients should be observed much more closely than patients with a classic pterygium. Individuals who are HIV positive and patients with xeroderma pigmentosa are more likely to develop conjunctival SCC, probably because of their diminished immune status. Often, small conjunctival masses are noted on routine eye examinations. The examination of conjunctival SCC should determine the full extent of the lesion; rose Bengal dye is helpful for this evaluation. In addition, assess any suspicion for intraocular involvement via slit lamp examination, gonioscopy, and echography. Orbital involvement should be investigated with computed tomography (CT) scanning or magnetic resonance imaging (MRI).

Unsuspected ocular surface neoplasia may be present within excised pterygia, and, for this reason, one study recommends the submission of all excised pterygia for histopathological analysis. [84] Verrucous carcinoma of the head and neck most commonly occurs anywhere in the oral cavity but most frequently on the buccal mucosa. It is also found in the larynx. Outside of the head and neck region, the anogenital region is a common site. Because of these anatomic locations and because this neoplasm resembles virally induced warts, human papillomavirus (HPV) is frequently implicated in its genesis. Findings from sophisticated molecular studies confirm the viral etiology of many of these lesions. Identifying high-risk lesions Advanced-stage cutaneous SCC exhibits an aggressive clinical course with a greater likelihood of recurrence and cervical metastasis (see Prognosis). Therefore, recognition of these higher risk lesions and subsequent treatment by a qualified specialist is critical. Lesions found on or around the ear have a 5-18% rate of metastatic spread, roughly 3 times the average rate. Those located in the preauricular region are particularly troublesome given their propensity to invade the parotid gland (see the image below). Cutaneous SCC of the lip also shows a high rate of nodal involvement. Therefore, prophylactic neck dissection for select cutaneous SCC located at these sites may be warranted.
Contrast-enhanced, axial computed tomography (CT) scan of a patient with softtissue invasion of the right parotid gland (arrow) by an ulcerative cutaneous squamous cell carcinoma (cSCC).

As discussed in Prognosis, size is the most important determinant of outcome for patients with cutaneous SCC. Both the depth and width of the lesion influence the potential for recurrence and metastasis. Lesions larger than 2 cm have a higher rate of recurrence (15.2% vs 7.4%) and metastasis (30.3% vs 9.1%) than those smaller than 2 cm. Similarly, lesions that extend to a depth greater than 4 mm have a 45.7% rate of metastatic spread versus 6.7% for those less than 3 mm. Cutaneous SCC that arises in immunocompromised patients has a high incidence of both initial and recurrent lesions, as well as has the potential for rapid growth and early metastatic spread. Some evidence suggests that these lesions metastasize at a more shallow depth and smaller width than those in nonimmunocompromised patients.

Definitions and Clinical Terminology

In this section, the following are reviewed briefly in relation to pathology:

Keratosis Atypia and dysplasia Pleomorphism, anaplasia, and desmoplasia Leukoplakia Erythroplasia and erythroplakia Metaplasia Malignancy Carcinoma Keratosis Keratinization is the response of the squamous epithelium to physical trauma, which includes not only mechanical trauma but also thermal and chemical trauma. Wherever friction or exposure to other irritating stimuli are present, keratin deposition occurs at the surface. Therefore, skin is keratinized over most of its surface, but mucosal surfaces are selectively keratinized. The dorsum of the tongue and the hard palate are subjected to masticatory stress, hot foods, noxious industrial vapors, dry air, and other stimuli. Therefore, these areas are always keratinized. Likewise, the linea alba, literally white line, is a horizontal line on both buccal mucosal surfaces. It corresponds to the bite line and is the response to frequent bite trauma of the buccal mucosa in the occlusal plane of teeth. The rest of the head and neck mucosa is not normally keratinized. However, physical trauma produces keratinization, which appears as a white line or patch in the area where the injury took place. Any area is susceptible to this keratinization. Keratin is frequently seen on the vocal cords, epiglottis, soft palate, and anywhere the mucosa is exposed to physical stimuli. The white patch is referred to clinically as leukoplakia. Of importance, this patch is not diagnostic of malignancy or even in situ carcinoma. The most abundant keratinization often overlies an entirely benign epithelium. It is reasonable to suppose that this keratinization protects the epithelium from the noxious stimuli and, therefore, no dysplasia has resulted. Atypia and dysplasia The 28th edition of Dorland's Illustrated Medical Dictionary, defines atypia as the condition of being irregular or not conforming to type; it defines dysplasia as abnormality of development.[85] In pathology, alteration is size, shape, and organization of adult cells. Empirically, most pathologists reserve the term atypia for individual cells and dysplasia for the cells and the organization or architecture of a structure. The term atypia is largely applied with a focus on the nuclear details. Even when the term cytoplasm is invoked, it almost always refers to the size relationship of the cytoplasm to the nucleus, or the nuclear-cytoplasmic ratio. Atypia of an individual cell refers to an

enlarged nucleus (ie, an increased nuclear-cytoplasmic ratio), darkening of the nucleus (hyperchromasia), increased lobulation, angulation, or other geometric distortions of the nuclear outline. These phenomena are really just a reflection of increased DNA content (ie, polyploidy). Included in this category of nuclear atypia is the prominence of a nucleolus, intranuclear cytoplasmic inclusions, and abnormal mitotic figures. Dysplasia is almost always associated with individual cell atypia but not always. In one particular lesion of the salivary glands (eg, lowgrade polymorphous adenocarcinoma) the cells are necessarily bland and monotonous, as defined by established criteria for the diagnosis. Only the architecture is polymorphous. Architectural distortion ranges from hyperplasia, which is simply an increase in the number of cell layers seen at a particular anatomic site, to carcinoma in situ (CIS). This latter term, when used in the context of SCC of the head and neck, is virtually synonymous with severe dysplasia. Squamous CIS can and should be thought of as full-thickness atypia. For decades, experienced pathologists have used the following trick to determine if CIS or moderate to severe dysplasia is present: The pathologist simply imagines the stroma to be nonexistent and focuses on only the epithelial-cell layers. If they cannot determine the top from the bottom by viewing the epithelium alone, the lesion is CIS, for this is truly full-thickness atypia. If, however elongated basal cells or flattened surface cells are present, these give away the original orientation, and the lesion is downgraded to moderate to severe dysplasia at most. By convention, head and neck pathologists heavily rely on keratinization and mitotic figures to determine the degree of dysplasia. If a mitotic figure is observed halfway up the epithelial layers to the surface, full-thickness atypia is extremely likely. Similarly, keratin should not be below the top 2-3 cell layers. Its presence lower than these layers is virtually always associated with full-thickness atypia nearby. Pleomorphism, anaplasia, and desmoplasia Pleomorphism is the term used for variance of the size, shape, and staining properties of cells with respect to their neighbors. Anaplasia is the term applied to the most severe grades of pleomorphism. This term is used when the index cell (eg, the squamous cell) is no longer easily discernible. With anaplasia, the origin, type, and differentiation of the tumor are highly speculative. Simply put, the cells in anaplasia do not resemble their neighbors, and they do not even vaguely resemble any normal differentiated cells.

Desmoplasia is a fascinating phenomenon and an interesting word. Desmo is the Greek prefix for band or ligament, and plasia is the Greek term for molding. What is so intriguing about this term is that desmoplasia has numerous synonyms in medicine, because the ultimate outcome of many pathologic events in the body result in end-stage scarringthat is, a desmoplastic reaction. The terms, scarring, fibrous deposition, sclerosis, desmoplasia, scirrhous reaction, and collagen deposition are all virtually interchangeable. In addition, other terms are frequently applied, especially with exuberant reactions involving collagen deposition. In essence, both hypertrophic scar and keloid formation are exaggerated desmoplastic reactions. These terms are frequently used to describe squamous cell carcinomas (SCCs) and really indicate a reaction to the tumor or therapy by the stromal cells. Desmoplasia is especially prominent after irradiation. Leukoplakia Taken literally, leukoplakia should be restricted to clinical use and not used in pathologic assessments. The term simply refers to a white patch on a mucous membrane that does not rub off. Glycogen and fungi can cause this clinical appearance. However, in most cases, this is the gross correlation to the microscopic finding of keratosis or hyperkeratosis. Keratosis refers to any deposition of keratin on a surface that is not normally keratinized, whereas hyperkeratosis is a somewhat subjective term that refers to excessive keratin deposition on a normally keratinized surface. Leukoplakia is an indication that something is not right with the underlying epithelium. This something is not necessarily malignancy or even premalignancy. Although leukoplakia may be the first clinical presentation of a neoplastic process, it may also be a simple reaction to trauma, as in callus formation, or part of a mucocutaneous disease, as in some forms of psoriasis. The finding of leukoplakia should alert the clinician to examine the area. After that, the clinician can decide to order biopsy or not on the basis of the clinical setting. Erythroplasia and erythroplakia Both erythroplasia and erythroplakia have come into clinical use over the years. Erythroplasia is used far more frequently than erythroplakia; however, strictly speaking, these 2 terms are etymologically different. The 28th edition of Dorland's Illustrated Medical Dictionary defines these terms as follows[85] : Erythroplasia is a condition of the mucous membrane characterized by erythematous papular lesions, and erythroplakia is a slow-growing, erythematous, velvety red lesion with well-defined margins occurring on a mucous membrane. As is apparent, the erythroplakia involves observation over time. Practically speaking, the 2 terms refer to red patches. These are

more often associated with dysplastic or neoplastic changes than is leukoplakia. Once again, it is ultimately the clinician's decision to order biopsy or to watch. However, given the association of erythroplasia with neoplastic and preneoplastic change, the threshold to perform biopsy should be lowered in this context. Metaplasia Metaplasia is the change of an adult differentiated cell to a different type of an adult differentiated cell that is not normal in that location. In most cases in the head and neck, glandular or respiratory cells are undergoing metamorphosis to squamous cells. Physical trauma, such as prolonged hot or cold thermal excesses causes metaplasia of the respiratory lining cells to squamous cells. Normal respiratory, ciliated columnar cells of the false vocal cords are not unusually lined by squamous cells instead. The stimulus that precipitates this event is typically known and may be exposure to industrial or natural noxious gases, heated air, or cigarette smoke. These cells are not definitely committed to undergo malignant degeneration. However, this process does suggest that some irritant is causing cellular change; therefore, investigation is merited. The widely held notion that metaplasia is synonymous with simplification of the epithelium is untrue. Although ciliated, columnar, and mucus-secreting cells that are converting into squamous cells may be simplification, this is not always the case. In fact, chronic reflux with the concomitant exposure of esophageal squamous mucosa to gastric acids and enzymes produces the opposite result. The squamous cells evolve into mucous-secreting cells. Examples of this type of metaplasia occurring in the body are numerous. What the various forms of metaplasia have in common is that the cells change their type to one that is better suited than the former type to deal with the new environment. Malignancy Malignancy is surprisingly one of the most loosely defined terms in the field of oncology. Ask any group of medical students, residents, or attending physicians what this term means, and the variety of answers is startling. Given the essential importance of determining what is malignant and what is not simply underscores the need to clarify this term. The terms metastatic, locally invasive, monoclonal, neoplastic, autonomous, and numerous others have been used to define malignancy. However, tumors can have some but not all of the properties of each type and thus easily refute the usefulness of these terms.

For example, most malignant brain tumors do not metastasize. Conversely, the entity benign metastasizing leiomyoma is an oxymoron if one considers metastases identical to malignancy. Endometriosis is another example in which tissue somehow metastasizes to a site distant from its origin. Therefore, it is best to think of the term malignant as Dorland's Illustrated Medical Dictionary defines it[85] : (1) tending to become progressively worse and to result in death and (2) having the properties of anaplasia, invasion, and metastasis. The second half of the definition must be tempered with the understanding that not every malignant tumor possesses all of these features. Therefore, the term malignancy is probably best understood as an empirical or working definition. Malignant tumors are those that continue to produce severe damage. Carcinoma Carcinoma is an epithelial malignancy. That is, it is epithelial tissue that causes severe damage. SCC causes local invasion, it becomes ulcerated, and it metastasizes to produce its damage. Basal cell carcinomas are locally invasive, and they become ulcerated, but they only rarely metastasize. Every head and neck surgeon is aware that, despite the lack of metastasis, these lesions can cause death by causing infection or by eroding the brain or other vital structures.

Histologic Nomenclature
Squamous cell carcinoma (SCC) is an epithelial malignancy with morphologic features of squamous cell differentiation without additional features suggestive of other differentiated tissues. The features of squamous differentiation, observable on routine stained tissues under light microscopy, include one or more of the following: (1) flattened polyhedral, round, or ovoid epithelial cells; (2) intracellular or extracellular keratinization; and (3) intercellular bridges. If features of spindle cell differentiation, glandular differentiation, or basal-cell differentiation are present with the squamous features just listed, the tumors are named to reflect these distinctive features (see the following image).
Squamous cell carcinoma with spindle cell elements illustrates the totipotential nature of epithelial-cell malignancies.

The overall architecture is also included in the nomenclature of some select variants of SCC. Papillary carcinomas have cytologic features necessary for the lesions to be referred to as SCCs, but the unusual gross morphologic appearance and the microscopic architecture justifies special subcategorization. The head and neck possesses more tissue types than any other comparably sized anatomic region. In the head and neck region,

salivary glands, squamous epithelium, neural tissue, skeletal muscle, smooth muscle, parathyroid tissue, thyroid tissue, ceruminous glands, sebaceous glands, sweat glands, retinal tissue, corneal tissue, lymphoid tissue and numerous other tissue types are all present in close proximity. See Histologic Findings.

SCC Staging and Classification

Squamous cell carcinoma (SCC) is staged according to American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) guidelines, which use the "tumor, node, metastasis" (TNM) classification system.[58] This clinical staging system used for head and neck cancers is one that allows physicians to compare results across patients, assess prognosis, and design appropriate treatment regimens. The same system is employed for laryngeal tumors. The basic premise of these systems is that smaller cancers with no nodal disease have a better prognosis than a larger lesion with positive neck nodes. The staging system previously classified tumor stage based solely on tumor diameter and invasion of deep structures (ie, cartilage, muscle, or bone). Along with tumor diameter, the new system incorporates high-risk features and incorporates information about tumor factors that influence prognosis (see Prognosis).Cutaneous SCC of the eyelid is excluded from the updated system. High-risk tumor features include the following: Greater than 2 mm thickness or Clark level IV or higher Perineural invasion Primary anatomic location on the ear or nonhair-bearing lip Poorly differentiated or undifferentiated cellular histology Primary tumor (T) The T classification is as follows: TX - Primary tumor cannot be assessed (minimum requirements to assess primary tumor cannot be met). T0 - No evidence of primary tumor Tis - Carcinoma in situ (preinvasive cancer) T1 - Tumor 2 cm or smaller in greatest dimension and with 0 or 1 high-risk features T2 - Tumor larger than 2 cm but smaller than 4 cm in greatest dimension or with 2 or more high-risk features T3 - Tumor larger than 4 cm or involving facial bones (maxilla, mandible, orbit, or temporal T4 - Tumor invades deep extradermal structures (ie, extension to other bones, muscle, cartilage) or with perineural invasion involving the skull base Regional lymph nodes (N)

The new TNM staging system also revised nodal staging. Previously, the system had only had a single N1 level to signify nodal involvement. The new system has 5 levels. The decision to stage patients according to extent of nodal disease was based on significant findings of several studies, both prospective and retrospective, showing that the number and size of lymph node involvement correlated with patient prognosis.[86, 87, 88, 89, 90] In the new staging system, N1 disease involves a single ipsilateral node 3 cm or smaller in its largest dimension. N2a disease includes cases with a single ipsilateral node greater than 3 cm but less than or equal to 6 cm. N2b refers to those with multiple ipsilateral nodes smaller than or equal to 6 cm. N2c includes cases of bilateral or contralateral involvement less than or equal to 6 cm. N3 disease is reserved for cases with any involved node greater than 6 cm. The N classification is as follows: NX - Regional lymph nodes cannot be assessed (ie, minimum requirements to assess the regional nodes cannot be met N0 - No evidence of regional lymph node metastasis N1 - Regional lymph node metastases in a single ipsilateral lymph node and 3 cm or smaller in greatest dimension N2a - Metastasis in a single ipsilateral lymph node larger than 3 cm but not larger than 6 cm in greatest dimension N2b - Metastasis in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension N2c - Metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension N3 - Metastasis in a lymph node larger than 6 cm in greatest dimension In early 2010, Milross et al proposed an alternative nodal staging system (the N1S3), which also stages cutaneous SCC based on the number (single or multiple) and size (< or >3 cm) of lymph nodes involved, as well as incorporates the parotid as one of the regional levels, as follows[91] : Stage I nodal disease refers to those with a single lymph node measuring less than or equal to 3 cm. Stage II nodal disease includes cases with a single lymph node greater than 3 cm or multiple lymph nodes less than or equal to 3 cm, Stage III nodal disease consists of any patient with multiple lymph nodes greater than 3 cm. Milross et als system was found to have a significant predictive capacity for locoregional control, disease-specific survival, and overall survival in a group of 215 patients and was reproduced on external validation in a cohort of 250 patients.[91] Distant metastasis (M)

Distant metastases are staged according to the presence (M1) or absence (M0) of metastases in distant organs or sites outside of regional lymph nodes. This remains unchanged from the previous TNM staging system and is as follows: MX - Distant metastasis cannot be assessed (ie, minimum requirements to assess the presence of distant metastases cannot be met). M0 - No distant metastasis M1 - Distant metastasis TNM Staging Classification Stage 0 is equivalent with in situ disease. Disease stages I and II include patients with T1 and T2 tumors, respectively, who have no nodal or distant metastasis (N0, M0). Stage III disease includes T3 cases without nodal involvement (N0) or cases with N1 involvement. Stage IV includes those with T4 disease, or N2 or N3 disease, or distant metastasis (M1). The TNM staging classification is as follows (see also Table 2, below): Stage 0 - Tis/N0/M0 Stage I - T1/N0/M0 Stage II - T2/N0/M0 Stage III - T3/N0/M0, T1/N1/M0, T2/N1/M0, or T3/N1/M0 Stage IV - T4/N0, N1/M0; any T/N2, N3/M0; any T/any N/M1 Table 2. TNM Stage Grouping (Open Table in a new window) Stage Stage Stage Stage Stage 0 I II III Primary Tumor Tis T1 T2 T3 T1, T2, T3 T4 Any T Any T Regional Distant Lymph Metastasis Nodes N0 M0 N0 M0 N0 M0 N0 M0 N1 M0 N0, N1 M0 N2, N3 M0 Any N M1 Proceed to Differential Diagnoses

Stage IV

Other Conditions to Be Considered The following conditions should also be considered when evaluating a patient with suspected SCC: Cancerous lesions - Sebaceous cell carcinoma and rhabdomyosarcoma Congenital tumors - Dermoids, dermolipomas, and episcleral osseous choristoma Conjunctival degeneration - Pinguecula and amyloidosis Hereditary lesions - Benign hereditary intraepithelial dyskeratosis Lymphoid tumors - Lymphoid neoplasia, benign reactive lymphoid hyperplasia, and leukemic infiltrates

Neuroectodermal tumors - Nevus, primary acquired melanosis, and melanoma Papillomas Human papillomavirus (HPV)-induced papillomas Pseudocancerous lesions - Pseudoepitheliomatous hyperplasia and keratoacanthoma Vascular lesions - Angioma, lymphangioma, Kaposi sarcoma, and pyogenic granuloma Xanthomatous lesions -Juvenile xanthogranuloma and fibrous xanthoma

Differential Diagnoses
Actinic Keratosis Atopic Dermatitis Atypical Fibroxanthoma Basal Cell Carcinoma Benign Skin Lesions Bowenoid Papulosis Chemical Burns Contact Dermatitis Limbal Dermoid Pyoderma Gangrenosum

Approach Considerations

Although no specific laboratory analysis is required to confirm a diagnosis of squamous cell carcinoma (SCC), history and physical examination findings help determine specific laboratory and imaging needs. Any history of bleeding abnormalities, impaired healing, allergic reactions (eg, anesthetics, other medications), and significant cardiac or other systemic medical problems must be elicited. Imaging is not routinely indicated for diagnosing cutaneous SCC. However, radiologic imaging should be obtained in patients with regional lymphadenopathy and/or neurologic symptoms suggestive of perineural involvement, for nodal staging, and for preoperative planning in patients in whom deep or extensive tissue involvement is suspected. Computed tomography (CT) scanning, magnetic resonance imaging (MRI), ultrasonography, or positron-emission tomography (PET) scanning may be used depending on the specific question being addressed, although the selection of one modality over another is often based on clinician and institutional preference. Currently, no formal guidelines have been developed regarding the use of radiologic imaging in cutaneous SCC. Few data are available to guide decisions about staging of nodal basins in high-risk squamous SCC. However, PET scanning, ultrasonography-guided fine need aspiration (FNA) biopsy for cytology or excisional biopsy, and sentinel lymph node biopsy (SLNB) all appear to offer a good chance of detecting subclinical

nodal metastasis with low morbidity. Thus, nodal staging may be considered in patients with high-risk SCC. Development of prognostic models that better predict the risk of nodal metastasis will allow for more rational decisions about which patients should undergo nodal staging. See the following for more information: Sentinel Lymph Node Biopsy for Squamous Cell Carcinoma Urogenital Squamous Cell Carcinoma Imaging of Nasopharyngeal and Laryngeal Squamous Cell Carcinoma Cell Biology of Head and Neck Squamous Cell Carcinoma Targeted Molecular Therapy in Head and Neck Squamous Cell Carcinoma. Mohs Micrographic Surgery Mohs Surgery

Laboratory Evaluation
Perform routine hematologic examination to assess the overall medical condition of the patient and the possibility of spread to distant organs. Anemia may be detected with a complete blood cell (CBC) count with platelet count. Liver function tests help determine hepatic spread. Blood gases and pulmonary function tests in conjunction with chest radiographs are useful in heavy smokers. Genetic analysis for xeroderma pigmentosum and/or a test for human immunodeficiency virus (HIV) infection may be helpful if patient is young and there is no history of occupational exposure or excessive sun exposure.

CT Scanning and MRI

In advanced-stage cutaneous squamous cell carcinoma (SCC), anatomic imaging using computed tomography (CT) scanning or magnetic resonance imaging (MRI) can be helpful in defining the extent of disease. CT scanning is useful for determining the presence of bone or soft tissue invasion (see the first image below) and for evaluating cervical lymph nodes at risk for metastasis. Lung and liver scans or a full-body CT scan is performed if metastasis is suspected. For evaluation of perineural invasion and orbital or intracranial extension, MRI with intravenous contrast enhancement is the preferred imaging modality (see the second image below).[92] MRI is also the preferred method for staging SCC of the oral cavity and oropharynx.
Contrast-enhanced, axial computed tomography (CT) scan of a patient with softtissue invasion of the right parotid gland (arrow) by an ulcerative cutaneous squamous cell carcinoma (cSCC).

Axial magnetic resonance image (MRI) of a large squamous cell carcinoma of the left lower eyelid with invasion of the anterior orbit.

Only a few studies have reported on the utility of radiologic imaging in cutaneous squamous cell carcinoma. One study of CT scanning and MRI in patients with histologically proven, perineurally invasive SCC showed that only 20% of asymptomatic patients have positive findings discovered from imaging studies. [76] Thus, both modalities appear to be poor in detecting asymptomatic nerve involvement. However, positive imaging findings did correlate with worse outcomes. The 5-year survival rate was 50% if CT scanning or MRI findings were positive compared with 86% if they were negative.[76]

Overall accuracy of nodal staging with CT scanning (90-95%) appears superior to the accuracy obtained by clinical nodal staging (75-80%). Thus, more metastases are detected when CT scanning is incorporated into the staging protocol of patients with primary head and neck SCC. The overall accuracy of MRI in staging lymph nodes is similar to that of CT scanning.

Positron Emission Tomography

Positron emission tomography (PET) scanning has been proposed as an additional diagnostic tool to improve the accuracy of computed tomography (CT) scanning. In early radiologic studies, the combination of CT and PET scanning resulted in improved accuracy of staging, but this is not yet the standard of care.[93] PET scanning and ultrasonography-guided fine-needle aspiration (FNA) biopsy may be capable of detecting many cases of subclinical nodal metastasis.[94, 95] In a small study of PET scanning in 9 patients with high-risk SCC, this modality detected subclinical nodal metastasis in 3 of 9 patients.[95]

Ultrasonography
A study of vulvar squamous cell carcinoma (SCC) indicated that ultrasonography followed by fine-needle aspiration (FNA) biopsy for suspicious nodes was superior to computed tomography (CT) scanning in staging subclinical nodal metastasis, with ultrasonography-guided FNA biopsy demonstrating 80% sensitivity and 100% specificity.[94] Echography can be used to assess any suspicion of intraocular invasion.[96]

Biopsy
A biopsy should be performed for any lesion suspected of being a cutaneous neoplasm. For most lesions, the biopsy can be readily accomplished in the clinic or physicians office under local anesthesia. The type of biopsy performed depends on the size of the lesion. Small skin lesions in noncritical areas may be amenable to

excisional biopsy, where the entire area of concern is removed. This method has the benefit of being diagnostic as well as potentially therapeutic without the need for a second procedure. For larger lesions or those located in cosmetic or functionally critical areas, confirming the diagnosis before embarking on surgical excision that may be extensive and require reconstruction is often preferable (eg, eyelid lesions suggestive of squamous cell carcinoma [SCC]). In these cases, an incisional or punch biopsy should be performed initially with further treatment based on the pathology results. Whatever biopsy method chosen, several principles should be followed, such as: The biopsy should contain the full thickness of the skin in order to evaluate the depth of the lesion and to allow for a determination of the presence or absence of invasive disease. Given recent information about depth being an important prognostic factor (analogous to melanoma), a large punch biopsy through the center of the lesion or excisional biopsy may be best, particularly in high-risk lesions or immunosuppressed patients.[4] Therefore, a shave biopsy is generally not recommended when malignancy is suspected. The biopsy should be centered over the transition point between normal and involved skin, thereby providing a reference for comparison by the pathologist. When possible, incisions should be made parallel to the natural lines of skin tension (Langer lines) for optimal cosmetic outcome. For punch biopsies, stretching the skin perpendicular to the Langer lines creates an ellipse oriented in this optimal direction and facilitates closure. For high-risk lesions, a larger sample may be helpful to assess for perineural invasion and other histologic features that confer a greater risk of metastasis. Toluidine blue, which clinically stains malignant lesions dark blue but does not stain normal mucosa, is recommended for early detection as a guide for optimal biopsy. The dye is absorbed by the nuclei of malignant cells with increased DNA synthesis. If the diagnosis of carcinoma is made, endoscopic examination should proceed under general anesthesia with random biopsies of Waldeyer ring, the hypopharynx, nasopharynx, and other common sites of metastasis and any suspicious lesions. Subglottis, esophagus, and tracheobronchial tree are routinely evaluated to rule out synchronous primaries, which may have an incidence of 20%. Patients with regional lymphadenopathy identified by clinical examination or imaging studies should undergo a lymph node biopsy or fine-needle aspiration (FNA) biopsy for histologic evaluation.

Specimen Collection

The biopsy specimen must be representative of the lesion and processed properly. Selection of the biopsy site Squamous cell carcinomas (SCCs) typically appear as a surface abnormality visible to the eye, such as a surface with decreased reflectivity, the white discoloration of keratosis or ulceration, the red and velvety appearance of erythroplasia, or elevation or umbilication of the surface. However, some SCCs demonstrate relatively little in terms of visual anomaly. Easily elicited bleeding is also often an important clue to an underlying malignancy. A carcinoma may appear as a subepithelial mass. In this case, a papule may be visible, or the lesion may be detected only on the detection of firmness to palpation. A supravital stain, such as toluidine blue, reliably indicates surface atypia, which is not deeper than 5 cell layers from the surface. Avoid biopsy of a healing area, because rapidly growing tissue mimics malignancy in many morphologic ways. Obtaining the specimen A specimen from the oral cavity, nasal cavity, palate, tonsil, and pharynx can be obtained by using topical or local anesthesia in the office setting. Lesions in the tongue base, pharynx, or larynx are best evaluated and sampled with the patient under general anesthesia. Excisional biopsy is preferred when possible. After the procedure, the wound is left to heal without sutures. A sharp instrument, such as a basket punch or a scalpel, is used to cut rather than tear the specimen. Use of a sharp instrument prevents stretch artifact in the histologic specimen. The specimen should always include the marginal adjacent tissue as well as the tumor itself. A biopsy sample from the center of the lesion is usually of least value, especially if the lesion is ulcerated. Excisional biopsy Excisional biopsy is en bloc excision of the entire lesion, including a narrow margin of the normal tissue. It is particularly suited for evaluating superficial lesions without obvious fixation to underlying muscle. Excisional biopsy has several advantages, such as the following: With serial sectioning and histologic examination, the entire lesion can be evaluated. If the lesion is completely excised, no further treatment is required. When only microinvasion is present, positive mucosal margins may be observed safely. When the biopsy wound heals, clinical evidence of atypia often clears. If not, further excision is performed.

If the entire lesion cannot be excised, further treatment is needed. The type of treatment is selected on the basis of the information obtained during attempted excisional biopsy. Excisional biopsy is consistent with the goals of minimal treatment. This approach allows for the removal of no more tissue than necessary to treat the disease, preserving as much tissue as possible. Therefore, the benefit-cost ratio is high. A suitable candidate for excisional biopsy is a patient who can undergo anesthesia and who has a lesion that is entirely visible. A patient with early glottic cancer is particularly suited for excisional biopsy. Glottic cancer has a predilection for the ventricular surface of the vocal fold, where removal of the mucosa interferes minimally with the vocal wave (voicing). The ventricular surface has typically undergone polypoid degeneration (Reinke edema) with a marked accumulation of fluid just below the surface, which makes dissection easy and safe. The following images are examples from excisional biopsies.
Specimen on a carrier. Vocal-fold epithelium has been stained with toluidine blue O, and all suspected tissue is excised (excisional biopsy). The specimen has been unfolded and laid flat onto a slice of cucumber. The specimen and cucumber are then flooded with fixative (10% formalin) and together serially sectioned for histologic evaluation. This excisional biopsy specimen is well prepared for evaluation. The amorphous material deep to the specimen is the cucumber carrier. The specimen has been serially sectioned with alignment perpendicular to the surface to make evaluation of the entire specimen easy and reliable.

Fine-needle aspiration biopsy

Fine-needle aspiration (FNA) biopsy can aid in evaluating a neck mass of uncertain origin, including most non-Hodgkin lymphomas (see the image below). This procedure is easy to perform and helps provide a quick, reliable diagnosis when the results are positive for cancer; however, FNA biopsy is not reliable when the results are negative. This biopsy does not complicate later attempts at curative surgery. Of note, FNA biopsy of a parotid mass releases digestive enzymes into the gland that may make histologic evaluation of the excised gland unreliable.
Fine-needle aspirate from a neck node. Clumps of cells obtained by means of fine-needle aspiration by using a 20-gauge needle and strong negative suction allow for histologic and cytologic evaluation. Sampling error is possible, particularly with small lesions.

Sentinel lymph node biopsy Sentinel lymph node biopsy (SLNB) has been used to identify micrometastasis in patients with high-risk SCC and clinically negative nodes, with 21% positivity.[63] Although SLNB appears to be able to detect most subclinical metastasis, whether early detection of lymph node metastasis leads to enhanced survival in

SCC is unknown, because controlled studies have not been conducted. A review of 85 reported cases of SLNB in high-risk, nonanogenital cutaneous squamous SCC showed that 21% of cases were positive based on SLNB findings. This indicates that SLNB likely can detect many cases of subclinical nodal metastasis. How the sensitivity of SLNB compares with that of positron emission tomography (PET) scanning or ultrasonography-guided fine-needle aspiration (FNA) biopsy and whether detection of subclinical nodal metastasis impacts survival are unknown.[63] However, because the 5-year survival rate of patients with nodal metastasis is as high as 73% with aggressive treatment,[62] early detection of nodal metastasis may prove more beneficial in SCC than in melanoma. Complete lymphadenectomy of the draining nodal basin has also been suggested for high-risk tumors with an estimated metastatic risk of 20% or greater. However, because prognostic models do not exist, knowing precisely which patients fall into this category is difficult. Thus, when it is feasible, SLNB offers a low-morbidity approach to accurately staging high-risk SCC. Open biopsy Do not perform open biopsy of neck masses unless findings from fine-needle aspiration (FNA) biopsy, paranasal sinus radiographs, and panendoscopy with random biopsy of the Waldeyer ring under general anesthesia fail to confirm a diagnosis. The surgeon who has ultimate responsibility for the patient's care and who will select an incision site that can be included in any future resection is best suited to make the incision for open biopsy. A small specimen (< 1 cm) that is to be fixed must be uncurled, flat, and oriented during fixation so that the histotechnologist can mount and section the specimen properly. The surgeon flattens the specimen and attaches it to a carrier. A suitable carrier is a slice of preserved cucumber pressed to the inside of the specimen bottle lid, which has been sprayed with benzoin and then allowed to dry and become sticky. After it is well positioned on the carrier, the specimen is flooded with 10% formalin as a fixative, and the specimen bottle is screwed onto the lid (ie, the lid remains topside down on the table) and transported to the laboratory in the upside-down position. The surgeon and/or a map drawing of the lesion and the biopsy site should accompany the specimen to the laboratory to explain its location and orientation in the patient. If the diagnosis of lymphoma rather than carcinoma is suspected, the lymph node should be sent to the pathologist immediately after its removal when it is fresh, moist, and not preserved. Otherwise, the node should be immersed in a 10% formalin fixative.

When the specimen's representation of the lesion is doubted, frozen sectioning is helpful.

Histologic Findings
Pathologic analyses may be completed by a dermatologist or a general pathologist, but they are preferably completed by a dermatopathologist with extensive experience in squamous cell carcinoma (SCC). Most SCCs have a gelatinous surface on gross inspection, which frequently is permeated by fibrovascular cores, giving it a papillomatous appearance. The histologic hallmark of SCC is the presence of keratin or "keratin pearls." These are well-formed desmosome attachments and intracytoplasmic bundles of keratin tonofilaments. The term epidermoid can be substituted for squamous. Conventional cutaneous SCC can be divided into 3 histologic grades based the degree of nuclear atypia and keratinization found. Welldifferentiated cutaneous SCC is characterized by more normalappearing nuclei with abundant cytoplasm and extracellular keratin pearls. In contrast, poorly differentiated cutaneous SCC shows a high degree of nuclear atypia with frequent mitoses, a greater nuclearcytoplasmic ratio, and less keratinization, and it may be difficult to distinguish from mesenchymal tumors, melanoma, or lymphoma. Moderately differentiated cutaneous SCC shares exhibits features of both well-differentiated and poorly differentiated lesions. See the following images.
Progressively severe atypia. The epithelium to the left is close to normal, but the epithelium to the right shows full-thickness atypia (ie, carcinoma in situ). This image illustrates carcinogenesis, the process whereby the cells exposed to a carcinogen become cancerous over time. Squamous cell carcinoma. The lesion closely approximates the specimen in the previous image. Field cancerization is illustrated; that is, if >1 cell is exposed to a carcinogen, >1 cell becomes cancerous. Note the marked inflammatory-cell response. Should limited biopsy reveal only severe atypia with a severe inflammatory response, the lesion should be investigated further. A cancer is likely nearby.

Histopathologic features of cutaneous SCC remain important for the clinician, as they carry prognostic value and help to define the most appropriate treatment for patients. Pathologic features, including poor differentiation, perineural invasion, and lymphovascular involvement, are more likely to be seen with regional lymph node involvement. Poorly differentiated cutaneous SCC demonstrates rates of metastatic spread significantly higher than those of other grades (17% vs 4%). Those exhibiting perineural and lymphovascular invasion also exhibit higher rates of metastasis. SCC in situ

SCC in situ (SCCIS), sometimes referred to as Bowen disease, is a precursor to invasive cutaneous SCC. This lesion is characterized by an intraepidermal proliferation of atypical keratinocytes. Keratinization results in the production of squamous eddies or keratin pearls. The neoplastic cells may demonstrate varying degrees of squamous differentiation and atypia. Hyperkeratosis, acanthosis, and confluent parakeratosis are seen within the epidermis, and the keratinocytes lie in complete disorder, resulting in the classic "windblown" appearance. Cellular atypia, including pleomorphism, hyperchromatic nuclei, and frequent mitoses, is prominent. Atypical keratinocytes may be found in the basal layer and often extend deeply down hair follicles, but they do not invade the dermis. SCCIS is differentiated from actinic keratosis, a similar precancerous skin lesion, by full-thickness involvement of the epidermis. See the image below.
Carcinoma in situ. Full-thickness atypia is clinically observed as a red-velvet patch (erythroplasia) and stains strongly with supravital stain, such as toluidine blue O.

SCCIS is the correct nomenclature for full-thickness atypia of the squamous cells without invasion by any tumor cells beyond the basement membrane. This collective atypia of the cells, being full thickness by definition, results in architectural distortions. Architectural distortion of a normal biologic structure is, again, by definition, dysplasia. From a consideration of the anatomy and this definition, 2 corollaries follow: (1) Without invasion, the nerves, lymphatics, and blood vessels are not in contact with the tumor and therefore, SCCIS does not metastasize; and (2) full-thickness atypia must demonstrate atypia that includes the surface. The second point is of clinical importance. The surface atypia of SCCIS often has clinically identifiable anomalies. It may appear as leukoplakia because of excessive keratin. It may result in irregular surface contours that may be more or less optically reflective than the surrounding mucosa. This change results in pale, dull, shiny, and/or irregular surface features. The cells also may not absorb certain vital stains in the same manner as the normal mucosa. This is why various mouth rinses containing toluidine blue or iodine solutions have been used, with varying degree of success, to target areas for biopsy. The most important issues to consider with respect to SCCIS of the head and neck are: (1) SCC in situ may develop into invasive SCC, and (2) given the concept of field defect (see Anatomy), frankly invasive carcinoma in proximity frequently accompanies SCCIS. One final fact is absolutely essential for the clinician to appreciate: Not all invasive SCCs go through a progressive cycle of dysplasia to

in situ carcinoma to invasive carcinoma. This is of extreme importance, because a normal-appearing surface may hide de novo invasive SCC. Invasive SCC Invasive cutaneous SCC is differentiated from SCCIS and actinic keratosis by the invasion of the basement membrane by malignantappearing cells (see the following images). With invasive cutaneous SCC, nests of atypical cells are found within the dermis, surrounded by an inflammatory infiltrate similar, if not identical, to basement membrane. This is because the cells can still produce the necessary biomolecules that create the basement membrane, or they can induce the stroma to contribute to the basement membrane. This ability does not indicate lack of invasion. Breaching of the normal infrabasaloid basement membrane defines invasive SCC.
Microinvasion and cellular atypia are observed deep to the expected junction between the epithelium and the stroma. Pink material (basement membrane) is evident around the clumps of malignant cells in the stroma. Surface keratin is present. On clinical evaluation, this lesion would have been observed as a white patch that does not rub off. Invasion with normal surface. The top 4-5 cell layers are without atypia and mucosal surface changes. Toluidine blue O would not reveal the underlying cancer.

The dangers of invasive SCC are numerous. First, the cells have access to structures that allow them to travel to distant sites. Lymphatics, blood vessels, and nerves are ideal conduits. Second, they can erode into vital structures and cause pain, paresthesias, hemorrhage, vocal changes, or obstructive phenomenon. Third, surgery is complicated, because individual cells or small clusters of cells may lie beyond what may appear to be a free margin. Fourth, selecting the ideal therapeutic option is difficult. One is never sure if lymph-node dissection of the tumoral drainage area or if irradiation to this area is prudent. Microscopic metastases cannot be detected by clinical or radiologic means. Fifth, depending on the location of the tumor in the head and neck, the natural barrier to explosive invasion and distant metastases may be limited. For example, the tongue is rich in nerves, lymphatics, and blood vessels. Therefore, invasive tongue tumors have many routes to spread widely. In addition, the rich vascularity guarantees an abundant supply of oxygen and nutrients to support rapid growth. Last, the tongue musculature has evolved to produce motion in all directions and thus effectively move the tumor to distant sites. When dealing with SCC, the pathologist must inform the clinician of several parameters, such as the following: Whether the tumor is invasive: The report states "SCC in situ, no invasion identified" or "SCC, invasive." The simple designation

"SCC" should not be accepted, because it may indicate an oversight on the part of the pathologist or the typist of the report. The assessment of invasion, or its lack, must be mentioned. Invasion: If possible, the pathology report must state the structures that are invaded. Simply stating "invasive" informs the clinician that the tumor has breached the natural basement membrane. This is most often the case. However, it is not too unusual for the pathologist to state that perineural invasion, lymphatic invasion, or vascular invasion is present. By convention, "vascular invasion" indicates vascular and not lymphatic invasion. Degree of differentiation: This is a difficult and debated topic. Strict criteria that are universally accepted simply do not exist. In addition, on examination of many fields of any given tumor, one often identifies considerable variability. Fields that most pathologists agree are well differentiated may be adjacent to fields that they would agree are poorly differentiated. Therefore, the degree of differentiation is subjective. Many pathologists accept the subjective nature of the degree of differentiation and use this simple rule: If the lesion is obviously malignant but takes considerable time to determine that it is squamous in origin, it is classified as poorly differentiated. If the lesion demonstrates obvious squamous differentiation but a prolonged search for atypical cells or atypical mitotic figures is necessary, the lesion is classified as well differentiated. All other lesions are moderately differentiated. One must remember that a well-differentiated tumor may metastasize with moderately or poorly differentiated nests. Likewise, a well-differentiated SCC in a lymph node does not mean that the primary is also well differentiated. In addition, therapy affects the degree of differentiation. A poorly differentiated SCC of the buccal mucosa treated with irradiation or chemotherapy that produces an incomplete response may demonstrate well-differentiated carcinoma in its wake. The histologic appearance of a usual invasive SCC varies with the degree of differentiation. In common to all are the following: Atypical squamous cells with enlarged, angulated nuclei Increased nuclear diametertocytoplasmic diameter ratio Evidence of keratinization, more in well-differentiated and less in poorly differentiated lesions Intercellular bridges or cytoplasmic projections that radiate outward from the cytoplasm and connect adjacent cells Increased mitotic figures: No specific number is diagnostic of malignancy Atypical mitotic figures: These are mitotic figures that do not fit into any of the known phases of cell division. Even anaphaselike mitotic figures demonstrate multipolarity, whereas normal cell

division has 2 poles that the genetic material is oriented toward; atypical mitotic figures may have 3 or more poles. Hyperchromasia: The nuclei are darkly staining because of increased ploidy. Invasion below the usual level of the basement membrane: This may be in a large pushing front of dozens of cohesive squamous cells. It may also invade as small cell nests containing 5-10 cells per cluster, often with an elongated stabbing pattern. Finally, individual cells may be percolating through the stroma. Inflammation: Invasive carcinomas almost always have a surrounding and/or intermingling inflammatory response. This response may be exclusively of 1 cell type (eg, lymphocytes or plasma cells), or it may be a mixture of any combination of cells, including macrophages, neutrophils, eosinophils, lymphocytes, and plasma cells. SCC histologic variants Several variants of SCC can be distinguished by clinical and/or histologic criteria. In some cases, these tumors may be difficult to distinguish from other malignancies based on routine histology findings alone. Therefore, immunohistochemical staining with antibodies to cytokeratins and epithelial membrane antigen is often used to confirm the epithelial (ie, keratinocyte) origin of the tumor. The salient features of keratoacanthoma, spindle cell SCC, acantholytic (adenoid) SCC, and verrucous carcinoma are highlighted in Table 3, below. Table 3. Histologic and Clinical Features of Squamous Cell Carcinoma (SCC) Variants (Open Table in a new window)
Tumor Keratoacanthoma Histologic Characteristics Keratin-filled crater Clinical Characteristics Solitary nodule

Well-differentiated (mild atypia)

Central craterlike depression

Rapid growth Neutrophil microabscesses May spontaneously involute Eosinophils in dermal infiltrate

Elastic tissue trapping

Lack of acantholysis

Spindle cell carcinoma

Atypical spindle cells

Resembles typical SCC

Foci of squamous differentiation

May be clinically aggressive

May resemble other spindle cell tumors (eg, atypical fibroxanthoma)

Acantholytic (adenoid) SCC

Glandlike differentiation

Arises on sun-damaged skin

Acantholysis

Elderly patients

May resemble adenocarcinoma or sweat gland carcinoma

Resembles typical SCC

Clinically aggressive

Verrucous carcinoma

Well-differentiated (glassy atypia)

Oral, genital, or plantar foot

Indolent growth Surface resembles verruca Locally destructive Bulbous downward proliferation Rarely metastasizes "Bulldozing" invasion

Sarcomatoid SCC

Poorly differentiated cells resembling sarcoma

Clinical appearance may be that of typical SCC or may have more nodular appearance with less surface change

Elevated risk of local recurrence and metastasis

Spindle cell carcinoma, basaloid SCC, papillary SCC, mucoepidermoid carcinoma, and nasopharyngeal carcinoma are variants of SCC and will be discussed in this section. Spindle cell carcinoma Spindle cell carcinoma may contain intercellular bridges and incipient keratinization. In other cases, spindle cells are intermingled with collagen and may be arranged in whorls. In such cases, special stains for cellular markers can be used to distinguish SCC from other cancers. For example, an S100 stain returns negative results for SCC

and positive results for melanoma. Specifically, synaptophysin, CD99, leukocyte common antigen, nonspecific esterase, S100, homatropine methylbromide, and neurofilament stains return negative findings for SCCs, whereas cytokeratin, vimentin, and epithelial membrane antigen stains return positive findings. This morphologically deceptive and unusual tumor has also been referred to as spindle-cell carcinoma, carcinosarcoma, spindle cell SCC, or sarcomatoid carcinoma. All of these terms have distinct disadvantages. Carcinosarcoma is a different tumor with both malignant epithelial and malignant mesenchymal elements. Use of this term to mean a spindle cell tumor with exclusively epithelial elements on immunoperoxidase testing is never justified. Spindlecell SCC is an oxymoron; the word squamous is derived from the Latin for scale and implies a plate and not a needle or spindle shape. Sarcomatoid carcinoma is etymologically a good term, but mistyping, miscommunication, and poor coding have led to patients being informed that they have a sarcoma, which spindle cell carcinoma certainly is not. Therefore, the preferred term is spindle cell carcinoma. The lesion is a polypoid, exophytic, or fungating mass that occurs in head and neck sites (in order of decreasing frequency): larynx, oral cavity, hypopharynx and pyriform sinus, sinonasal tract, and oropharynx. Surface ulceration is common with these tumors. As with any ulcerated lesion, these are likely to be infected and therefore may exude pus or contain abscess formation. On histology, one may see spindle cells, which are elongated cells with central, elongated nuclei. These are arranged in entangled fascicles and intertwining bundles. The degree of hyperchromasia, enlarged nuclear to cytoplasmic ratio, mitoses and pleomorphism are strongly suggestive of a leiomyosarcoma or a fibrosarcoma. Not infrequently, foci of a storiform pattern may be seen; these may resemble findings of a malignant fibrous histiocytoma. Vascular structures are occasionally associated with the tumor. However, this is not to be confused with an angiosarcoma, as vessel-lining endothelial cells do not display atypia. The stroma may be heavily collagenized, presenting a hyalinized appearance or, at the other end of the spectrum, the stroma may be loose and myxoid. Multinucleated giant cells occur at times and, in the setting of hyalinized collagen, which resembles osteoid; confusion with an osteogenic sarcoma is a pitfall to be avoided. Simply having knowledge that tumors such as spindle cell carcinoma exist should eliminate the danger of a missed diagnosis. Two key procedures should be followed to ascertain if one is dealing with a true mesenchymal neoplasm or an epithelial malignancy mimicking a sarcoma. The easiest, quickest, and least expensive method is to examine the surface epithelium overlying the neoplasm. If one sees

a conventional SCC with a gradual transition into elongated cells as one looks deep into the stroma, special studies are not necessary. The search for these intermediate cells (ie, ovoid-to-shortened versions of true spindle cells) should be the first step when one sees a spindle-cell malignancy in the head and neck. If a transitional region is not present or not identified, spindle cell carcinoma is not ruled out. In this case, immunoperoxidase testing is useful. However, some keratin stains of the spindle cells are not always positive. Therefore, the best method is to perform a battery of keratin stains. AE1/AE3 and CAM 5.2 are particularly useful. Verrucous carcinoma As the name suggests, verrucous carcinoma is a lesion with a gross appearance of a verruca or wart. Verrucous carcinomas are often immense in size at presentation. Despite their size, however, pure forms of verrucous carcinoma rarely, if ever, metastasize. The tumors are indeed carcinomas in that they are locally destructive. However, they are extremely well-differentiated SCCs. In cytologically terms, they do not possess any of the qualities that one usually associates with malignancy. They have no increased nuclear-to-cytoplasmic ratio, hyperchromasia, increased number of atypical mitotic figures, or pleomorphism. Therefore, a deep, large biopsy sample is required to examine the specimen for the necessary diagnostic criteria of verrucous carcinoma (ie, the architecture). The architecture is that of a broad, pushing, and expansile epithelial lesion that extends into the stroma. Variably intense infiltration of mononuclear inflammatory cells at the interface of the tumor with the stroma is always present. The most important consideration in diagnosing verrucous carcinoma is that an unknown percentage of these lesions contain a focus or foci of standard SCC. When this is found, the neoplasm has the potential of conventional carcinomas to metastasize. Given the large size of verrucous carcinomas on presentation, the entire specimen is not examined histologically every time. This practice leads to occasional underdiagnosis of areas of conventional SCCs. Therefore, the pathologist must adequately sample all putative verrucous carcinomas to rule out SCC of the usual type. Basaloid SCC Basaloid SCC is less common than conventional SCC of the head and neck; men are 4 times more likely than women to have this cancer, and most patients are aged 40-70 years. This tumor is considerably more aggressive than unqualified SCC, with a tendency to involve the tongue base, supraglottic larynx, the pyriform sinuses, esophagus, lungs, anal region, and uterine cervix. The reputation for aggressive behavior is well earned in that, aside from widespread local invasion at the time of presentation, many patients have local metastases when the lesion becomes apparent.

Almost all basaloid SCCs have regions in common with conventional SCC. In addition, they have a follicular or lobular pattern of invasion, with peripheral, slightly elongated, palisaded cells surrounding each lobule. On serial sections, these follicles are interconnected. The lobules often contain central comedo necrosis with visible necrotic material. At other times, the central material completely "drops out," giving a pseudoglandular appearance. Of interest is that a hyaline basement membranelike material is occasionally present in the center of these islands. Because the islands have an architecture of interlocking masses similar to that seen in adenoid cystic carcinoma, the addition of these eosinophilic regions sometimes makes this tumor hard to distinguish from adenoid cystic carcinoma. Increasing evidence suggests that human papillomavirus (HPV) is involved in the genesis of at least some of these lesions. Furthermore, HPV-positive basaloid SCCs may be less aggressive than HPV-negative basaloid SCCs. In fact, some oncologic pathologists contend that HPV-positive basaloid SCC is less aggressive than any other type of SCC in the same anatomic location. Papillary SCC Papillary SCC is uncommon but certainly merits discussion because of the confusion it may cause the pathologist and surgeon. Papillary or exophytic lesions with full-thickness atypia (ie, SCCIS) and/or frankly invasive SCC as a component have been reported in many locations in the body. These include the skin, uterine cervix, and even the eye, as well as the larynx, oropharynx, nasal septum, and nasopharynx. Papillary SCCs have been reported in both sexes and in patients aged 30-80 years. The mean age of presentation is in the 60s, and women are affected less often than men. On histology, in situ or invasive papillary SCCs have similar architectures. They contain benign, fibrovascular cores with overlying squamous epithelium. The epithelial layer may be keratinizing or nonkeratinizing and, with in situ lesions, full-thickness atypia is present. As usual, this atypia manifests as an increased nuclear-tocytoplasmic ratio, hyperchromasia of the nuclei, angulated nuclei, various degrees of pleomorphism, increased mitotic figures (especially above the basal layers), and atypical mitoses. In addition, an unusual type of cellular atypia, koilocytotic atypia, is present. Koilocytotic atypia is defined as nuclei with perinuclear halos where the nucleus itself is twisted with bilobed to multilobed outlines and where indentations of nuclear contour are frequent. This particular form of cellular distortion is well related to HPV infection of the cells. What is interesting about this koilocytotic atypia is that it is not expressed in all cells of papillary SCC. In fact, it is seen in fewer cells than it is in benign laryngeal papillomatosis.

If the lesion is of the in situ variety, full-thickness epithelial atypia is observed without an invasive component. This is the same situation as in conventional SCC in situ. The invasive variety demonstrates frank stromal invasion. This component is indistinguishable from any other form of invasive SCC. Papillary SCC does present a unique difficulty to the pathologist and surgeon. The very architecture of this neoplasm leads to sampling errors. The base of the lesion is often not represented in the biopsy sample, or the histologic technicians do not cut them thoroughly enough. These situations lead to potential false-negative results for an invasive component. It is absolutely necessary to evaluate the epithelial and/or stromal interface of the entire lesion to rule out invasion. Papillary lesions always present a clinical differential diagnosis rather than a confident single diagnostic entity. However, the histologic criteria for the main lesions in the clinical differential diagnosis are rigid. This clarity should enable the pathologist to make an unequivocal diagnosis in most cases. The 3 main entities in the clinical considerations with papillary epithelial lesions are (1) benign squamous papilloma, including those associated with adult and juvenile laryngeal papillomatosis; (2) papillary SCC, in situ or invasive; and (3) verrucous carcinoma. Benign squamous papilloma has a fibrovascular core and may occur in the same age ranges and anatomic locations as those of papillary SCC. However, the epithelium itself should allow for easy distinction by the pathologist. Although epithelial atypia, especially koilocytotic atypia, may be present in benign squamous papilloma, it is not widespread and never of the degree seen in papillary SCC in situ. The invasive variant of papillary SCC is not to be confused with benign lesions. Any unequivocal stromal invasion by malignant epithelium, defines the lesion as a carcinoma. Verrucous carcinoma is also an exophytic mucosal lesion that affects the same anatomic areas and age groups as does papillary SCC. Verrucous carcinoma may demonstrate epithelial atypicality, including koilocytic atypia; however, the atypia is mild. In fact, the cytologic picture of verrucous carcinoma is that of bland epithelium rather than that seen in conventional or papillary SCC. Papillary SCC may have keratinization on the surface, but it is never as thick or as widespread as that of verrucous carcinoma. Finally, verrucous carcinoma invades with broad pushing fronts, not the thinned, stabbing edges, small nests, or individual cells seen in papillary SCC. Table 4 below summarizes the epithelial, invasive and inflammatory characteristics of benign squamous papillomas, papillary SCCIS, invasive papillary SCC, and verrucous carcinoma. Table 4. Summary of Characteristics of Papillary Epithelial Lesions and Verrucous Carcinoma (Open Table in a new window)

Tumor Benign squamous papilloma Papillary SCCIS

Epithelium Minimal to no epithelial atypia without any stromal invasion Full-thickness epithelial atypia without invasion Epithelial atypia, which may or may not be full thickness, overlying stromal invasion; invasion occurs by means of elongated, stabbing fronts, small nests or individual cells

Papillary SCC, invasive

Verrucous carcinoma

Bland, highly keratinized, squamous epithelium, with invasion in broad, rounded, pushing fronts

Invasion and Inflammation No inflammation in stroma; no epithelial cells, nests, or broad fronts in stroma No invasive epithelial component in stroma; minimal inflammatory reaction Pointed, narrow epithelium extending into stroma, with epithelial nests and/or individual cells surrounded by inflammatory cells, which may be eosinophils, neutrophils, macrophages, plasma cells, and/or lymphocytes in any combination No individual cells or squamous nests in stroma; advanced portion of the epithelial pushing front surrounded by tightly hugging infiltrate of mononuclear inflammatory cells

Mucoepidermoid carcinoma Although mucoepidermoid carcinoma is a neoplasm of the salivary glands, it occurs in most of the locations in the upper aerodigestive tract where SCCs and their variants occur. This is true because the head and neck is an area rich in mucous glands from which this tumor arises. Mucoepidermoid carcinoma occurs over a wide age range, including the pediatric population. Therefore, although it most commonly is seen in those aged 20-60 years, mucoepidermoid carcinoma should never be ruled out as a possibility clinically on the basis of the patient's age alone. As the name implies, mucoepidermoid carcinoma is a malignant epithelial neoplasm with both mucus producing cells and epidermoid (ie, squamous) cells. These 2 cell types are present in various tumors in different proportions. The ratio of these cell types is the criterion for grading the malignancy. The higher the percentage of squamous cells, the higher the grade of the tumor. Technically, a third cell type, the intermediate cell, is also present in mucoepidermoid carcinoma. The cytologic description of these cells is inconsistent and somewhat vague. They are of theoretic interest only in terms of therapy and prognostication. The grade is of particular interest, because the correlation between behavior and grade is fairly good. Low-grade tumors are slow growing, and unless they are ulcerated and superinfected, they are uncomfortable but painless. High-grade tumors are rapidly growing masses that do produce pain with or without ulceration. Intermediate-grade tumors are slightly more aggressive than lowgrade tumors but have a growth rate closer to that of low-grade tumors than that of high-grade tumors.

Although mucoepidermoid tumors preferentially metastasize to the regional lymph nodes of the neck, they also frequently metastasize to distant sites (eg, lungs, bones, skin and subcutis) by the time the disease is diagnosed. Nasopharyngeal Carcinoma In more than 50% of cases of nasopharyngeal carcinoma studied by means of radiologic investigations, the fossa is deeper than 10 mm, and the opening is less than 5 mm. These features make the area difficult to examine, and blind biopsy is often preformed because of suspected malignancy during an investigation for an occult primary carcinoma. Nasopharyngeal carcinoma arises from an area in the Waldeyer ring, and that characteristic alone places it in an unusual category of carcinomas. The epithelium of this immunologically protective ring is histologically distinct from that of other regions of the head and neck, and tumors from this area differ in etiology, appearance, and behavior from other tumors originating elsewhere. The epithelium of the Waldeyer ring epithelium is intimately associated with the underlying mononuclear inflammatory cells. This means that, architecturally, no sharp distinctive barrier is observed between the epithelium and the lymphocytes in the vicinity. The lining epithelial surface does not abruptly stop in a palisading basal layer at a stromal interface. Rather, the epithelial cells and lymphocytes intermingle. In addition, the mucosa of the Waldeyer ring is not the planar, flat surface seen throughout much of the head and neck area; instead, the surface dives into deep crypts and involutions. This knowledge is clinically important because it adds to the difficulty of early detection of malignancy in the region with the anatomy of the fossa of Rosenmller. The histopathologic characterization of this interesting neoplasm also merits recognition as one of the more complicated and controversial in medical history. Although the 1991 classification of the World Health Organization (WHO) is now universally recognized, nasopharyngeal carcinoma has been extensively recategorized and renamed throughout its history. The terms Schmincke tumor, Regaud tumor, keratinizing SCC WHO type I, nonkeratinizing carcinoma WHO type II, undifferentiated carcinoma of nasopharyngeal type III, and lymphoepithelioma have all been applied to its various manifestations. The current system has been simplified as follows: (1) SCC (keratinizing SCC) or (2) nonkeratinizing carcinoma, which is subdivided as (a) differentiated or (b) undifferentiated (undifferentiated carcinoma of nasopharyngeal type). These are discussed below Keratinizing SCC

This type of nasopharyngeal tumor is not morphologically distinct from the conventional SCC with keratinization occurring anywhere else in the body. As elsewhere, keratinizing SCC is a dysplastic, invasive epithelial malignancy with increased mitotic figures, atypical mitoses, an increased nuclear-to-cytoplasmic ratio, atypical and enlarged hyperchromatic nuclei with intercellular bridges, and keratin pearls and intracellular keratin. Although this is a common morphologic manifestation of SCCs elsewhere, it is the least common form of nasopharyngeal carcinoma. In addition, EpsteinBarr virus (EBV) may well be identified in these tumors but not as frequently as it is in nonkeratinizing carcinoma of the nasopharynx. Differentiated and undifferentiated nonkeratinizing SCC The nonkeratinizing SCC is most frequently seen where the neoplasm is endemic. It is therefore the most common variety. Virtually all patients have antibodies to EBV antigens, and EBV is extremely frequently identified in tumor cells. On histology, the differentiated variety has distinctly epithelial cells with polyhedral outlines and distinct cell borders on most cells. These may be individual, but most often they are arranged in elongated strands that intertwine to form an overall reticular pattern. They may be seen streaming from surface stratified squamous epithelium. Extracellular or intracellular keratinization is rare or absent. Epithelial differentiation on light microscopy is so limited that initially the tumor was suspected of having both lymphoid and epithelial origins. The malignant cells, which are epithelial, do not have the distinct cell borders of the differentiated type of nonkeratinizing carcinoma. The cells may be round, ovoid, polyhedral, or spindled. Nevertheless, immunoperoxidase stains do prove all these variants are epithelial in origin. As stated earlier, the cells may individually percolate throughout the lymphoid tissue, or they may be arranged in a reticular or syncytial pattern vaguely connected to each other. Nearly every tumor has some version of both regions. Nonkeratinizing nasopharyngeal undifferentiated type is the type of nasopharyngeal carcinoma that has been responsible for much of the early confusion of the origin of nasopharyngeal tumors. It has driven much of the controversy regarding classification schemes. When this tumor type metastasizes to cervical lymph nodes, it often presents a diagnostic dilemma, and tests for epithelial markers and mesenchymal and melanocytic markers are required to rule out other neoplasms. After a cervical metastasis with a poorly differentiated to undifferentiated morphology is proven to be a carcinoma on routine staining, the likelihood that the unknown primary is nasopharyngeal is high.

Surgeon and Pathologist Communication

The pathology report describes the pathologist's interpretation of the evidence offered for examination. It indicates the disease, which, like any other indicator, may not be correct. Close cooperation between the surgeon and the pathologist optimizes factors (eg, biopsy specimen, clinical information) that influence interpretation of the results. On a practical level, certain aspects of squamous cell carcinomas (SCCs) must always be included in the pathology report regardless of the clinician's presumed familiarity with the pathology. Valuable information may be lost because the pathologist and the surgeon miscommunicate. Every experienced surgeon and every experienced pathologist can recall small miscommunications that delayed treatment or reassurance of the patient. The examples below are real events or based on real events that occur with alarming frequency. The best way to avoid these and other communications errors is clear and complete communication and not just imparting news. Example 1 A surgeon is operating on the oral mucosa to treat a tongue carcinoma. During surgery, she sees a 1.2-cm pigmented lesion on the buccal mucosa that causes concern. She obtains a sample and sends it to the pathologist for frozen sectioning. The requisition accompanying the sample states, "Patient with malignancy, rule out melanoma." The pathologist reviews the slides and sees an amalgam tattoo; that is, a benign, incidental, and clinically unimportant pigmented lesion that forms around dental amalgam. About 15 minutes later, the pathology report to the surgeon states, "No evidence of melanotic neoplasm." The surgeon was unfamiliar with amalgam tattoos; therefore, she did not consider this possibility when she sampled the lesion. Confused by the blue-black, irregular, and large lesion, she assumed that the lesion was missed during biopsy. She repeats the biopsy and receives the same report. In disbelief, the surgeon left the operating room and went to the pathology laboratory to review the slide with the pathologist. Only then, 45 minutes after the start of the procedure, did a 20-second discussion with the pathologist resolve the situation. The surgeon was then return to the original operation. The breakdown in communication was the clear cause of the preventable delay. The surgeon was really asking, "What is this dark, ugly lesion, and should I be concerned?" However, the pathologist thought, "The surgeon knows a malignancy is present. Does this sample represent the melanoma, or does she have to keep taking biopsy samples to define the borders of the malignancy until she finds its center?"

Example 2 A surgeon sees a 3.0-cm, ulcerated lesion on the buccal mucosa of a 50-year-old man. It is in an area, the linea alba, that frequently has dental trauma. The surgeon obtains a biopsy sample from the area and sends the specimen with a requisition stating, "Ulcerated lesion along bite line; rule out malignancy." On the slides, the pathologist sees an ulcer, marked acute and chronic inflammation, and scant peripheral epithelium. The pathologist sends a report stating, "Ulcer, acute and chronic inflammation, and scant squamous epithelium with mild atypia, probably benign reactive change. No evidence of malignancy." The surgeon's secretary informs the patient that immediate followup is not needed and that the patient can go on the 4-month vacation he had planned. The patient leaves on vacation but returns 1 month early and immediately goes to the surgeon, because the lesion is enlarged and painful, and a neck mass is probably present. The surgeon performs a repeat biopsy of the lesion. The pathology report now states, "Squamous cell carcinoma, moderately differentiated, invasive, keratinizing." Once again, the problem was miscommunication. Despite the requisition, the surgeon's real question was, "Should I be concerned at all about this or simply follow it at a later date?" However, the pathologist read, "Does this biopsy contain definite cancer?" In this case, the problem is a bit more complicated than that in the first example. The pathologist was definitely correct in what was seen and reported. However, the statement, "No evidence of malignancy," misleads the surgeon into thinking, "Do not worry about this. This is probably a bite-induced lesion." What is misleading is that ulceration and acute and chronic inflammation are evidence of malignancy. However, they are nonspecific findings that can be seen in trauma and certain vasculitic conditions as well as malignancy. Example 3 At 1 AM, a 60-year-old man presents to the emergency department with uncontrolled esophageal hemorrhage. Emergency esophagectomy is considered. A biopsy specimen of the esophagus is sent to pathology with the question, "Malignancy?" The pathologist comes in from home and by 2 AM is reviewing the slides, which demonstrate bizarre cells that meet the criteria of a poorly differentiated malignancy. A peculiarity in the vascular walls strikes the pathologist as interesting and provokes a call to the surgeon with the question, "Has this patient ever received radiation in this area?"

The surgeon tells the pathologist "Yes, for previous malignancy 10 years ago." The somewhat angry pathologist replies, "Why didn't you tell me this? I was about to call this a sarcoma, but these are radiationrelated fibroblasts! No malignancy is present." The surgeon later apologized and explained, "I didn't want to give you too much information and prejudice you." The key is imparting all the news that is necessary to treat this patient. This requires an active participation of both parties, not the black box approach to pathology, an unfortunately too common occurrence. This is the term pathologists use for the one question to the pathologist and one answer back to the surgeon scenario. Questions to ask The age-old expression "I am responsible for what I say. I am not responsible for what you hear" is not acceptable in interactions between the surgeon and the pathologist. An appropriate expression is, "I am responsible for the other physician's understanding of what I mean to say." To actively participate, the pathologist should ask himself or herself the following questions: What is the surgeon really asking me? What is prompting this question? That is, what observation led to this question? What information is essential for optimal treatment of this patient? Did I make myself clear enough for the surgeon to understand exactly what he or she needs to know? To actively participate, the surgeon should ask himself or herself the following questions: Am I giving the pathologist all the information he or she needs to answer my specific questions? Might I be misunderstood? How can I make myself clear? Am I (tactfully) reminding the pathologist what information I need? Is the information from the pathologist consistent with the clinical findings? Proceed to Treatment & Management

Most squamous cell carcinomas (SCCs) are readily treated in the physician's office by surgical or destructive methods, with a high expectation of cure. The treatment of these tumors must take into account multiple patient- and lesion-specific factors. Because SCC is a lesion that can recur, metastasize, and cause death, and, because recurrent disease carries a worse prognosis, every opportunity

Approach Considerations

should be taken to effect complete tumor extirpation at first presentation. Factors that influence choice and type of treatment are the site and stage of the primary tumor. The tumor, node, metastasis (TNM) staging system used for head and neck cancers is a clinical staging system that allows physicians to compare results across patients, assess prognosis, and design appropriate treatment regimens. The same system is employed for laryngeal tumors. The basic premise of these systems is that smaller cancers with no nodal disease have a better prognosis than a larger lesion with positive neck nodes. Depth of infiltration is predictive of prognosis. With increasing depth of invasion of the primary tumor, the risk of nodal metastasis increases and survival decreases. See SCC Staging and Classification under Clinical Presentation. See the following for more information: Sentinel Lymph Node Biopsy for Squamous Cell Carcinoma Urogenital Squamous Cell Carcinoma Imaging of Nasopharyngeal and Laryngeal Squamous Cell Carcinoma Cell Biology of Head and Neck Squamous Cell Carcinoma Targeted Molecular Therapy in Head and Neck Squamous Cell Carcinoma. Mohs Micrographic Surgery Mohs Surgery High-risk SCC The use of electrodessication and curettage (ED&C) in the treatment of high-risk SCC (see Electrodessication and Curettage), particularly in immunocompromised individuals, is best avoided, because histologic margin status cannot be evaluated. Clear margins must be obtained for optimal outcomes. Ensuring clear surgical margins wherever possible is highly recommended. A systematic review of available data for high-risk SCC compared cases with clear surgical margins versus those in which margins were not specified and demonstrated statistically better outcomes in cases in which clear margins were documented, with risks of local recurrence, regional metastasis, distant metastasis, and disease-specific death of 5%, 5%, 1%, and 1%, respectively, in clear-margin cases, compared with 8%, 14%, 7%, and 7% in cases with undocumented margins.[97] A prospective study identified several risk factors for incomplete excision of SCC, namely, ear lesions, invasive lesions, and previously incompletely excised lesions referred for reexcision. The study also recommended more care with tumor markings, taking margins of at least 5 mm, deeper margins, and referring such lesions to centers with personnel who have more experience.[98]

No controlled comparative studies of Mohs micrographic surgery versus excision in high-risk SCC have been performed, but case series data suggest that Mohs is superior to excision for these tumors.[99] No comparative studies of surgery versus surgery plus adjuvant radiotherapy for high-risk SCC have been performed. With no clear evidence of benefit and the potential of significant morbidity, clinical judgment is required in deciding which patients should receive adjuvant radiation. One systematic review of available outcome data suggests that adjuvant radiation be considered in patients with uncertain or positive surgical margins or advanced nerve involvement (eg, involvement of named nerves, nerves 0.1 mm or larger in diameter, or with clinical or radiologic evidence of nerve invasion).[97] Adjuvant medication may also be considered in select highest-risk cases. Options include oral 5-fluorouracil (5-FU) (Xeloda) and epidermal growth factor receptor (EGFR) inhibitors via oncology treatment centers. Although survival data are lacking, these medications are generally well tolerated with few adverse effects. The results of one study found that the use of 5-FU 1% is effective as an adjuvant to surgical excision in treating patients with localized ocular surface squamous neoplasia (OSSN). Although frequent shortterm complications were noted, a low rate of local recurrence was found; a full course is usually tolerated, and serious complications were uncommon.[100] See Overview of Nonsurgical Management.

Overview of Nonsurgical Management

Nonsurgical options for the treatment of cutaneous squamous cell carcinoma (SCC) include the following: Topical chemotherapy Topical immune response modifiers Photodynamic therapy (PDT) Radiotherapy Systemic chemotherapy Reduction in immunosuppression Cryotherapy Low-grade SCCs and well-differentiated lesions, such as actinic keratosis, keratoacanthoma, and Bowen disease (SCC in situ [SCCIS]), may be managed with medical therapies. No topical treatment is available for treatment of SCC; the use of topical therapy and PDT is generally limited to premalignant (ie, actinic keratoses) and in situ lesions. Radiation therapy is a primary treatment option for patients in whom surgery is not feasible and is an adjuvant therapy for those with metastatic or high-risk cutaneous SCC. In current practice, systemic chemotherapy is used exclusively for patients with metastatic

disease. However, newer, more targeted drugs, such as epidermal growth factor receptor (EGFR) antagonists (eg, cetuximab), have favorable adverse effect profiles and await trials to determine if they are beneficial in high-risk SCC. Precancerous Lesions Several effective treatment modalities exist for precancerous skin lesions, including carcinoma in situ (CIS) and actinic keratosis. Most of these treatments are easily performed in an outpatient setting. Topical application of 5-fluorouracil (5-FU) (Efudex) or imiquimod is effective in treating precancerous lesions of the head and neck. Similarly, the application of liquid nitrogen cryotherapy or electrocautery and curettage is used, with cure rates reported at greater than 95%. Although efficacious in the treatment of CIS and actinic keratoses, these methods should not be used on confirmed or suspected invasive cutaneous SCC, because they fail to provide a diagnostic tissue sample or a way to assess the adequacy of treatment. For confirmed or suspected cutaneous SCC, surgical excision with microscopic assessment of tissue margins is the treatment of choice. Many patients with a history of extensive sun exposure and light skin develop epidermal atypia in the form of actinic keratosis and SCCIS over large areas of their skin. Most of these patients also develop multiple invasive SCCs. The management of such patients is highly labor intensive and involves the following steps: Surgically remove all tumors that clinically appear to have to have an invasive (dermal) component and confirm clearance of histologic margins. Evaluate for underlying immunosuppression, such as from chronic lymphocytic leukemia or an overly impaired immune system from immunosuppressive or immunomodulatory therapy. If this is suspected, discuss with the patients other doctors whether the immunosuppression can be safely remedied or lessened. Perform field treatment of the areas of epidermal atypia. Treatment options include topical chemotherapy with 5-FU or PDT. Imiquimod has limited utility in diffuse disease because adverse effects increase when applied to large surface areas. If 5-FU therapy is planned, remove any hyperkeratotic lesions with a curette just before beginning therapy to enhance penetration of the medication to the basal layer. A full course of 5-FU therapy is twice-daily administration for 4 weeks. Patients who cannot tolerate this duration may try shorter courses and then resume treatment after a healing phase. Subsequent treatments become more tolerable as the epidermal damage is corrected. Follow the patient closely for recurrence of actinic keratosis/SCCIS and for new invasive SCCs. Field treatment may need to be repeated every 6-12 months to keep precursor actinic keratosis and SCCIS lesions to a minimum.

Oral retinoids in the form of low-dose acitretin can decrease new cancer formation, but they do not generally alter the course of existing tumors.[101] Although most patients do not require retinoids if the above measures are taken, patients who are still developing multiple cancers 6-12 months after beginning an intensive program to clear disease may benefit from retinoid therapy. Once the desired effect is achieved, considering a dose reduction of long-term maintenance therapy rather than discontinuing therapy is better, because the latter typically leads to a rebound of multiple SCC formation. Conjunctival intraepithelial neoplasia Topical cytotoxic therapy (ie, 5-fluorouracil [5-FU], mitomycin C [MMC]) has been used to treat conjunctival intraepithelial neoplasia and to debulk large carcinomas before surgical excision. Orbital invasion may be observed despite topical therapy, however, and careful monitoring of patients on these agents is warranted.[102, 103] Despite its significant potential deleterious effects on limbal stem cells, mitomycin C 0.04% is effective as a neoadjuvant agent or postoperative agent in the treatment of CIN and primary acquired melanosis. Its utility is less well proven for truly invasive tumors such as melanoma and carcinoma.[104]

Topical Chemotherapy
Topical formulations of 5-fluorouracil (5-FU) are available for the treatment of actinic keratoses and superficial basal cell carcinomas (BCCs). Successful treatment of in situ squamous cell carcinoma (SCCIS) has also been reported.[105] Invasive SCC should not be treated with topical chemotherapy. A month-long course of daily topical 5-fluorouracil (5-FU) can successfully improve skin areas with severe diffuse actinic damage and clusters of actinic keratoses. However, even if newer, lowconcentration 5-FU cream is used (0.5% vs previously available 5% concentration), significant discomfort and irritation are inevitable and residual erythema at the site of application may persist for months. An oral form of a 5-FU prodrug (capecitabine), which is approved by the US Food and Drug Administration (FDA) for other forms of cancer, may be considered in patients with diffuse SCCIS over large skin areas, on which topical 5-FU is difficult to apply. However, studies of efficacy have not yet been performed. Topical diclofenac sodium gel has been approved for the treatment of actinic keratoses. Twice-daily applications for 60-90 days may similarly clear actinic damage, with the longer course potentially offset by a lesser degree of cutaneous irritation. Success is difficult to measure when treatment of actinic damage is attempted with

topical medications, because biopsies are rarely performed before and after treatment (ie, to compare results). Instead, improved skin appearance is used as a gauge for apparent resolution of early SCCIS lesions.

Topical Immune Response Modifiers

Imiquimod is an imidazoquinoline that enhances cell-mediated immune responses via the induction of proinflammatory cytokines; that is, it up-regulates interferon and other cytokines. This agent is approved by the US Food and Drug Administration (FDA) for the treatment of genital warts (ie, condylomata acuminata), actinic keratoses, and superficial basal cell carcinoma (BCC). Imiquimod cream has also shown effectiveness in the treatment of Bowen disease as monotherapy and in combination with topical 5fluorouracil (5-FU).[106] However, systemic flulike symptoms and other adverse effects can occur when applied to large surface areas; therefore, using this agent in patients with diffuse in situ squamous cell carcinoma is difficult.[107, 108] Case reports document success in the treatment of squamous cell carcinoma in situ (SCCIS) of the glans penis and perianal region. This modality seems particularly reasonable for genital SCC, because of the association of SCC in this area with human papillomavirus (HPV) infection, against which imiquimod is known to have therapeutic activity. Imiquimod treatment 3 times per week for 4-6 weeks appears to be effective in the treatment of actinic cheilitis. Local adverse reactions during treatment include increased erythema, induration, and erosions or ulcerations. Studies continue to confirm the effectiveness of imiquimod for clearing actinic keratoses. Overall, imiquimod may be most effective for treating actinic keratoses and borderline SCCIS rather than invasive SCC. Some practitioners are concerned that the ease of use of this therapy may result in enthusiastic overprescription for lesions that are not clearly superficial; the result may be inadequate treatment of primary invasive SCC, which may lead to the preventable morbidities of recurrence or metastasis.

Photodynamic Therapy
Treatment with photodynamic therapy (PDT) uses a photosensitizing drug, light, and oxygen to induce targeted cell death of neoplastic or abnormal tissue. Specifically, sensitization of the target tissue is selective and occurs through the topically or systemically administered photosensitizing agent. The resulting photochemical reaction causes inflammation and destruction of the targeted lesion(s) via highly reactive oxygen intermediates and free radicals. PDT is used primarily to treat large numbers of actinic keratoses in a single session. Squamous cell carcinoma in situ (SCCIS) is also

amenable to PDT, although a wide range of recurrence rates (0-52%) have been reported. A study of organ transplant recipients with multiple actinic keratoses and field actinic damage showed PDT to be superior to topical 5fluorouracil (5-FU).[109] A 2009 noncomparative study showed repeated cycles of PDT to be associated with significant reduction in SCC formation in organ transplant recipients.[110] At this time, PDT is not recommended for treatment of invasive disease due to poor long-term cure rates.[111] The introduction of a new photosensitizing prodrug, 5-aminolevulinic acid (ALA), is a novel approach for the induction of photosensitization, because ALA penetrates the stratum corneum to reach the deep stroma of skin tumors, where it is transformed into the highly photoactive endogenous protoporphyrin IX. This agent can also be used for patients with discrete eyelid lesions who are unable or unwilling to undergo an extensive surgical excision of the lesion.[13, 112] One of the most successful indications for ALA-PDT in dermatology is the treatment of actinic keratosis. A number of studies report response rates of 71-100% for facial actinic keratoses after a single treatment. Various noncoherent and coherent light sources have been used, with wavelengths ranging from 417 to 630 nm and light doses and dose rates ranging from 10 to 540 J/cm 2 and 10 to 300 mW/cm2, respectively. Most studies of ALA-PDT for actinic keratosis are limited by a lack of histologic confirmation, and they have short follow-up periods (3-20 mo). Nonfacial hyperkeratotic lesions respond poorly to ALA-based PDT and have weighted clearance rates of 44%, compared with 91% clearance rates for facial lesions. Response rates to ALA-PDT appear to be comparable to those associated with topical 5-FU and cryotherapy. Lesions not completely resolved after PDT may be treated a second time after 8 weeks. Patients should avoid excessive sun exposure before, during, and after treatment. Thus far, the procedural complexity and posttreatment photosensitivity associated with PDT have limited its popularity among physicians and patients. Indeed, although recent medical literature is replete with reports and trials of PDT used for the treatment of actinic keratosis and Bowen disease, the inevitable bias in favor of new technology should not obscure the fact that this treatment is currently used for only a very small minority of patients. In 2007, Brewster et al reported the results of a randomized trial of adjuvant 13-cis -retinoic acid (13-CRA) and interferon-alpha for patients with aggressive skin SCC.[113] Their results did not show a benefit from this treatment.

Braathen et al have set forth guidelines for the use of PDT to treat SCCIS.[114]

Radiation Therapy
Radiation therapy as a primary form of treatment is typically reserved for patients who are unable to undergo surgical excision. More frequently, radiation therapy is used as an adjuvant to surgery for improved locoregional control. Postoperative radiotherapy is considered for tumors that exhibit perineural invasion or other highrisk features and for those that involve regional metastasis. Primary radiation therapy as a treatment option for squamous cell carcinoma (SCC) offers the potential advantage of avoiding the deformity and trauma of a surgical procedure.[115] Cure rates for T1 lesions range from 85% to 95%. However, a number of disadvantages are associated with radiation therapy. For example, radiation therapy is expensive and requires a significant time commitment, because treatments are usually given 3-5 times per week for 4-8 weeks (eg, over 15-20 sessions, so-called fractionations of total dosages). Most patients experience significant irritation at the radiation site, and they frequently develop erythema, erosions, alopecia, and pain, which may require narcotic-level analgesia. In addition, although the initial cosmetic result following radiation is usually good, the long-term outcome is often poor, owing to the development of cutaneous atrophy, dyspigmentation, and telangiectasia in the radiation field. Patients treated with radiation also have a slightly increased risk of developing cutaneous carcinoma (most commonly SCC, 15-20 years after the initial treatment) or sarcoma later in life. Radiation therapy does not involve histologic margin control and has a lower cure rate compared with surgery. For these reasons, as well as those discussed above, radiation as a primary therapy is usually confined to a small subset of tumors in which the cosmetic or functional outcome would be superior to that of surgery [116] or in elderly patients with inoperable SCC. In contrast, radiation is routinely used as an adjunct to surgical treatment in cases of nodal metastasis, and the reported 5-year cure rate is 73% for combined surgical and radiation therapy to involved nodal basins.[62] Nearly all patients with advanced disease require adjuvant radiotherapy, preoperatively or postoperatively. Preoperative radiotherapy has the risk of increased complications of surgery. Radiation dosage in excess of 6000 cGy is recommended with a boost to areas of high risk. Indications for radiotherapy include a bulky tumor with significant risk of recurrence (T3 and T4), histologically positive margins, and perineural or perivascular invasion of tumor. SCCs with advanced perineural invasion have an elevated risk of recurrence, even when

surgical margins are thought to be clear.[60, 63, 73] Thus, adjuvant radiation may be considered, particularly in cases involving larger nerves, although its utility has yet to be proven. Until recently, the nasopharynx was regarded as an unapproachable surgical area, and therapy consisted of irradiation alone. In each case, treatment is individualized, and chemotherapy is occasionally used in addition to irradiation. The response to irradiation and, therefore, the prognosis of patients with nasopharyngeal carcinoma is strongly related to the category. Keratinizing SCC responds poorly to irradiation, and the overall 5-year survival rate is approximately 15%. The 5-year survival rate for nonkeratinizing carcinoma of the nasopharynx, which responds to irradiation therapy, is approximately 60%. Approaching this tumor by surgical means has been a topic of recent interest. For the neck, indications for radiotherapy include elective treatment of the N0 neck not treated surgically where risk of micrometastasis is high, gross residual tumor in the neck following neck dissection, multiple positive lymph nodes, and extranodal extension of tumor. A systematic review analyzing all reports related to outcomes of high-risk SCC treated with surgical monotherapy compared with those treated with surgery plus adjuvant radiation was unable to show an advantage of adjuvant radiation in the treatment of squamous cell carcinoma with perineural invasion.[97] However, the available studies were uncontrolled for tumor stage and more advanced tumors with a worse baseline prognosis likely received radiation. In summary, the additional benefit of adjuvant radiotherapy is uncertain, especially when clear surgical margins are obtained. However, it may be considered in patients with multiple high-risk factors, those with significant nerve involvement (particularly named nerves or nerves >0.1 mm in diameter), those with uncertain surgical margins (eg, poorly differentiated, infiltrative, or multiply recurrent tumors), or as salvage therapy for in-transit metastasis or other tumors which cannot be cleared surgically. A lower threshold for adjuvant radiation should be used in immunocompromised patients with high-risk SCC.[97]

Systemic Chemotherapy
A variety of different chemotherapeutic agents have been used to treat metastatic cutaneous squamous cell carcinoma (SCC). Adaptation of traditional chemotherapeutics to local and regional administration techniques in treating head and neck cancers is being actively pursued to provide higher local concentrations of otherwise systemically toxic drugs. Bleomycin with or without electroporation has been used.

Cisplatin is another chemotherapeutic drug of choice for head and neck cancers. Although this agent is one of the most successful in the treatment of cancer, it produces major toxicities to normal cells and organs at the concentrations necessary for effective treatment of malignancies. Combination chemoradiotherapy with cisplatin and concurrent radiation therapy has improved locoregional control in locally advanced SCC. Chemoradiotherapy is now considered the standard of care in locally advanced disease following surgical resection and in unresectable disease. Cisplatin-based combination chemotherapy with 5-fluorouracil (5-FU), methotrexate, bleomycin, and doxorubicin have all been used to treat advanced SCC with variable outcomes. A combination of cisplatin with interstitial laser therapy has also been reported. Hyperthermia produced by the laser is known to augment the cytotoxic effects of both radiation therapy and some chemotherapy drugs. Temperatures above 38C enhance cisplatin therapy. The oral 5-FU prodrug, capecitabine (Xeloda), has been designed to be metabolized to 5-FU selectively within tumor tissues, thus producing less systemic toxicity. Used either alone or in combination with interferon alfa, it has shown some efficacy in the treatment of advanced cutaneous SCC.[117] Cetuximab, a chimeric immunoglobulin G1 monoclonal antibody that inhibits epidermal growth factor receptor (EGFR), has had reported as successful in several case reports.[118, 119, 120] In the head and neck literature, phase I and II trials of capecitabine, used with cisplatin or paclitaxel[121, 122] or in combination with radiation therapy[123] also showed favorable outcomes. EGFR inhibitors are well tolerated with relatively low risks, so they may be considered in cases not amenable to surgery or radiation or as an adjuvant in cases considered to have a high risk of death. Current recommendations are to use cetuximab as an alternative to chemotherapy in patients who cannot tolerate chemotherapy.[124] See Targeted therapy under Future Directions in the Treatment of SCC.

Reduction in Immunosuppression
In organ transplant recipients, a reduction in the magnitude of immunosuppression may be an effective adjuvant therapeutic strategy in the treatment of aggressive squamous cell carcinoma (SCC). Because a decrease in immunosuppression may increase the risk for rejection of the transplanted organ, this strategy should only be considered in selected high-risk patients and under the careful management of the transplantation physician, who must closely monitor the patient for signs and symptoms of organ rejection. [125]

Newer immunosuppressive agents (eg, sirolimus) are associated with a lower incidence of SCC when compared with more traditional agents (eg, calcineurin inhibitors), without compromise in graft function.[126, 127] Patients on sirolimus also produce thinner, less vascularized tumors,[128] likely due to the drugs antiangiogenic and antitumor properties. In a study of 182 organ transplant recipients, the mean cumulative doses of prednisone, cyclosporine, azathioprine, and mycophenolate were significantly higher in those with skin cancer. Conversely, the cumulative doses of sirolimus and tacrolimus were significantly lower in those with skin cancer, suggesting that these drugs may be protective.

Cryotherapy
Cryotherapy uses liquid nitrogen to cool small squamous cell carcinomas (SCCs) to tumoricidal temperatures. This is a safe and low-cost procedure for the ablation of selected in situ squamous cell carcinomas (SCCISs), and it is judged especially useful in patients with bleeding disorders and in those who refuse surgery, are poor surgical candidates, or for whom surgery is contraindicated. The 5-year cure rate for (SCC) can be 95% or greater with proper tumor selection and technique. Graham and Clark reported a cure rate of 97.3% for 563 primary SCCs, the majority of which were 0.51.2 cm in diameter.[129] Recurrences generally become evident within 2 years. In the United States, cryosurgery is routinely used for in situ disease and actinic keratoses. It is not often used for invasive SCC, because deeper portions of the tumor may not be eradicated by this technique and because the development of scar tissue at the site of cryotherapy might obscure a recurrence. The risks associated with cryotherapy include transient pain, edema, and blistering. Hypopigmentation and alopecia are also common and may be permanent, so treatment of hair-bearing areas and in darkly pigmented individuals is generally not recommended. [130]

Overview of Surgical Intervention

Surgical resection remains the criterion standard for treatment of head and neck cancer. Management of all but the earliest confirmed neck metastases is best achieved with surgical removal. The literature reports radiation therapy for patients with N0 or N1 necks and concludes that radiation or surgery can treat them equally well. Because patients with cancers of the head and neck often have had previous radiation therapy, flaps must have an adequate blood supply. Guidelines of care have been developed for the management of cutaneous squamous cell carcinoma (SCC). Surgical approaches include the following:

Electrodessication and curettage (ED&C)/curettage and electrosurgery This procedure is deemed less effective for recurrent lesions or those that invade the subcutis. Excision, described as useful in both primary and recurrent tumors, the margins of which can be verified by pathology Mohs micrographic surgery, for recurrent tumors and primary lesions displaying 1 or more factors associated with biologic aggressiveness Laser surgery, which may be used for excision or destruction and may have the added benefit of ensuring hemostasis Surgery is the preferred method of treatment for the following tumors, including select SCC variants: Conjunctival SCC - Unfortunately, recurrence rates as high as 50% are common for incompletely excised tumors. Secondary orbital invasion - Orbital exenteration is preferred. [67] Spindle cell carcinoma, where anatomically feasible - Despite its odd appearance, the behavior of this tumor is about the same as that of conventional SCC of the same stage. Verrucous carcinoma - Interest in chemotherapy and radiotherapy to treat this lesion increases from time to time. Basaloid SCCs Unfortunately, the 2-year mortality rate is still 3040%. Papillary SCC, with free margins - This is true for both the in situ and the invasive types. All 3 grades of mucoepidermoid tumors See below. Low- and intermediate-grade mucoepidermoid lesions are initially treated more conservatively than are high-grade mucoepidermoid tumors, but margins are still made wide enough to ensure reasonable success in complete resection. Neck dissection is not necessary if the lesion is low or intermediate grade, unless clinical or pathologic findings are highly suggestive of metastases to the regional nodes. On respective review, this situation includes fixed, firm, and enlarged neck nodes or unequivocal lymphatic invasion by the main tumor. Many advocate postoperative radiation therapy, particularly for intermediate- or high-grade tumors. High-grade mucoepidermoid tumors are initially treated with surgery; however, wide resection usually includes margins that are more generous than those obtained with lower-grade lesions, because these tumors frequently extend deeper than what their clinical appearance might suggest, even when observed during surgical examination under anesthesia. Therefore, removal of the facial nerve is likely necessary with high-grade parotid-based lesions. In addition, because of the increased rate of metastatic disease with high-grade mucoepidermoid tumors, neck dissections are frequently included in the surgical procedure. Finally, postoperative radiation is usually given to the tumor bed in cases of high-grade mucoepidermoid tumors.

Until recently, the nasopharynx was regarded as an unapproachable surgical area, and therapy consisted of irradiation alone. However, using a surgical approach has been a topic of recent interest. Conjunctival SCC Excisional biopsy is the treatment of choice for conjunctival SCC. For extremely large lesions, incisional biopsy may be performed; however, strict notation of the biopsy site and minimal handling of the surrounding tissues is imperative to prevent seeding of the tumor. Surgical excision is best performed under the operating microscope.[131] Removal of a cuff of normal conjunctival tissue surrounding the lesion is prudent, and an episclerectomy at the base of the lesion is also advisable if it is adherent to the sclera in order to remove any superficial cells infiltrating the sclera. Involved corneal tissues may be best removed following treatment with 100% ethanol. The tissues superficial to the Bowman layer are removed easily in a single sheet and sent to the laboratory for analysis. Care should be taken not to incise into the Bowman membrane. Cryotherapy is performed, in a double freeze-thaw manner, to the edges of the uninvolved conjunctiva and Tenon capsule. It also can be applied to the involved limbal area. The exposed sclera occasionally is treated with 100% ethanol to devitalize any remaining tumor cells. All excised tissues are submitted for histopathologic analysis. Reconstruction is performed with direct closure, local flaps, or free conjunctival grafts. Extensive lesions with orbital involvement require exenteration. Radiation therapy may be used as adjunctive therapy in cases of extensive lesions with poorly defined margins and as palliative therapy in cases where the patient cannot tolerate extensive surgery. Invasive SCC Primary surgical excision and Mohs micrographic surgery are the 2 primary treatment options for invasive cutaneous SCC. With appropriate patient selection, these techniques have comparable cure rates. Mohs surgery was developed by Frederic E. Mohs in the 1930s and is a method of tumor excision in which the surgeon first excises the visible tumor with a small margin of normal tissue. Horizontal frozen sections are then prepared, and the entire margin is evaluated under the microscope. Areas that demonstrate residual microscopic tumor involvement are reexcised, and the margins are reexamined. This cycle is completed until no further tumor is visualized.

This technique has a high reported cure rate for early stage cutaneous SCC and is considered ideal for removing small lesions on the face. However, Mohs surgery is time consuming and highly dependent on technique. Mohs surgery is ill suited for large, aggressive, or recurrent cutaneous SCC, in which the risk of recurrence or regional metastasis is high (see image below). In these cases, en bloc surgical excision is the standard method of treatment.
Large, neglected cutaneous squamous cell carcinoma (cSCC) of the right ear that requires wide local excision via auriculectomy and reconstruction. The risk of lymph node metastasis with this deeply ulcerative tumor is sufficient enough to warrant elective neck dissection.

Unlike melanoma, no large randomized studies have addressed the issue of appropriate margin size in cutaneous SCC. Margins of 4 mm and 6 mm have been suggested for lesions less than and greater than 2 cm, respectively, providing a clearance rate of 95% or greater. However, these should be taken only as rough guidelines with the understanding that large, aggressive lesions frequently have substantial extension beyond the apparent superficial boundary. Therefore, surgeon experience and judgment in planning surgical margins is paramount to the successful treatment of cutaneous SCC. For patients at risk for metastatic spread to lymph nodes, the standard treatment is surgical excision of the primary lesion along with the involved lymph node basins. Skin cancers located in the periauricular region, frontotemporal scalp, and mid face often drain via lymph nodes in the parotid gland. Consequently, the parotid is the most frequently involved site of metastatic spread. In cases that involve parotid involvement, a parotidectomy with or without a simultaneous neck dissection is the procedure of choice.

Electrodessication and Curettage

Electrodessication and curettage (ED&C) is a simple technique that can be used to treat low-risk squamous cell carcinoma (SCC) on the trunk and extremities. This procedure destroys the tumor and a surrounding margin of clinically unaffected tissue via cauterization and scraping of the area with a curette. The process is repeated several times to maximize the probability of complete tumor extirpation. The tumor indications are similar to those of cryotherapy (see Cryotherapy). In addition, ED&C can be used to treat superficially invasive SCCs without high-risk characteristics. However, the thick scars that often occur after ED&C can delay the diagnosis of cancer recurrence. Subsequently, ED&C should be used with caution in invasive SCC. It is not appropriate for certain anatomic locations (ie, eyelids, genitalia, lips, ears).

The technique is based on the delineation of tumor margins with a curette, because tumor tissue is generally more friable than the surrounding normal tissue. ED&C is known to be very technique dependent, and cure rates improve with a practitioner's experience. The main disadvantage of ED&C is that no specimen is available for margin evaluation, and most dermatologic surgeons believe the actual long-term cure rate for invasive SCC is much lower than that quoted in the literature. Nevertheless, the 5-year cure rates for small primary SCC may be as high as 96%. Cure rates for high-risk tumors are much lower, although no well-controlled prospective studies have been performed. Tumor recurrence may result from failure of ED&C treatment to eradicate atypical cells residing deep in the hair follicles or in the dermis. Studies of subjects with Bowen disease treated with only curettage reveal a 10-40% rate of recurrence. Nonetheless, the procedure is fast, minimally invasive, well tolerated, and effective for properly selected lesions.

Excision With Conventional Margins

Standard excision with conventional permanent (ie, paraffinembedded) tissue sections is an excellent, highly effective, and welltolerated therapy for primary squamous cell carcinomas (SCCs) that lack high-risk features and are located in areas where tissue sparing is not critical. Surgical excision offers the advantages of histologic verification of tumor margins, rapid healing, and improved cosmesis. Cure rates following simple excision of well-defined T1 lesions may be as high as 95-99%. The generally accepted 5-year cure rate for primary tumors treated with standard excision is 92%; this rate drops to 77% for recurrent SCC. A 4-mm margin of healthy tissue is recommended for lower-risk lesions (< 2 cm, well-differentiated, without subcutaneous fat invasion) on the trunk and extremities. For lesions larger than 2 cm, invasive to fat, and in high-risk locations (ie, central face, ears, scalp, genitalia, hands, feet), a 6-mm margin of healthy tissue is recommended. Given the cosmetic and functional impact of these wider margins, tumors in this latter category are often removed via Mohs surgery to achieve high cure rates while sparing normal tissue. The depth of an excision should always include a portion of the subcutaneous fat. Disadvantages of excision include the risks of hematoma, seroma, infection, and wound dehiscence. One pitfall of standard excision is that histologic margins can be reported to be negative when they are, in fact, positive (false negative), because the traditional breadloaf method of tissue sectioning typically results in evaluation of less than 1% of the specimens margins. For this reason, cure rates for SCC following excision do not significantly differ from cure rates following electrodessication and curettage (ED&C). Moreover,

excision may even be somewhat less efficacious, with aggregate 5year cure rates of only 92% for primary SCC. More commonly, a greater amount of healthy tissue is removed than is necessary for complete tumor extirpation. To achieve a 95% clearance rate, a 4-mm margin around the clinical borders of the lesion has been recommended for well-differentiated tumors smaller than 2 cm in diameter not occurring on the scalp, ears, eyelids, lips, or nose and not involving subcutaneous fat. Therefore, simple excision is most valuable in the treatment of small primary SCCs on the trunk, extremities, or neck, where tissue sparing is less essential.[132] Recurrence rates after the excision of low-risk lesions range from 5-8%. For tumors in high-risk sites or those larger than 2 cm, a 6-mm margin is recommended. However, individuals with high-risk tumors have an increased risk of recurrence, with tumors larger than 2 cm recurring at a rate of 15.7% after excision and tumors smaller than 2 cm recurring at a rate of 5.8%. Poorly differentiated lesions recur at a rate of 25% after excision, as opposed to well-differentiated lesions, which recur at a rate of 11.8%.

Neck Dissection
Lymphatic metastasis is the most important mechanism in the spread of head and neck SCCs. The rate of metastasis probably reflects the aggressiveness of the primary tumor and is an important prognostic indicator. Regardless of the site of the primary tumor, the presence of a single lymph node in either the ipsilateral or contralateral side of the neck reduces the 5-year survival rate by 50%. Modified neck dissection Modified neck dissection is designed to preserve the spinal accessory nerve, the great auricular, and the sternocleidomastoid muscle. The jugular vein and submandibular gland also have been preserved. In addition, successful results can be achieved through less than complete lymph node removal, selectively removing only those lymph node levels likely to be involved by metastases. Modified radical neck dissection removes all 5 lymph node levels, preserving one or all of the spinal accessory nerves, jugular vein, and sternocleidomastoid muscle. Selective dissection removes either levels 1, 2, and 3 (supraomohyoid neck dissection); levels 2, 3, and 4 (anterior neck dissection); or levels 2, 3, 4 and 5 (anterolateral neck dissection). Modified and selective neck dissections clearly have been demonstrated as oncologically equal to the radical neck dissection in treating N0 neck disease. However, when there is one positive node, the likelihood of another positive node in an unexpected location increases significantly. For this reason, selective neck dissection is

usually limited to patients without pathologically involved lymph nodes on the side of the dissection. Classic radical neck dissection Classic radical neck dissection was described by Crile in 1901 and includes removal of all 5 levels of cervical lymph nodes en bloc down to the deep muscular fascia. This removal includes the sternocleidomastoid muscle, submandibular gland, jugular vein, and spinal accessory nerve. This operation remains the best procedure for definitive control of neck disease. Radical neck dissection can be combined with resection of the primary cancer and postoperative radiation therapy. Radical neck dissection has significant morbidity because of the resection of the spinal accessory nerve and, in bilateral dissection, the sacrifice of the internal jugular veins. Severing the spinal accessory nerve results in paralysis of the trapezius muscle in approximately 70% of patients. In most patients, the shoulder subsequently loses support, rotates forward, and droops, and the patient has pain and difficulty lifting his or her arm.

Mohs Micrographic Surgery

Mohs micrographic surgery (MMS) is a specialized technique for removing many forms of skin cancer, including squamous cell carcinoma (SCC). Because of its many advantages, Mohs micrographic surgery is the procedure of choice for SCC in which tissue preservation is needed, for ill-defined SCC, recurrent tumors, and for high-risk SCC. The main advantage of this procedure over simple excision is the ability to histologically examine nearly 100% of the surgical margins (as compared with < 1% of the margin visualized via standard histologic sectioning) and to carefully map residual foci of invasive carcinoma, making incomplete excision much less likely than with standard pathologic processing. This residual tumor is mapped before removal, removed in a step-wise fashion until clear margins are obtained, and the excised specimens are managed in a way that maintains orientation relative to the operative site. Consequently, Mohs surgery offers both microscopic margin control and tissue sparing, thus facilitating small, minimally disfiguring reconstructions of the resulting defects. Nail SCC Mohs micrographic surgery is the treatment of choice for nail unit SCC because of the technique's tissue-sparing properties and the concurrent need to limit damage to the nail matrix. This procedure may also be appropriate when the visible borders of SCC are indistinct or if they are masked by hypertrophic tissue (as in rhinophyma). Genital SCC, including disease of the penile shaft, is another potential indication for Mohs micrographic surgery.

Extensive or deep SCC In some cases, when tumor is very extensive or very deep, radical surgical procedures may be indicated. Primary or metastatic SCC deriving from chronic osteomyelitis is often amenable to Mohs micrographic surgery as a limb-sparing procedure, but certain cases may require limb amputation. Similarly, if SCC lesions invade deep into muscular, glandular, or bony structures or if they involve the viscera, this procedure may be relegated to obtaining clearance of peripheral skin margins, with other surgical techniques used to clear the deep margins. High-risk SCC After excision of massive or high-risk cutaneous SCC using Mohs micrographic surgery, some practitioners advise adjuvant radiotherapy, but this has not been shown to lengthen survival or decrease morbidity. Indeed, in the absence of any data supporting the efficacy of adjuvant radiotherapy for locally invasive disease, the associated morbidity from such radiotherapy may be in itself a contraindication. Some authorities have recommended sentinel lymphadenectomy in combination with Mohs micrographic surgery for the treatment of high-risk SCCs. As an experimental therapeutic intervention, sentinel lymphadenectomy may help identify regional metastases, which may later be extirpated in a timely manner. Cure rates for Mohs surgery Mohs micrographic surgery provides the best available cure rates (94-99%) for SCC. This procedure achieves a 5-year local cure rate of 96.9% for primary cutaneous SCCs at all sites except for the lips and ears, in contrast to a 5-year local cure rate of 92.1% for other modalities. Mohs reported a 5-year cure rate of 98.1% in 213 cases of eyelid SCCs that had been treated.[133] Wide local excision with frozen-section monitoring of margins may be performed when Mohs micrographical excision is not readily available.[67] Furthermore, Mohs surgery is associated with 5-year cure rates of 90-93.3% for recurrent SCC, in contrast to recurrence rates of 23.3% for recurrent tumors treated with standard excision. For SCCs associated with perineural invasion, Mohs offers a cure rate of approximately 90%, compared with a rate of only 50% for wide surgical excision. In a comprehensive historical review, Rowe et al noted that local recurrences are less frequent when SCC is treated with this procedure compared with all non-Mohs modalities.[3] This local recurrence rate differential in favor of Mohs micrographic surgery was observed in primary SCC of the skin and lip (3.1% vs 10.9%), for locally recurrent SCC (10% vs 23.3%), for poorly differentiated SCC

(32.6% vs 53.6%), and for SCC with perineural involvement (0% vs 47%). This technique offers the added benefit of preserving healthy tissue, thus facilitating reconstruction and optimizing cosmetic and functional outcomes. It is performed on a single operative day in an outpatient setting with local anesthesia and is therefore a safe and cost-effective procedure, even in very elderly patients with multiple morbidities.[134, 135] Mohs micrographic surgery is less expensive than surgical excision with anesthesia in a hospital setting.[134, 135] As a result of the fellowship training programs in Mohs surgery overseen by the American College of Mohs Surgery and the new Accreditation Council for Graduate Medical Education (ACGME) accredited Procedural Dermatology Fellowship programs, this technique has become widely available throughout the United States.[99, 136]

Laser Surgery
Laser surgery may be used for excision or destruction and may have the added benefit of ensuring hemostasis. This modality is most useful for the treatment of superficial skin cancers in sensitive locations. The cure rate is dependent on the depth of the squamous cell carcinoma (SCC).

Future Directions in the Treatment of SCC

This section will discuss experimental therapies such as photosensitizers and interstitial laser therapy and immune, gene, and targeted therapy. Photosensitizers and interstitial laser therapy Photosensitizing drugs that concentrate in cancer cells form the basis for photodynamic therapy. Activation of the drug with light results in cancer cell death. Laser photothermal ablation may be an alternative to surgery for the palliative treatment of head and neck cancer because of its tissue-sparing access, the possibility of repeated treatment, and experimental evidence suggesting lower recurrence at tumor margins compared with surgery. The combination of interstitial laser therapy with regional chemotherapy agents that are activated by light or heat is under investigation as a combined therapeutic regimen. Immune therapy Recruitment of immune cells and administration of stimulatory immune factors to augment treatment of cancer through the host immune response have been advocated but have had little success to date in treating head and neck cancers. Nonspecific immunoadjuvant systemic treatment with factors, such as levamisole or bacillus Calmette-Gurin (BCG), or targeted treatment with purified or recombinant factors, such as interferons or

interleukin-2 (IL-2), have not improved either response rate or duration. Severe toxicities also are associated with the systemic use of these factors. Gene therapy Gene therapy involves various delivery vehicles that can transfer therapeutic genes to target cells. Therapeutic genes may encode a product that induces a biologic response, such as activation of the immune system with transferred interleukin sequences. Head and neck cancers are known to have high levels of TP53 mutations. Normal functions of TP53 are cell growth regulation. Insertion of the TP53 gene into various tumor cell lines in vitro and into animal models in vivo has resulted in suppressed cell growth through cell cycle arrest and apoptosis. Head and neck cancers are accessible to injection therapy and are good candidates for trials of TP53 gene therapy. Another form of therapeutic gene delivery is the adenovirus vector, which uses a genetically engineered virus that is replication incompetent.[137] Prodrug gene therapy, also known as suicide gene therapy, is designed to induce negative selection of cancer cells. By transducing cancer cells with a gene encoding an enzyme that metabolizes a nontoxic prodrug into its toxic form, cancer cells can be selectively killed. Herpes simplex virus (HSV) is a common human virus that produces a unique thymidine kinase. This viral enzyme preferentially phosphorylates the prodrug ganciclovir, a guanine nucleoside analogue, to produce a metabolite that, after cellular phosphorylation, is incorporated into replicating DNA, inhibiting DNA polymerase and ultimately killing the cell. This therapy is most effective in treating cancer cells growing in tissues where normal cells are not proliferating. Many phase I and II trials are being pursued, and may ultimately provide nontoxic, tumor-specific, locally and regionally active, and biologically active injectable modalities that add therapeutic advantages to the existing treatment of head and neck cancers. Roman et al noted that gene therapy might have a role in plastic and reconstructive surgery,[138] and Rea and OSullivan suggested that polymerase chain reaction (PCR) currently impacts modern plastic surgery practice, specifically in area involving normal and abnormal wound healing, the diagnosis of craniofacial anomalies, the diagnosis and treatment of cancer including melanoma and squamous cell carcinoma of the head and neck, and burns. [139] Targeted therapy

Molecular markers that have prognostic and treatment value are currently under investigation.[140] Epidermal growth factor receptors (EGFR) and human papillomavirus (HPV) are already being used in this manner, and many new markers are currently under investigation.[141] These markers will allow the development of new therapies and the individualization of existing treatment options to create personally tailored regimens for each patient.[124] More recently, cetuximab, an EGFR inhibitor, has reportedly had success in several case reports.[118, 119, 120] In the head and neck literature, phase I and II trials of capecitabine, used with cisplatin or paclitaxel[121, 122] or in combination with radiation therapy[123] also showed favorable outcomes.

Complications
A primary complication following treatment of squamous cell carcinoma (SCC) is recurrence, which typically occurs within the first year after excision but may occur much later. In intraocular cases, invasion has been demonstrated in 2-8%. Orbital invasion has been reported in 12-16% of cases. Poor conjunctival and/or corneal healing may occur, especially if aggressive keratectomy, sclerectomy, or 100% ethanol application were performed. Symblepharon formation is a common surgical complication following tumor resection and ocular surface reconstruction. Limbal stem cell damage may result from excision of large lesions. Surgery for SCC may cause bleeding, infection, scar formation, physical deformity, and nerve damage. The removal of deeply invasive lesions may lead to substantial morbidity, including paralysis and pain syndromes.

Special Considerations
Malpractice suits are uncommon following the diagnosis and treatment of squamous cell carcinoma (SCC) because, in most cases, both are straightforward and readily accomplished. Nonetheless, SCC is a lesion with the potential to cause substantial morbidity and even mortality, and physicians who diagnose and treat squamous cell carcinoma are held legally accountable for actions that are taken (or not taken) that fall outside the standard of care. Failure to diagnose SCC Failure to diagnose SCC may also lead to substantial morbidity and occasionally mortality. Confusion of SCC with other cancers, such as desmoplastic melanoma (which can mimic SCC), and a failure to treat such cancers properly can be a source of liability. Seeking the services of a skilled dermatopathologist to assess SCC is, therefore, advisable.

Large court awards have been set for cases in which failure to diagnose SCC has led to death. Failure to treat/perceived inadequate treatment Failure to treat and perceived inadequate treatment are common causes of malpractice claims against physicians. These cases occur most frequently when physicians fail to use an adequately aggressive primary treatment or fail to recognize a high-risk lesion. Some of the newer medical therapies (eg, imiquimod 5% cream, photodynamic therapy) may not yield adequate destruction of the tumor and could heighten the morbidity risk. Their use should be limited to actinic keratoses and biopsy-confirmed in situ lesions. Recognizing that high-risk SCC may metastasize and lead to death is important. Therefore, appropriately aggressive and prompt treatment is indicated in such cases. However, because defined prognostic criteria and models have not been developed, little information is available to guide clinicians in the most appropriate staging and treatment for individuals with high-risk SCC. Due to a lack of data, care standards regarding nodal staging, radiologic imaging, and postsurgical adjuvant therapy have not been developed. Subsequently, a lack of uniformity exists among experienced physicians in the treatment of high-risk SCC.[60] Failure to provide appropriate follow-up Failure to provide appropriate follow-up is a potential pitfall. The courts hold the physician, not the patient, responsible for appropriate follow-up. Because primary treatment of SCC is not a guarantee of cure, ensuring adequate patient follow-up is essential. Failure to inform patients of the potential morbidity associated with SCC may lead to the lesion being regarded as trivial and not requiring follow-up. Missed appointments may indicate the patient is worried or angry. Thus, patients with a history of SCC who miss follow-up appointments should be contacted by phone (or when necessary, with a certified letter) to reschedule. All medical staff are advised to document phone calls in writing and to save certified letter documentation. It is critical for the operating physician to provide the medical record and operative/pathology report to the patient who is moving to another region (eg, out of state/country) and to encourage the patient to continue frequent follow-up with the new physician. The patient also should be assisted in locating a new physician to provide this care. Failure to explain operative risks and complications Informed consent should always be obtained and documented before proceeding with any procedure. Failure to explain all possible risks and complications of surgery is a legal pitfall. Explaining all possible risks before surgery is essential (see Complications). Such

explanations should ideally be documented in written consent forms signed by the treating physician and the patient. Additionally, the physician should not treat lesions outside the realm of his or her comfort zone. If a surgical complication develops, the physician who performed the primary procedure is held legally responsible, regardless of who handles the complication.

Prevention of Squamous Cell Carcinoma

Given the central role that ultraviolet (UV) radiation plays in the pathogenesis of cutaneous squamous cell carcinoma (SCC), methods aimed at decreasing such exposure form the cornerstone of disease prevention. Use of sunscreens, wearing protective clothing, and avoiding excessive sun exposure (or artificial sources of UV light [eg, tanning beds]), such as by limiting outdoor activities (especially between 10:00 am and 4:00 pm), should be recommended to all patients, especially fair-skinned elderly patients. Even young patients should be advised to take precautions against excessive sun exposure to reduce risk of developing cutaneous malignancies in future. Sunscreens The efficacy of UV protection is measured by its sun protection factor (SPF), which is the ratio of the least amount of UVB radiation that will induce erythema on covered skin to the amount of UVB required to generate the same amount of erythema on uncovered skin. Often, it is described as the amount of additional time a person can spend in the sun with protection versus without protection. For patients at risk for SCC, if avoiding sun exposure is not possible, the minimum recommended SPF is 30 or higher. Sunscreen should be reapplied every 30 minutes during acute sun exposure. Several randomized controlled clinical trials have shown a protective role for the daily application of a broad-spectrum sunscreen in the prevention new actinic keratoses and new cutaneous SCC. All patients should be advised to protect their eyelids from sun exposure. Physical sunblocks with the active ingredients of zinc oxide or titanium oxide provide the most complete protection from UVA and UVB rays.[142] Alternatively, a combination chemical sunblock of octocrylene, ecamsule, and avobenzone also provides excellent broad-spectrum UV protection.[143] Clothing Clothing is the simplest method of protection; however, it is often inadequate. For example, a cotton T-shirt has an SPF of less than 10, which decreases sharply when the cloth is wet. Hats with a wide brim or extra-long bill may offer additional protection. Clothing with a high SPF rating is available but these are often expensive and restrictive. Skin screening

Treatment of precancerous actinic keratoses and in situ SCC may prevent the future development of invasive lesions. Current recommendations for screening skin examinations from the American Cancer Society call for a skin examination every 3 years for persons aged 20-39 years and annually after age 40 years. The American Academy of Dermatology recommends annual screening for all patients. Other preventive measures The evidence behind other measures to prevent cutaneous SCC is lacking. Large well-controlled studies failed to show a beneficial role for dietary supplements in the prevention of skin cancers, including selenium, beta-carotene, retinal, and isotretinoin. Chemoprevention with systemic retinoids is effective for reducing the number of new SCCs in both immunocompetent and immunosuppressed patients. Most recent studies have focused on the prophylactic use of oral acitretin, which has a relatively long halflife compared with isotretinoin. Low doses are often sufficient for prophylaxis. However, treatment must be continued indefinitely, because a relapse in tumor development occurs following discontinuation of oral retinoids. Furthermore, systemic retinoids have not been shown to be beneficial in treating existing SCC or at reducing the risk of recurrence after treatment.[144] The mechanisms by which retinoids protect against the development of SCC have not been fully elucidated. Data suggest that retinoids induce the expression of proapoptotic and antiproliferative genes, including TP53, caspases, and P73, in keratinocytes. The increase in epidermal Langerhans cells noted in one study suggests that retinoids may also enhance cutaneous immunosurveillance.[145, 146] Many patients are unable to tolerate the adverse effects associated with systemic retinoid therapy, although lower doses are better tolerated than higher doses. Organ transplant recipients appear to be more sensitive to the adverse effects of systemic retinoids than other patients. Adverse effects of systemic retinoids include mucocutaneous xerosis, dyslipidemia, liver function abnormalities, and teratogenicity.

Consultations
Most cases of squamous cell carcinoma (SCC) are easily and successfully treated by dermatologists or Mohs surgeons. However, in certain cases, a multidisciplinary approach may be needed, such as in the following cases: Large or deep tumors in which excision and reconstruction under local anesthesia is not feasible When clear surgical margins are not achieved or are in doubt Cases of nodal or distant metastasis

A multidisciplinary approach using Mohs micrographic surgery performed in conjunction with an otolaryngologist and/or a plastic surgeon may aid in completely removing deeply invasive SCC, preserving a vital structure (eg, facial nerve), and facilitating the reconstruction of a large operative defect. For example, Mohs micrographic surgery may be used in cases of SCC of the scalp involving bone to establish peripheral margins to the level of the galea. Mohs micrographic surgery is then followed by resection of the deep margin, including bone, with the patient under general anesthesia, performed by a head and neck or plastic surgeon. Because the peripheral margins are established in advance, the head and neck or plastic surgeon can then focus on the deep margin and reconstruction. The patient is often spared hours of anesthesia time, lowering surgical morbidity. Metastatic disease also requires aggressive management by a multidisciplinary team. Surgical treatment of metastatic disease may require the expertise of an otolaryngologist, a general surgeon, or a surgical oncologist. Adjuvant or palliative radiotherapy may be administered by a radiation oncologist. A medical oncologist should be consulted if systemic chemotherapy is considered for metastatic disease.

Long-Term Monitoring
With exposure to risk factors, patients require vigilant follow-up care even after successful treatment, because they continue to be at risk for development of additional cutaneous skin malignancies (eg, basal cell carcinoma [BCC] and squamous cell carcinoma [SCC] of eyelid). The incidence of multiple primaries is 40% in long-term survivors. Therefore, early detection of head and neck cancers and cessation of alcohol and tobacco use is essential to improve prognosis. Low-risk tumors are usually cured with appropriate surgical therapy; however, patients who develop one SCC have a 40% risk of developing additional SCCs within the next 2 years. This risk is likely even greater as more time elapses. Thus, patients with a history of SCC should be evaluated with a complete skin examination every 612 months. Patients with high-risk tumors require skin and lymph node examinations at 3- to 6-month intervals for at least 2 years after diagnosis. In very high-risk cases, surveillance with computed tomography (CT) scanning or magnetic resonance imaging (MRI) may be considered. Recurrent lesions should be treated aggressively. For example, occasionally, pyogenic granulomas can occur soon after tumor excision in areas of bare sclera. These lesions typically respond quickly to topical steroid treatment and must be differentiated from

recurrent tumor. Success in treating recurrences with topical mitomycin C drops has been reported. Encourage patients to follow up with the various specialists involved in their care. Proceed to Medication

Nonsurgical management for cutaneous squamous cell carcinoma (SCC) includes the use of systemic and topical chemotherapy. Various topical agents are used to treat patients with a history of extensive sun exposure or actinic keratosis and SCC in situ. The addition of chemotherapy to radiotherapy may also be beneficial in improving survival in squamous cell carcinoma of the head and neck but it is associated with adverse effects.

Medication Summary

Topical Chemotherapy
Class Summary Nonsurgical options for the treatment of cutaneous squamous cell carcinoma (SCC) include topical chemotherapy and topical immune response modifiers. The use of topical therapy and photodynamic therapy (PDT) is generally limited to actinic keratoses and in situ lesions.
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5-Fluorouracil (Efudex, Carac, Fluoroplex) 5-Fluorouracil (5-U) is a classic antimetabolite anticancer drug with a chemical structure similar to endogenous intermediates or building blocks of DNA or RNA synthesis. It inhibits tumor cell growth through at least 3 different mechanisms that ultimately disrupt DNA synthesis or cellular viability. Topical 5-FU is approved for the treatment of multiple actinic or solar keratoses.
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Imiquimod (Aldara, Zyclara) Imiquimod is approved by the FDA for the treatment of genital warts, actinic keratoses, and superficial basal cell carcinoma (BCC). Imiquimod is an imidazoquinoline that enhances cell-mediated immune responses via the induction of proinflammatory cytokines; that is, it up-regulates interferon and other cytokines.
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Diclofenac (Solaraze) Diclofenac gel is approved by the FDA for the treatment of actinic keratoses. It is applied to lesion areas twice a day for a duration of 60-90 days.

Systemic Chemotherapy

Class Summary Multiple chemotherapeutic agents have been used to treat metastatic cutaneous squamous cell carcinoma (SCC). Adaptation of traditional chemotherapeutics to local and regional administration techniques in treating head and neck cancers is being actively pursued to provide higher local concentrations of otherwise systemically toxic drugs.
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Cetuximab (Erbitux) Cetuximab is approved for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN). Cetuximab when used alone is indicated for the treatment of patients with recurrent or metastatic SCCHN, for whom prior platinum-based therapy has failed. It is a chimeric immunoglobulin G1 monoclonal antibody that inhibits epidermal growth factor receptor (EGFR) and has been reported as successful in several case reports. EGFR inhibitors are well tolerated with relatively low risks, so they may be considered in cases not amenable to surgery or radiation or as an adjuvant in cases considered to have a high risk of death. Current recommendations are to use cetuximab as an alternative to chemotherapy in patients who cannot tolerate chemotherapy.
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Cisplatin Cisplatin has been used in the treatment of squamous cell carcinoma of the head and neck. Although this agent is one of the most successful in the treatment of cancer, it produces major toxicities to normal cells and organs at the concentrations necessary for effective treatment of malignancies. Combination chemoradiotherapy with cisplatin and concurrent radiation therapy has improved locoregional control in locally advanced SCC. Chemoradiotherapy is now considered the standard of care in locally advanced disease following surgical resection and in unresectable disease. Cisplatin-based combination chemotherapy with 5-fluorouracil (5-FU), methotrexate, bleomycin, and doxorubicin all have been used to treat advanced SCC with variable outcomes.
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Docetaxel (Taxotere) Docetaxel is a semisynthetic taxane, a class of drugs that inhibits cancer cell growth by promoting assembly and blocking the disassembly of microtubules, thereby preventing cancer cell division, leading to cell death. It is indicated in combination with cisplatin and 5-fluorouracil for induction therapy of locally advanced SCCHN before patients undergo chemoradiotherapy and surgery.
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Methotrexate Methotrexate is an antimetabolite that inhibits dihydrofolate reductase, thereby hindering DNA synthesis and cell reproduction in malignant cells. It has been used in combination with other chemotherapeutic agents for the treatment of cancers of the head and neck.
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Paclitaxel Paclitaxel is an antimicrotubule agent. Its mechanism of action includes tubulin polymerization and microtubule stabilization, which, in turn, inhibits mitosis and may result in breakage of chromosomes.
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Carboplatin Carboplatin is an analog of cisplatin. This is a heavy metal coordination complex that exerts its cytotoxic effect by platination of DNA, a mechanism analogous to alkylation, leading to interstrand and intrastrand DNA cross-links and inhibition of DNA replication. It binds to protein and other compounds containing the SH group. It has been used in the treatment of advanced and recurrent SCCHN.
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Bleomycin Bleomycin is a cytotoxic glycopeptide antibiotic whose main mechanism of action may include inhibition of DNA synthesis and possible inhibition of RNA and protein synthesis. It is used as palliative treatment of SCCHN.

Background
Basal cell carcinoma (BCC) is the most common skin cancer in humans, yet it accounts for less than 0.1% of patient deaths due to cancer. Basal cell skin cancer tumors typically appear on sunexposed skin, are slow growing, and rarely metastasize (0.0280.55%). BCC usually appears as a flat, firm, pale area that is small, raised, pink or red, translucent, shiny, and waxy, and the area may bleed following minor injury. Tumor size can vary from a few millimeters to several centimeters in diameter. (See Clinical Presentation.) See the clinical images below of basal cell carcinoma.
A superficial basal cell carcinoma (BCC). Clinically, an erythematous, wellcircumscribed macule with minimal scale is present. This tumor is often

misdiagnosed as eczematous dermatitis or guttate psoriasis and is often difficult to distinguish clinically from Bowen disease (squamous cell carcinoma in situ). Features that suggest the diagnosis of superficial BCC are the absence of significant white, adherent scale, and a history of the lesion remaining unchanged for several months or years. Treatment options for this tumor include electrodesiccation and curettage, surgical excision, cryosurgery, 5-fluorouracil, 5% imiquimod cream, and superficial radiographic therapy. Electrodesiccation and curettage is the modality most commonly used, with a cure rate of approximately 95%. Basal cell carcinoma. A 68-year-old patient presenting with an advanced basal cell carcinoma (BCC) of the right periorbital region, frontal view (Images courtesy of M Abraham Kuriakose, DDS, MD)

BCC is a nonmelanocytic skin cancer (ie, an epithelial tumor) that arises from basal cells, which are small round cells found in the lower layer of the epidermis. Basal cells invade the dermis but seldom invade other parts of the body. The deoxyribonucleic acid (DNA) of certain genes is often damaged in patients with BCC; therefore, inheritance may be a factor. Most DNA alterations result from damage caused by exposure to sunlight. (See Pathophysiology.) Body distribution of BCCs is as follows: On the head (most frequently on the face[1] ; most common location is the nose, specifically the nasal tip and alae) - 70% On the trunk[2] - 25% On the penis,[3] vulva,[4, 5] or perianal skin - 5% The anatomic distribution of BCCs correlates with embryonic fusion planes. Recent data indicate that after adjusting for surface area, BCC occurrence is greater than 4 times more likely on embryonic fusion planes than on other regions of the midface, a finding that supports the possibility of an embryologic role for BCC pathogenesis.
[6]

BCC can develop on unexposed areas, and cases of BCC of the prostate have been reported. In some patients, contributing factors are exposure to or contact with arsenic,[5, 7] tar, coal, paraffin,[8] certain types of industrial oil, and radiation. BCC can also be associated with scars (eg, burn complications), [9] xeroderma pigmentosum,[10] , previous trauma.[11] vaccinations, or even tattoos. (See Etiology.) A skin biopsy (most often a shave biopsy is sufficient) may be necessary to confirm the diagnosis and is often required to determine the histologic subtype of BCC. A punch biopsy may be used to obtain a thick specimen, especially when the clinical suspicion of a BCC is still present after shave biopsy results are negative. (See Workup.) Neglected tumors can continue to grow and lead to significant local destruction and even disfigurement. Surgery, in almost all cases, is the recommended treatment,[12, 13] with treatments varying on the

basis of cancer size, depth, and location. (See Treatment and Management.) Superficial BCCS have been successfully treated with imiquimod 5% cream,[14, 15, 16, 17, 18, 19] and topical 5-fluorouracil 5% cream may be used to treat small, superficial BCCs.[20] Several studies have shown success in treating small nodular BCCs with imiquimod 5% cream, although this is an off-label indication and patients should be informed of this fact. (See Medication.) Anatomy Basal cell carcinomas (BCCs) occur predominantly on the head, with 70% of BCCs occurring on the head (most frequently on the face), 25% on the trunk, and 5% on the penis, vulva,[4] or perianal skin. Very rarely, other organs are affected.

Pathophysiology
Although the exact etiology of BCC is unknown, a well-established relationship exists between BCC and the pilosebaceous unit, as tumors are most often discovered on hair-bearing areas. Many believe that BCCs arise from pluripotential cells in the basal layer of the epidermis or follicular structures. These cells form continuously during life and can form hair, sebaceous glands, and apocrine glands. Tumors usually arise from the epidermis and occasionally arise from the outer root sheath of a hair follicle, specifically from hair follicle stem cells residing just below the sebaceous gland duct in an area called the bulge. Signaling pathways The patched/hedgehog intracellular signaling pathway plays a role in both sporadic BCCs and nevoid BCC syndrome (Gorlin syndrome). This pathway influences differentiation of various tissues during fetal development. After embryogenesis, it continues to function in regulation of cell growth and differentiation. Loss of inhibition of this pathway is associated with human malignancy, including BCC. The hedgehog gene encodes an extracellular protein that binds to a cell membrane receptor complex to start a cascade of cellular events leading to cell proliferation. Of the 3 known human homologues, sonic hedgehog (SHH) protein is the most relevant to BCC. Patched (PTCH) is a protein that is the ligand-binding component of the hedgehog receptor complex in the cell membrane. The other protein member of the receptor complex, smoothened (SMO), is responsible for transducing hedgehog signaling to downstream genes.[21, 22] A published article by Zhang et al demonstrates that the ultraviolet (UV)-specific nucleotide changes in 2 tumor suppressor genes, TP53

and PTCH, are both implicated in the development of early-onset BCC.[23] When SHH is present, it binds to PTCH, which then releases and activates SMO. SMO signaling is transduced to the nucleus via Gli. When SHH is absent, PTCH binds to and inhibits SMO. Mutations in the PTCH gene prevent it from binding to SMO, simulating the presence of SHH . The unbound SMO and downstream Gli are constitutively activated, thereby allowing hedgehog signaling to proceed unimpeded. The same pathway may also be activated via mutations in the SMO gene, which also allows unregulated signaling of tumor growth. How these defects cause tumorigenesis is not fully understood, but most BCCs have abnormalities in either PTCH or SMO genes. Some even consider defects in the hedgehog pathway to be requirements for BCC development. UV-induced mutations in the TP53 tumor suppressor gene, which resides on band 17p13.1, have been found in some cases of BCC. [24] In addition, frameshift mutations of the BAX gene (BCL2 associated X protein) have been found in sporadic cases of BCC. A reduction of bcl-2 proteins is observed in the aggressive, infiltrative type of BCC. A recent study also showed an association of a COX-2 gene variant with a lower risk of developing BCC in patients who underwent organ transplantation before age 50 years; this finding suggests a possible role for dysregulation of COX-2 expression in carcinogenesis. Radiation and immunologic origins Radiation has proven to be tumorigenic by two mechanisms. The first entails the initiations of prolonged cellular proliferation, thereby increasing the likelihood of transcription errors that can lead to cellular transformation. The second mechanism is direct damage of DNA replication, leading to cellular mutation that may activate proto-oncogenes or deactivate tumor suppressor genes. Immunologically, the mechanism by which prolonged ultraviolet radiation exposure leads to the development of BCC includes suppression of the cutaneous immune system and immunologic unresponsiveness to cutaneous tumors. This local effect includes a decrease in Langerhans cells, dendritic epidermal T cells, and Thy1+ cells. Furthermore, systemic proliferation of suppressor T cells and the release of immunosuppressive factors (eg, tumor necrosis factoralpha [TNF-alpha], interleukin 1 [IL-1], prostaglandin [PG], interleukin 10 [IL-10]) are believed to be pathogenic to the development of BCC. DNA mismatch repair proteins DNA mismatch repair (MMR) proteins are a group of proteins that physiologically stimulate G2 cell cycle checkpoint arrest and apoptosis. Failure of MMR proteins to detect induced DNA damage results in the survival of mutating cells. MMR proteins have been found to be increased in nonmelanoma skin cancers as compared to

normal skin, and there is also some evidence of MMR dysregulation.

[25]

Etiology
The exact cause of BCC is unknown, but environmental and genetic factors are believed to predispose patients to BCC. Radiation exposure Sunlight, particularly chronic exposure, is the most frequent association with development of BCC; risk correlates with the amount and nature of accumulated exposure, especially during childhood. Patient geographic location affects the risk of developing skin cancer. A latency period of 20-50 years is typical between the time of ultraviolet (UV) damage and BCC clinical onset. Radiation exposure that contributes to BCC development may include tanning booths and UV light therapy. Both short-wavelength UVB radiation (290-320 nm, sunburn rays) and longer wavelength UVA radiation (320-400 nm, tanning rays) contribute to the formation of BCC. UVB is believed to play a greater role in the development of BCC than UVA, however, and is the primary agent responsible for most skin cancer.[26] UVB and UVC can modify unsaturated chemical bonds of nucleic acids, which may lead to mutations. UVC does not penetrate the atmospheric ozone layer. The UVA spectrum is absorbed by melanin and, through free-radical transfer, affects cellular deoxyribonucleic acid (DNA). Mutations caused by UV radiation typically include cytosine (C) to thymine (T), or CC to TT, translocation. This process can cause activation of oncogenes or inactivation of tumor suppressor genes, leading to tumor initiation and progression. [27] The skin can repair superficial damage, but the underlying cumulative damage remains, including DNA damage. The damage worsens with each successive sun exposure, causing a lifetime progression.[28] In a 2012 systematic review and meta-analysis of 12 studies with 9328 cases of non-melanoma skin cancer, Wehner et al found that indoor tanning was associated with a significantly increased risk of both basal and squamous cell skin cancer. The risk was highest among users of indoor tanning before age 25. The authors estimate that the population attributable risk fraction in the United States is 8.2% for squamous cell carcinoma and 3.7% for basal cell carcinoma, corresponding to more than 170,000 cases of nonmelanoma skin cancer annually caused by indoor tanning.[29] Gene mutations Recent studies demonstrate a high incidence of TP53 gene mutations in BCC. Researchers speculate that ultraviolet sunlight may play an important role in the genesis of this mutation; yet,

genetic involvement has been demonstrated on chromosome 9 only in patients with familial basal cell nevus syndrome (Gorlin syndrome). Such mutation involves the patched (PTCH) gene, a tumor suppressor gene. Inappropriate activation of the hedgehog signaling pathway is found in both sporadic and familial cases of BCC. This results in loss-offunction mutations in tumor-suppressor protein patched homologue 1 (PTCH1) and gain-of-function mutations in sonic hedgehog ( SHH), smoothened (SMO), and Gli. Other radiation exposure X-ray and grenz-ray exposure are associated with basal cell carcinoma formation. Arsenic exposure through ingestion Arsenic has been used as a medicinal agent, predominantly the Fowler solution of potassium arsenite, which was used to treat many disorders, including asthma and psoriasis. Historically, a contaminated water source has been the most common source of arsenic ingestion. Immunosuppression A modest increase in the lifetime risk of BCC has been noted in chronically immunosuppressed patients, such as recipients of organ or stem cell transplants and patients with AIDS. Organ transplant patients must be instructed to limit sun exposure and alerted that skin cancer is a serious problem for them. In fact, immunosuppression and sun damage may cooperate to cause skin cancer. The skin cancer incidence is 10-fold higher in transplant patients than in the general population; up to 65-75% of patients with long-term immunosuppression develop skin cancer. Skin cancers can significantly alter and reduce the transplant recipients quality of life; some patients may develop more than 100 skin cancers per year. Xeroderma pigmentosum This autosomal recessive disease results in the inability to repair ultraviolet-induced DNA damage. Pigmentary changes are seen early in life, followed by the development of basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. Other features include corneal opacities, eventual blindness, and neurological deficits. Epidermodysplastic verruciformis Epidermodysplastic verruciformis is an autosomal recessive disorder characterized by the development of basal cell carcinoma and squamous cell carcinoma from warts (human papillomavirus infection).

Nevoid basal cell carcinoma syndrome In addition to basal cell carcinoma, this autosomal dominant disorder can result in the early formation of multiple odontogenic keratocysts, palmoplantar pitting, intracranial calcification, and rib anomalies. Various tumors such as medulloblastomas, meningioma, fetal rhabdomyoma, and ameloblastoma also can occur. [30] Odontogenic keratocysts, palmoplantar pitting, intracranial calcification, and rib anomalies may be seen. Mutations in the hedgehog signaling pathway, particularly the patched gene, are causative.[31] Go to Nevoid Basal Cell Carcinoma Syndrome to see more complete information on this topic. Bazex syndrome Features of Bazex syndrome include follicular atrophoderma (socalled ice pick marks, especially on dorsal hands), multiple basal cell carcinomas, and local anhidrosis (decreased or absent sweating). [28] Previous nonmelanoma skin cancer Persons who have been diagnosed with one nonmelanoma skin cancer are at increased risk of developing tumors in the future. The risk of developing new nonmelanoma skin cancers is reported to be 35% at 3 years and 50% at 5 years after an initial skin cancer diagnosis.[32] Skin type Albinism has been implicated in BCC. The Fitzpatrick skin-type scale, which ranges from very fair (skin type I) to very dark (skin type VI), categorizes cutaneous sensitivity to ultraviolet radiation. It is based on the individual's tendency to burn and tan and is a good predictor of relative risk among whites. The prevalence of BCC increases in areas of higher altitude and in areas of lower latitude. The incidence of BCC is rising, potentially because of atmospheric changes and the increased popularity of sunbathing. Rombo syndrome Rombo syndrome is an autosomal dominant condition distinguished by basal cell carcinoma and atrophoderma vermiculatum, trichoepitheliomas, hypotrichosis milia, and peripheral vasodilation with cyanosis.[33] Alcohol consumption A study among adults in the United States reports a strong association between excessive alcohol drinking and higher incidence of sunburn, suggesting a linkage between alcohol consumption and skin cancer.[34]

Epidemiology

The American Cancer Society reports skin cancer as being the most common cancer in the United States, with over 1 million new cases diagnosed and more than 10,000 deaths estimated yearly (ie, approximately 2% of all cancer deaths). The estimated lifetime risk for BCC in the white population is 33-39% for men and 23-28% for women. Basal cell carcinoma incidence doubles every 25 years. In states near the equator, such as Hawaii, BCC incidence is approaching 3-fold that of states in the Midwest, such as Minnesota. BCC incidence also varies globally. The highest rates of skin cancer occur in South Africa and Australia, areas that receive high amounts of UV radiation.[35] Australia has a trend toward increasing BCC incidence, while Finland has a low reported incidence that is approximately one quarter that in Minnesota; BCC incidence in Finland also appears to be increasing, however, especially among young women. BCC accounts for 80% of all skin cancers but is the least likely cancer to behave in a malignant fashion and metastasize. BCC differs from squamous cell carcinoma, which accounts for 16% of skin cancers and is more life threatening. Although BCC is observed in people of all races and skin types, darkskinned individuals are rarely affected, and it is most often found in light-skinned individuals (type 1 or type 2 skin). Those with type 1 skin are very fair and have red or blond hair and freckles; these individuals always burn and never tan. Those with type 2 skin are fair and burn easily while tanning minimally. Whites of Celtic ancestry have the highest risk for BCC. Incidence is low in blacks, Asians, and Hispanics.[36] Historically, men are affected twice as often as women. The higher incidence in men is probably due to increased recreational and occupational exposure to the sun, although these differences are becoming less significant with changes in lifestyle. The current maleto-female ratio is approximately 2.1:1. For tumors involving the periocular skin, Cook et al reported the incidence of BCC to be equal in men and women. [37] In addition, this investigative team found that the age-adjusted incidence rates for all malignant tumors of the eyelid in men and women, respectively, were 19.6 cases and 13.3 cases per 100,000 population per year. The age-adjusted incidence rates for BCC of the eyelid for men and women, respectively, were 16.9 and 12.4 cases per 100,000 population per year. The likelihood of developing BCC increases with age. With the exception of basal cell nevus syndrome, BCC is rarely found in patients younger than 40 years. Approximately 5-15% of cases of BCC occur in patients aged 20-40 years. Aggressive-growth basal cell carcinoma (AG-BCC) is more frequently noted in patients

younger than 35 years than in older individuals. AG-BCC includes morpheaform, infiltrating, and recurrent BCCs.[38] Data indicate that BCC incidence is far higher (more than 100-fold) in persons aged 55-70 years than in those aged 20 years or younger. Patients 50-80 years of age are affected most often (mean age, 55 y), but the damaging effects of the sun begin at an early age and may not appear for 20-30 years. BCC can develop in teenagers and now appears frequently in fair-skinned patients aged 30-50 years. The median age at diagnosis is 67 2.5 years, and the mean age is 64.4 5.6 years (age range, 20-90 y).

Prognosis
The prognosis for patients with BCC is excellent, with a 100% survival rate for cases that have not spread to other sites. Nevertheless, if BCC is allowed to progress, it can result in significant morbidity, and cosmetic disfigurement is not uncommon. Although BCC is a malignant neoplasm, it rarely metastasizes. The incidence of metastatic BCC is estimated to be less than 0.1%. Nevertheless, after treatment, which is curative in more than 95% of cases, BCC may develop in new sites. The most common sites of metastasis are the lymph nodes, lungs, [39] and bones.[40] Typically, basal cell tumors enlarge slowly and relentlessly and tend to be locally destructive. Periorbital tumors can invade the orbit, leading to blindness, if diagnosis and treatment are delayed. BCC arising in the medial canthus tends to be deep and invasive and more difficult to manage; this type of BCC can result in perineural extension and loss of nerve function. Patients who are diagnosed with BCC have a 35% chance of developing another tumor within 3 years and a 50% chance of developing another (not recurrent) BCC within 5 years. Therefore, regular skin screenings are recommended.[41] Recurrence The 5-year recurrence rate is about 5%, but it depends on the histologic subtype and type of treatment; the recurrence rate is less than 1% for primary (previously untreated) BCCs treated with Mohs micrographic surgery. Most reports show that the distance to the closest resection margin is an important predictor of recurrence. The following is a list of treatments and their 5-year recurrence rates for primary (previously untreated) BCCs: Surgical excision - 10.1% Radiation therapy - 8.7% Curettage and electrodesiccation - 7.7% Cryotherapy - 7.5% All non-Mohs modalities - 8.7%

Mohs micrographic surgery - 1% These rates are probably affected by the fact that clinicians use cryotherapy, curettage, and desiccation mostly on smaller and better-demarcated lesions. Pieh et al reported a recurrence rate of 5.36% after the first excision of the tumor; the rate increased to 14.7% after the second operation, and the rate reached 50% after the third and fourth operations.[42] The highest recurrence, approximately 60%, was seen with lesions arising from the medial canthus. Recurrences usually occur 4-12 months after initial treatment, and the risk of developing a second lesion in 3 years is about 44%, which is a 10-fold increase over that of the general population. [43, 44] Tumors on the nose or T-zone of the face have a higher incidence of recurrence. Recurrence is most common on the nose and nasolabial fold, but this observation may be secondary to lack of adequate margins obtained in these areas. Infiltrative, micronodular, and multifocal types are more likely than nodular types to recur. A recurrence of BCC should be suspected when one of the following conditions occurs: Nonhealing ulceration Tissue destruction Scar that becomes red, scaled, or crusted or enlarges with large adjacent telangiectasia Scar that slowly enlarges over time (months) Development of papule/nodule within a scar Histologic types of BCC at higher risk for recurrence include morpheaform (sclerotic), micronodular, infiltrative, and superficial (multicentric). Other conditions that contribute to a higher recurrence rate include recurrent tumors that have been treated previously, large tumors (>2 cm), and deeply infiltrating tumors.

Patient Education
Adequate patient education is essential in the prevention of recurrence and spread of basal cell carcinoma. Patients should avoid possible potentiating factors (eg, sun exposure, ionizing radiation, arsenic ingestion, tanning beds). The regular use of sun-protecting clothing (eg, wide-brimmed hat, long-sleeved shirts, sunglasses with ultraviolet [UV] protection) is recommended when outdoors. Instruct patients to avoid sun exposure particularly during the middle of the day (ie, 11:00 am to 3:00 pm), which is the most dangerous time. Also, the sun's rays are especially intense in sunny climates and at high altitudes, and UV radiation can also pass through clouds and water. Patients should be instructed to be careful on the beach and in the snow because sand, water, and snow reflect sunlight and increase the amount of received UV radiation.

During the initial consultation, the patient should be counseled regarding the extent of resection, type of reconstructive procedure, and attendant morbidity. High importance should be attached to adequately preparing the patient regarding the cosmetic and functional result of treatment. During posttreatment follow-up, the patient should be counseled regarding sunlight exposure and the risk of developing additional primary skin tumors. Sunscreen Regular application and reapplication of sunscreen is recommended prior to sun exposure. Note that SPF ratings correspond to the number of minutes required to get the equivalent of 1 minute of unprotected UVA exposure. People who use sunscreens have a 40% reduction in skin cancer incidence versus nonusers. Two types of sunscreen are available: the first reflect ultraviolet (UV)B and, to a lesser extent, UVA (reflectant); the second absorb UVB into specific chemicals re-emitting insignificant quantities of heat (absorbent). Educate the patient that use of sunscreens with at least a 15 sun protective factor (SPF) rating is very useful for any skin cancer prevention.[45] Emphasize also that sunscreens must be applied 2030 minutes before going outside and reapplied about every 2 hours, more often if swimming or sweating; lip balm with an SPF of 15 or higher is useful. Instruct parents to protect their children's skin with sunscreen or protective clothing to reduce the risk of BCC later in life. It has been estimated that intensive sun protection before age 18 years can reduce nonmelanoma skin cancer by 78%. Advise parents not to expose children younger than 12 months to direct sunlight and to cover up children aged 12-24 months with a hat, shirt, and a small amount of sunscreen (eg, more than 15 SPF) on the remaining exposed areas. Similarly, for children older than 2 years, instruct parents to consider using sunscreens with an SPF of 15 or more, covering the child's skin with clothing, and, when possible, restricting the child to shaded areas. Self-examination for skin changes Educate patients on how to recognize any unexplained changes in their skin, especially changes that last for more than 3-4 weeks. Also, educate patients on how to examine their own skin. The knowledge of mole distribution on the skin is helpful. Tell the patient to first look at the front and back of his or her body in a full-length mirror, using a hand mirror. The patient also should use the hand mirror to look at the back of the neck and scalp, the back, and the breeches. The patient then should turn and look at each side of the body with the arms raised. Next, the patient should bend the elbows and look carefully at the forearms, the back of the upper arms, and the palms. Instruct the patient to sit down and check the

backs of the legs and feet, including the spaces between the toes and bottoms of the feet. For those without a history of skin cancer, a dermatologic examination (skin cancer screening) is recommended every 3 years for persons aged 20-40 years and every year for persons older than 40 years. The American Cancer Society recommends a dermatologic examination every 3 years for people aged 20-40 years and every year for people older than 40 years. For patient education information, see Skin Cancer. Proceed to Clinical Presentation

Patients presenting with basal cell carcinoma (BCC) often report a slowly enlarging lesion that does not heal and that bleeds when traumatized. As tumors most commonly occur on the face, patients often give a history of an acne bump that occasionally bleeds.

History

People who sunburn are more likely to develop skin cancer than those who do not; however, sunlight damages the skin with or without sunburn. Consider BCC in any patient with a history of a sore or skin anomaly that does not heal within 3-4 weeks and occurs on sun-exposed skin, especially if it is dimpled in the middle. These tumors may take many months or years to reach even 1 cm in diameter. Patients often have a history of chronic sun exposure, including recreational sun exposure (eg, sunbathing, outdoor sports, fishing, boating) and occupational sun exposure (eg, farming, construction). History of any prior treatment to the index tumor should be elicited, as well as history of any prior non-melanoma skin cancer. In patients with recurrent tumors, deeper invasion should be expected. Recurrence following radiation therapy is often biologically more aggressive. Occasionally, patients have a history of exposure to ionizing radiation. X-ray therapy for acne was commonly used until 1950. Though not common, patients have a history of arsenic intake; arsenic is found in well water in some parts of the United States.

Physical Examination
Characteristic features of BCC tumors include the following: Waxy papules with central depression Pearly appearance Erosion or ulceration, often central Bleeding, especially when traumatized

Crusting Rolled (raised) border Translucency Telangiectases over the surface Slow growing (0.5 cm in 1-2 y) Basal cell carcinoma occurs mostly on the face, head (scalp included), neck, and hands.[46] It rarely develops on the palms and soles. BCC usually appears as a flat, firm, pale area that is small, raised, pink or red, translucent, shiny, and waxy, and the area may bleed following minor injury. BCCs may have one or more visible and irregular blood vessels, an ulcerative area in the center that often is pigmented, and black-blue or brown areas. Large BCCs may have oozing or crusted areas. The lesion grows slowly, is not painful, and does not itch. Periocular tumors most commonly involve the lower eyelid (48.972.1%), followed by the medial canthus (25-30%), the upper eyelid (15%), and the lateral canthus (5%). Examples are shown in the images below.
Basal cell carcinoma of the right lower lid. Biopsy-proven basal cell carcinoma of the upper lid margin. Note the loss of cilia (madarosis) in the area of the tumor. Medial canthal/lower lid basal cell. Note the pearly nodular surface with characteristic telangiectatic vessels. Proximity to the lacrimal system will impact its treatment and reconstruction.

Though a literature review showed all authors agreed that periocular BCC most commonly occurs in the lower eyelid, the remaining anatomical locations and the incidence of occurrence differ among the studies. Younger patients (< 40 y) may have a lower prevalence of BCC on the head and neck and a higher prevalence on the trunk, with greater tendency to superficial BCC, than in older patients. [47] Childhood BCC is exceedingly rare in the absence of other underlying conditions. Only 107 cases of de novo childhood BCC have been reported in the literature, but the majority (90%) occurred on the head and neck, and aggressive subtypes were observed in 20% of the total cases.[48] Clinical presentation of BCC varies by type. Physical examination of the skin aids in determination of tumor extent, subtype, and involvement of important cosmetic and functional structures. Matted BCCs may indicate deeper tumor invasion and involvement of deeper underlying structures. In patients with recurrent or deeply infiltrative tumors, involvement of the facial nerve or branches of the trigeminal nerve should be investigated. Facial nerve function can be monitored by comparing facial symmetry during voluntary facial movements with that at rest. Sensory nerve function can be

tested and compared to the nonaffected side by means of light touch and pinprick. Orbital invasion can cause diplopia, proptosis, and ophthalmoplegia. Any limitation in ocular movements and/or diplopia should be tested. BCC seldom causes regional or distant metastasis, with the exception of the metatypical basosquamous type. To evaluate for lymph node metastasis, particular attention should be taken to examine the parotid posterior auricular, suboccipital, and upper cervical groups of lymph nodes. Several different clinicopathologic types of BCC exist, each with distinct biologic behavior: Nodular - Cystic, pigmented, keratotic Superficial Infiltrative Micronodular Morpheaform Superficial Nodular basal cell carcinoma Nodular basal cell carcinoma is the most common type of basal cell carcinoma and usually presents as a round, pearly, flesh-colored papule with telangiectases. More than 60% of BCCs belong to this subtype. As it enlarges, it frequently ulcerates centrally, leaving a raised, pearly border with telangiectases, which aids in making the diagnosis. Fine vessels may bleed, resulting in hemosiderin deposition. The tumor may present as a cyst, which can be mistaken for inclusion cysts of the eyelid. Cystic BCC is an uncommon variant of nodular BCC and is often clinically indistinguishable from nodular basal cell carcinoma, although it might have a polypoid, cystic appearance. Typically, a bluish-gray cystlike lesion is observed. The cystic center of the tumor is filled with clear mucin that has a gelatinlike consistency. Often, one can see the typical features of a nodular basal cell carcinoma in addition to the cystic features. Most tumors are observed on the face, although the trunk and extremities also are affected. See the images below.
Nodular basal cell carcinoma. Nodular basal cell carcinoma appearing as a waxy, translucent papule with central depression and a few small erosions.

Pigmented basal cell carcinoma (see the images below) is an uncommon variant of nodular basal cell carcinoma that usually has brown-black macules in some areas or affecting nearly the entire tumor, occasionally making it difficult to differentiate from melanoma.

Typically, some areas of these tumors do not retain pigment, and pearly, raised borders with telangiectases that are typical of a nodular basal cell carcinoma can be observed. This aids clinically in differentiating this tumor from a malignant melanoma. See the images below.
Pigmented basal cell carcinoma. Pigmented basal cell carcinoma. Pigmented basal cell carcinoma has features of nodular basal cell carcinoma with the addition of dark pigmentation from melanin deposition. The pigmentation often has the appearance of dark droplets in the lesion, as shown here.

Keratotic BCC is a variant of nodular BCC and is usually clinically indistinguishable from nodular BCC histologically. Infiltrative basal cell carcinoma With this variant of BCC, tumor infiltrates the dermis in thin strands between collagen fibers, making tumor margins less clinically apparent. Mohs micrographic surgery is the treatment of choice for infiltrative basal cell carcinoma. Because of its growth pattern, electrodesiccation and curettage has a significantly higher recurrence rate when used to treat infiltrative BCC compared to the treatment of nodular BCC; other treatment methods should be sought. Micronodular basal cell carcinoma This aggressive BCC subtype has the typical BCC distribution. It is not prone to ulceration, it may appear yellow-white when stretched, and it is firm to the touch. It may have a seemingly well-defined border. Morpheaform (sclerosing) basal cell carcinoma Morpheaform basal cell carcinoma is an uncommon variant in which tumor cells induce a proliferation of fibroblasts within the dermis and an increased collagen deposition (sclerosis) that clinically resembles a scar. This form accounts for 10% of lesions. Such lesions appear as flat or slightly depressed, fibrotic, and firm. The tumor appears as a white or yellow, waxy, sclerotic plaque that rarely ulcerates. The morpheaform (sclerosing) type of basal cell carcinoma is often the most difficult type to diagnose, as it bears little resemblance to the typical nodular BCC. Because the tumor infiltrates in thin strands between collagen fibers, treatment is difficult because the clinical margins are difficult to distinguish from normal, uninvolved skin. Mohs micrographic surgery is the treatment of choice for morpheaform basal cell carcinoma because recurrence is more likely with other treatment modalities.

Ulceration, bleeding, and crusting are uncommon and these tumors are commonly mistaken for scar tissue (see the image below).
Large, scarlike morpheaform basal cell cancer.

Superficial basal cell carcinoma

Superficial basal cell carcinomas are seen mostly on the upper trunk or shoulders. This type of BCC grows slowly, has minimal tendency to be invasive, and appears clinically as an erythematous, wellcircumscribed patch or plaque, often with a whitish scale. Occasionally, minute eschars may appear within the patch or plaque. The tumor often appears multicentric, with areas of clinically normal skin intervening among clinically involved areas. A threadlike border is common but not always present. Erosion is less common in superficial BCC than in nodular BCC, although pinpoint areas of hemorrhage or eschar may be present. The papules may mimic psoriasis or eczema, but they are slowly progressive and are not prone to fluctuate in appearance. Numerous superficial BCCs may indicate arsenic exposure. See the images below.
Scale, erythema, and a threadlike raised border are present in this superficial basal cell carcinoma on the trunk. Large, superficial basal cell carcinoma.

Gorlin syndrome or basal cell nevus syndrome Basal cell carcinoma (BCC) is also a feature of basal cell nevus syndrome (ie, Gorlin syndrome),[49] an autosomal dominant inherited condition. The lesions in these patients cannot be distinguished histologically from ordinary BCCs. The gene responsible for this syndrome is located on arm 9q, and chromosome abnormalities develop in some patients. The number of BCCs in patients with this syndrome may number from one to hundreds. Multiple BCCs begin to appear after puberty on the face, trunk, and extremities. In many cases, the tumors are highly invasive and may involve areas around the eyes and nose. [50] Other features associated with Gorlin syndrome (fortunately, uncommon) include the following[51] : Mental retardation Congenital agenesis of the corpus callosum and medulloblastoma Odontogenic jaw cysts Bifid ribs and pectus excavatum Absent or undescended testes Mesenteric lymphatic cysts Palmar and plantar pits Ectopic calcification (particularly of the falx cerebri)

Ocular and skeletal abnormalities (eg, hypertelorism, shortening of the fourth and fifth metacarpals) Other basal cell carcinomas Other types of basal cell carcinoma include the following: Metatypical Infundibulocystic Follicular Pleomorphic

Diagnostic Considerations
Although basal cell carcinoma rarely metastasizes, a tumor can extend beneath the skin to the bone, causing considerable local damage due to tissue destruction. This process leads to an ulcer that is sometimes known as ulcus rodens, or a rodent ulcer. Other medical problems/issues to consider include the following: Dermatitis Desmoplastic trichoepithelioma Eczema Intradermal nevus Lichenoid benign keratosis Ringworm Fibroepithelioma of Pinkus Adnexal carcinoma (very rare) Actinic keratosis Sebaceous hyperplasia Nevi malignant melanoma Keratoacanthoma Seborrheic keratosis Bowen disease Darier disease (keratosis follicularis)[5] Cutaneous T-cell lymphoma (mycosis fungoides) Metastatic malignancies

Differential Diagnoses
Actinic Keratosis Angiofibroma Bowen Disease Fibrous Papule of the Face Malignant Melanoma Molluscum Contagiosum Nevi, Melanocytic Psoriasis Sebaceous Hyperplasia Squamous Cell Carcinoma Proceed to Workup

Approach Considerations

Given that basal cell carcinoma rarely metastasizes, laboratory and imaging studies are not commonly clinically indicated in patients presenting with localized lesions. Imaging studies may be necessary when involvement of deeper structures, such as bone, is clinically suspected. In such cases, CT scans or radiography can be used.

Skin Biopsy
A skin biopsy is often required to confirm the diagnosis and determine the histologic subtype of basal cell carcinoma (BCC). Most often, a shave biopsy is all that is required. Nevertheless, in the case of a pigmented lesion where there may be difficulty distinguishing between pigmented BCC and melanoma, an excisional or punch biopsy may be indicated; this is to ensure that the depth of the lesion can be determined if it proves to be a malignant melanoma. In most cases, a superficial biopsy specimen that contains dermis is all that is required to confirm the diagnosis of BCC, although it is possible to miss the tumor. For example, an ulcerated BCC may reepithelialize with normal epidermis while tumor is still present at a deeper level. Part or all of the BCC may be sampled, but avoid going beyond the clinical margins if the biopsy is only for diagnostic purposes. Punch biopsy is an easy method to obtain a thick specimen, but is rarely required. The most suspicious area of a lesion may be sampled, or multiple biopsy samples may be taken if the tumor is large or has a varied appearance in different areas. Avoid punch biopsy if curettage is planned for final treatment. Occasionally, suspected tumors may require more than a single biopsy to make the diagnosis; therefore, with a high clinical index of suspicion, a second biopsy may be needed to obtain a pathological diagnosis of BCC.

Cytology
To accurately and definitively diagnose BCC of the eyelid, histological confirmation is required and is most commonly obtained through excisional (shave or punch) biopsy, which provides more information regarding the histological subtype of BCC. Cytology does provide a rapid alternative that may yield and even help confirm a diagnosis during the initial visit, however. The accuracy of this technique has been reported to be good, but its sensitivity in diagnosing BCC of the eyelid is unknown. It is not considered to be sufficiently sensitive in planning surgical management. A study by Barton et al showed that for patients who underwent cytology followed by excisional biopsy, cytology had a sensitivity of 92% in diagnosing BCC with a predictive accuracy of 75%. [52] These

values were compared to a second group of patients who had incisional biopsy and histological examination followed by excision with histological confirmation. The second group showed a sensitivity of 100% in diagnosing BCC with a predictive accuracy of 96%.

Histologic Findings
Several histologic types of BCC exist. Distinctions are important because clinical detection of tumor margins is more difficult with certain histologic types.[53] Usually, BCCs are well differentiated and cells appear histologically similar to basal cells of the epidermis. Tumor cells of nodular BCC, sometimes called basalioma cells, typically have large, hyperchromatic, oval nuclei and little cytoplasm. Cells appear uniform, and if present, mitotic figures are usually few. The nuclei resemble that of the basal cells of the epidermis, although they have a larger nuclear-to-cytoplasmic ratio and lack intercellular bridges. A mitotic figure is very rarely observed. Nodular tumor aggregates may be of varying sizes, but tumor cells tend to align more densely in a palisade pattern at the periphery of these nests (see the image below).
Nodular basal cell carcinoma. Nodular aggregates of basalioma cells are present in the dermis and exhibit peripheral palisading and retraction artifact. Melanin is also present within the tumor and in the surrounding stroma, as seen in pigmented basal cell carcinoma.

Cleft formation, known as retraction artifact, commonly occurs between BCC nests and stroma because of shrinkage of mucin during tissue fixation and staining. Some lobules may have areas of pseudoglandular change, and this is the predominant change in adenoid BCC. In other instances, large tumor lobules may degenerate centrally, forming pseudocystic spaces filled with mucinous debris. These changes are seen in the nodulocystic variant of BCC. Early lesions usually have some connection to the overlying epidermis, but such contiguity may be difficult to appreciate in more advanced lesions. Increased mucin is often present in the surrounding dermal stroma. A histopathologic examination of paraffin-embedded sections of BCC usually reveals solid cellular strands, collections of cells with darkstaining nuclei and scant cytoplasm. The peripheral cell mass is in a palisade arrangement that resembles the basal layer of the epidermis, sometimes with pseudocystic aspects, and with a variable number of mitoses. The connective tissue stroma surrounding the tumor islands is arranged in parallel bundles and often shows young fibroblasts immediately adjacent to the tumor. The specific histologic pattern of

each type of BCC varies in terms of desmoplastic reaction of the morpheaform type and in the stromal islands separated by basal cells strands of the fibroepithelial type. Artificial retraction of the stroma from the tumor islands is frequently observed histologically. Additionally, the stroma is often mucinous. Cells from recurrent BCC often show squamous aspects. Histologically, BCC is divided into 2 categories: undifferentiated and differentiated. When there is little or no differentiation, it is referred to as solid BCC and includes pigmented BCC, superficial BCC, sclerosing BCC, and infiltrative BCC (a histologic subtype). Differentiated BCC often has slight differentiation toward cutaneous appendages, including hair (keratotic BCC), sebaceous glands (BCC with sebaceous differentiation), or tubular glands (adenoid BCC). Noduloulcerative (nodular) BCC is usually differentiated. See the images below.
Histologic pattern of a well-differentiated basal cell carcinoma (original magnification X140). (Image courtesy of Prof Pantaleo Bufo, University of Foggia, Italy) Histologic pattern of a well-differentiated basal cell carcinoma (original magnification X250). (Image courtesy of Prof Pantaleo Bufo, University of Foggia, Italy) Histologic pattern of a well-differentiated basal cell carcinoma (original magnification X250). (Image courtesy of Prof Pantaleo Bufo, University of Foggia, Italy)

When the presence of a dense inflammatory infiltrate obscures the histologic margins of BCC, immunohistochemical stains for cytokeratins can help to identify tumor cells. These stains can be used with fixed or frozen tissue. Such staining with frozen tissue can take as little as 19 minutes, making it practical for use with Mohs micrographic surgery or with standard excision with frozen section margin control.[54] Nodular basal cell carcinoma Nodular or noduloulcerative basal cell carcinoma, the most common type, generally consists of large, round or oval tumor islands within the dermis, often with an epidermal attachment. The solid (nodular) type accounts for approximately 70% of all cases. Artificial retraction of the tumor islands from the surrounding stroma is commonly seen. Ulcerations may be seen in large tumors. Micronodular basal cell carcinoma Another aggressive variant, micronodular BCC, appears as small, nodular aggregates of basaloid cells. See the image below.
Micronodular basal cell carcinoma often has an absence of retraction artifact. The

characteristic histology is small size and uniformity of the tumor nodules. (Image courtesy of Shang I Brian Jiang, MD)

Retraction artifact tends to be less pronounced than in the nodular form of BCC, and subclinical involvement is often significant. Micronodular basal cell carcinoma is similar to the noduloulcerative type, although the tumor islands are small (often < 15 cells in diameter). Pigmented basal cell carcinoma In pigmented basal cell carcinoma (BCC), benign melanocytes in and around the tumor produce large amounts of melanin. These melanocytes contain many melanin granules in their cytoplasm and dendrites. Superficial BCC (see the image below) appears as buds of basaloid cells attached to the undersurface of the epidermis. Nests of various sizes are often seen in the upper dermis. The tumor cell aggregates typically show peripheral palisading.
Histology of superficial basal cell carcinoma. Nests of basaloid cells are seen budding from the undersurface of the epidermis. (Image courtesy of Michael L Ramsey, MD)

Adenoid basal cell carcinoma The adenoid type consists of strands of basaloid cells in a reticulate pattern, frequently with prominent stromal mucin. It may occur with the solid type. Morpheaform (sclerosing) basal cell carcinoma The more aggressive morpheaform BCCs have growth patterns resulting in strands of cells rather than round nests, within a fibrous stroma. They constitute approximately 5% of BCCs. Morpheaform BCC arises as thin strands of tumor cells (often only 1 cell in thickness) that are embedded in a dense fibrous stroma. The morpheaform basal cell carcinomas exhibit islands of tumor extending into the tissue and may exhibit perineural invasion in 3% of patients. This finding helps classify these 2 histotypes as the most aggressive, with the highest rates of recurrence and positive margins after excision. Infiltrative basal cell carcinoma This type of BCC accounts for 10% of BCCs. Tumor cells have growth patterns resulting in strands of cells infiltrating between collagen bundles rather than round nests. The strands of infiltrating BCC tend to be somewhat thicker than those seen in morpheaform BCC, and they have a spiky, irregular appearance (see the image below).
Infiltrative basal cell carcinoma. Tumor cells are arranged in narrow strands, and mucin-rich stroma is often present. (Image courtesy of Shang I Brian Jiang, MD)

Infiltrating BCC usually does not exhibit the scarlike stroma seen in morpheaform BCC. Peripheral palisading and retraction are less pronounced in morpheaform and infiltrating BCC than in less aggressive forms of the tumor, and subclinical involvement is often extensive. Cystic basal cell carcinoma Cystic basal cell carcinoma consists of large, round or oval tumor islands within the dermis with mucin present in the center of the island. This space is caused by central tumor cell degeneration. Superficial basal cell carcinoma The (multifocal) superficial type (see the image below) is characterized by numerous small nests of tumor cells usually attached to the undersurface of the epidermis by a broad base. Approximately 10-15% of all BCCs are of this type. This is the most common pattern seen in BCCs of the shoulder.
Histology of superficial basal cell carcinoma. Nests of basaloid cells are seen budding from the undersurface of the epidermis. (Image courtesy of Michael L Ramsey, MD)

Keratotic basal cell carcinoma The keratotic type resembles the solid type and its nests of basaloid cells with peripheral palisading. The island centers display keratinization and squamous differentiation. See the image below.
Keratotic basal cell carcinoma. Rare type characterized by keratocysts. (Image courtesy of Shang I Brian Jiang, MD)

Infundibulocystic basal cell carcinoma

The infundibulocystic type is rare and is usually found on the face. It resembles the keratotic type. Nests are arranged in an anastomosing pattern and lack stroma. Many small, infundibular cyst-like structures with keratinous material are present. Melanin is sometimes present. Metatypical basal cell carcinoma Metatypical BCC is rare. In this type, nests and strands of cells mature into larger and paler cells, and peripheral palisading, if any, is less developed than in other types. Prominent stroma, prominent mitotic activity, and many apoptotic cells may be present. This form may be best diagnosed when one evaluates a BCC with features between those of a nodular BCC and squamous cell carcinoma. These tumors are often aggressive, with an increased tendency for lymphatic and perineural spread. Basosquamous carcinoma The basosquamous type is controversial. It has been defined as a basal cell carcinoma (BCC) with differentiation towards squamous

cell carcinoma (SCC). It is made up of basaloid cells that are a larger, paler, and rounder than those of a solid BCC. It also consists of squamoid cells and intermediate cells. Some consider the diagnosis of this type most appropriate when one evaluates a tumor with contiguous areas of BCC and SCC. This type is considered to have metastatic potential and is considered an aggressive skin cancer (see the image below).
Basosquamous basal cell carcinoma. Foci of neoplastic cells with squamous differentiation are present. (Image courtesy of Shang I Brian Jiang, MD)

Fibroepithelioma of Pinkus The fibroepithelioma type consists of thin, anastomosing strands of basaloid cells in a prominent stroma. According to some studies, the so-called fibroepithelioma of Pinkus, considered to be a premalignant skin condition, must be considered as a fenestrated variant of basal cell carcinoma.[55, 56, 57]

Ultrasonography
The use of ultrasonography is controversial. High-frequency (20 MHz) and ultra-high-frequency (40-100 MHz) ultrasound systems have been used; their accuracy in delineating malignant lesions from benign lesions remains inadequate, however, with a success rate of approximately 20%. Furthermore, the claims of reliable tumor sizing and depth of invasion are promising but still passionately debated. Laser Doppler As an adjunct tool, laser Doppler may assist ophthalmologists in distinguishing between benign and malignant adnexal skin lesions and in establishing the tumor margin. It is reported that cutaneous perfusion to the eyelids is statistically significantly higher than other regions of the body (eg, forearm). Furthermore, the mean perfusion in pretarsal skin has been shown to be 50% greater than that in preseptal skin. In histologically documented basal cell carcinoma of the eyelid, cutaneous perfusion was significantly greater.[58]

Staging
Basal cell carcinoma rarely metastasizes and is usually not staged, unless the cancer is very large and is suspected of spreading to other parts of the body. BCC staging may be similar to the staging of squamous cell carcinoma, which is according to the following scheme: Stage 0: Cancer involves only the epidermis and has not spread to the dermis

Stage I: Cancer is not large (ie, < 2 cm) and has not spread to the lymph nodes or other organs Stage II: Cancer is large (ie, >2 cm) but has not spread to lymph nodes or other organs Stage III: Cancer has spread to tissues beneath the skin (eg, muscle, bone, cartilage), and/or to regional lymph nodes but not to other organs. Stage IV: Cancer can be any size and has spread to other organs High-risk tumors High-risk BCCs include the following: Recurrent or incompletely excised BCC Primary BCC with clinically indistinct borders Lesions in high-risk (the H, or mask) areas, mainly the embryonic fusion planes (eg, eyelids, nose, ear, nasolabial folds, upper lip, vermillion border, columella, periorbital region, temples, preauricular and postauricular areas, and scalp) Lesions that develop in cosmetically and functionally important areas (eg, face, genitals, anal and perianal regions, hands and feet, and the nail unit areas) Tumors with aggressive clinical behavior (ie, growing rapidly or >2 cm) Tumors with aggressive histologic subtype, including sclerosing (morpheaform), basosquamous (metatypical or keratinizing), perineural, periappendageal, or perivascular invasion, infiltrating, adenoidal, or multicentric Tumors that develop in sites with previous radiation therapy Tumors that develop in immunosuppressed patients Proceed to Treatment & Management

Approach Considerations
According to the 2011 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Basal Cell and Squamous Cell Skin Cancers, the goal of treatment is elimination of the tumor with maximal preservation of function and physical appearance. As such, treatment decisions should be individualized according to the patient's particular risk factors and preferences. [59] In nearly all cases, the recommended treatment modality for basal cell carcinoma (BCC) is surgery.[12, 13] Treatments vary according to cancer size, depth, and location. Dermatologists may perform nearly all of the therapeutic options in an outpatient setting. Most therapies are well established and widely applied; nevertheless, researchers are studying some additional options (eg, photodynamic therapy with photosensitizers)[60, 61, 62] ) and awaiting further reports. Local therapy with chemotherapeutic and immune-modulating agents is useful in some cases of BCC. In particular, small and superficial BCC may respond to these compounds. Topical 5% imiquimod is approved by the US Food and Drug Administration (FDA) for the treatment of nonfacial superficial BCCs that are less

than 2 cm in diameter. Lesions are generally treated once daily, 5 days per week, for a duration of 6-12 weeks. Likewise, topical fluorouracil is approved by the FDA for the treatment of superficial BCC, administered twice daily for 3-6 weeks.[63] Although no formal restrictions on fluorouracil have been determined based on lesion size or location, it is most commonly used on smaller superficial BCC on the trunk and extremities. Both imiquimod and fluorouracil may be used topically for prophylaxis or maintenance in patients who are prone to having many BCCs For tumors that are more difficult to treat (ie, infiltrative BCC, morpheaform [sclerosing] BCC, micronodular BCC, and recurrent BCC) or those in which sparing normal (noncancerous) tissue is paramount, Mohs micrographic surgery should be considered and discussed with the patient. For metastatic BCC, the 2011 NCCN guideline recommends clinical trials of systemic chemotherapy, particularly platinum-based combination therapy, which has been observed to produce useful, even complete, responses in a few patients. Clinical trials of investigational biologic modifiers such as hedgehog pathway inhibitors are also recommended.[59]

Surgical Modalities and Guidelines

The goal of therapy for patients with BCC is removal of the tumor with the best possible cosmetic result. By far, surgical modalities are the most studied, most effective, and most used BCC treatments. The effectiveness of surgical modalities depends heavily on the surgeon's skills; considerable differences in cure rates have been observed among surgeons. Modalities used include electrodesiccation and curettage, excisional surgery, Mohs micrographically controlled surgery, and cryosurgery.[64, 65, 66] The 2011 NCCN guidelines recommend that low-risk patients younger than 60 years of age be treated with curettage and electrodessication in nonhair-bearing areas. If fat is reached, surgical excision should generally be performed. An alternative is excision with postoperative margin assessment. High-risk patients should undergo excision with postoperative margin assessment or a Mohs resection.[59] Some studies suggest that dermato-oncological surgery is associated with a high risk of infection.[34] This risk is greater in patients with diabetes and in those having such surgery in the thigh or lower leg and foot. See the Medscape Reference topic Surgical Treatment of Basal Cell Carcinoma for more complete information on this topic.

Topical Treatments

Several topical creams are used in the management of BCC that is nonrecurring and superficial. The NCCN 2011 guidelines state that low-risk patients with superficial BCC who cannot undergo surgery or radiation can be treated with topical therapies, although the cure rate may not be as high. Such treatments may also be used in patients with a high risk of multiple primary tumors.[59] Topical 5-fluorouracil 5% Topical 5-fluorouracil 5% cream[20] may be used to treat small, superficial BCCs in low-risk areas. It interferes with DNA synthesis by blocking methylation of deoxyuridylic acid and inhibiting thymidylate synthetase and, subsequently, cell proliferation. In properly selected (eg, thin) tumors, cure rates of approximately 80% have been obtained. The cream is generally applied twice daily and must be used for at least 6 weeks for the treatment of superficial BCC.[67] Given that 5-fluorouracil can act on BCCs that are too small to be seen with the unaided eye, it may be used in patients with basal cell nevus syndrome or to preemptively treat subclinical tumors. Nevertheless, because not all tumors respond completely, careful patient monitoring is essential. The use of 5-fluorouracil for other types of BCC is generally not recommended because it may not penetrate deeply enough into the dermis to eradicate all tumor cells. Irritation and crusting are common and expected; significant irritation and discomfort are not uncommon, but scars are unusual. The recurrence rate is very high. Interferon Interferon alfa-2b is a protein product manufactured using recombinant DNA technology. It has shown some success in treating small (< 1 cm), nodular, and superficial BCCs. In appropriate BCC tumors, cures rates of up to 80% have been obtained. Several early studies have shown variable responses of BCC to intralesional interferon alfa. In a small study by Greenway et al, 1.5 million IU interferon alfa-2b injected intralesionally 3 times per week for 3 weeks resulted in the clearing of 3 cases of primary nonrecurrent BCC and 5 cases of primary superficial BCC.[68] Because larger studies are needed, most practitioners consider this an experimental therapeutic modality. Further data are needed before this treatment modality is recommended for routine ophthalmic practice. Interferon has not become a mainstay in BCC treatment because of its cost, the inconvenience of multiple visits, the discomfort of administration, and its adverse effects, which include flulike

symptoms. Acetaminophen has been administered to alleviate the flulike symptoms associated with this therapy. Imiquimod Imiquimod 5% cream (Aldara) is approved by the US Food and Drug Administration for the treatment of nonfacial superficial BCC. [69, 70] Several studies have shown imiquimod to be curative in all patients with superficial BCC if used twice daily and in 73-82% of patients when used once a day for 6-12 weeks. Smaller studies have shown similar responses for nodular BCC. Studies for other histologic types of BCC are under way.[14, 15, 18, 17, 16, 19] Treatment is usually initiated at 3 times per week and is increased as tolerated to once daily, and even twice daily if tolerated, to maintain mild-to-moderate skin irritation.[71, 72] Patients can titrate the frequency of application to maintain low-to-moderate skin irritation. A 12-week course of treatment is often used, which does not need be contiguous.[64] Tazarotene The receptor-selective acetylenic retinoid tazarotene (Tazorac) can also be used to treat small low-risk BCCs. Tazarotene is thought to cause BCC regression by increasing apoptosis and by decreasing cell proliferation in the skin cancer cells. In one case series, about 70.8% of the BCCs had clinical and dermoscopic regression of more than 50%, and 30.5% healed without recurrence after 3 years; most unresponsive tumors showed keratotic differentiation. The study involved the application of tazarotene 0.1% gel for 24 weeks in 154 small, superficial, and nodular BCCs (109 patients). Changes were followed up by dermoscopy and histologic examination. [73] In a published article by Wilson, topically applied tazarotene gel was shown to decrease tumor size in 47% of cases, and in 53% of cases, the tumor was eliminated completely.[74] In addition to being an off-label indication, another drawback to topical tazarotene for the treatment of BCC is that it requires longterm therapy, for 5-8 months. The only reported adverse effect is dry/irritating skin that is relieved after discontinuation of tazarotene. GDC-0449 An investigational agent, GDC-0449, which is administered orally, shows promise for more advanced BCC. At the 2008 meeting of the American Association for Cancer Research, a preliminary report was presented on promising results in locally advanced, multifocal, and metastatic BCC with GDC-0449. This compound is a synthetic chemical designed to reproduce the properties of the naturally occurring compound cycloamine. GDC0449 blocks the hedgehog pathway in cells. This pathway contains 2 genes, patched and smoothened, which lead to a known tumor

promoting gene, Gli1. A change in any of these genes has been associated with the development of BCC. The 2011 NCCN guideline recommends patients with metastatic BCC be enrolled in clinical trials of hedgehog pathway inhibitors. [59] GDC0449 is an example of this class of agent. GDC-0449 is given orally once a day. Its side effects include some loss of sense of taste and some loss of hair and weight. In the first clinical trial of GDC-0449, approximately 90% of the patients responded to treatment with tumor shrinkage or stabilization. Decreased amounts of GLI1 were found in the skin of patients after treatment.[75, 76]

Radiation Therapy
Basal cell carcinomas are usually radiosensitive, and radiation therapy (RT) can be used for advanced and extended lesions and in those patients for whom surgery is not suitable (eg, because of allergy to anesthetics, current anticoagulant therapy, a tendency to form keloids,[77] or facial tumors). Postoperative radiation can also be a useful adjunct when patients have aggressive tumors that were treated surgically or when surgery has failed to clear the margins of the tumor.[78] In the past, RT was a common treatment modality because of its high cure rate (97% for primary tumors). It is now used sparingly, because it is time consuming and extremely expensive. With the advancement in surgical techniques and other treatment modalities, RT is a reasonable treatment choice for recurrent tumors. It may be reserved for primary lesions requiring difficult or extensive oculoplastic surgery. It also eliminates the need for skin grafting when surgery would result in an extensive defect. RT is contraindicated in young patients because of the high risk of radiodermatitis and scars; in lesions on the trunk and extremities; and in delayed cancer recurrence (eg, especially in patients previously treated with radiation). RT requires multiple visits. Treatment results in radiation damage and, therefore, should be reserved for older patients. RT is less effective for nonfacial tumors. RT also is contraindicated in patients with connective tissue diseases or genetic conditions predisposing to skin cancer (eg, xeroderma pigmentosum, epidermodysplasia verruciformis, and basal cell nevus syndrome.) This histologic type in conjunction with RT may induce more tumors in the treated area. Radiation adverse effects include dermatitis, keratinization of the conjunctiva, and chronic keratitis. Cosmetic results are generally good to excellent, with a small amount of hypopigmentation or telangiectasia in the treatment port. This therapy can be less disfiguring than surgical excision.

Nevertheless, long-term results after several years can be deforming. Another disadvantage of this technique is that surgical margins cannot be examined. Tumors recurring in previously radiated sites tend to be aggressive and difficult to treat and reconstruct. RT remains an important, feasible option in selected patients with BCC. The 2011 NCCN guideline supports radiation therapy for patients whose condition is appropriate, with the reservation that in order to achieve its benefits (high cure rates and good comesis), it must be administered carefully and with attention to algorithm details by well-trained specialists. Training and proper support are particularly essential to the use of intensity modulated radiation therapy as primary treatment. Medical physicists must provide the necessary support and training in this new technology.[59]

Photodynamic Therapy
Photodynamic therapy (PDT) for basal cell carcinomas (BCCs) has been used for more than 20 years.[79, 80] PDT is the process of using specific wavelengths of light to photoexcite porphyrins that have been applied to neoplastic and preneoplastic cells. This increased energy is rapidly absorbed by adjacent tissue oxygen, causing the formation of singlet oxygen radicals. These radicals rapidly react with adjacent tissue and destroy it. 5-Aminolevulinic acid (ALA-PDT) is the only US Food and Drug Administration approved photoreactive molecule for PDT in the United States, and it is only approved for actinic keratoses. It is photoactivated with blue light for 1000 seconds after 1 hour of incubation. PDT is administered orally or parenterally, as well as applied topically, and localizes into tumor cells before activation by exposure to light (eg, laser). The efficacy is low, and this treatment is frequently palliative. PDT may cause local edema, erythema, blistering, and ulceration, but the final cosmetic effect is good. PDT yielded only a 50% cure rate for superficial BCC, versus an 83% cure rate for nodular BCC, in a study by Calzavara-Pinton et al. [81] At present, PDT has no distinct advantage over other well-established therapies for BCC of the eyelid. In a study by Puccioni et al, PDT using methyl aminolevulinate showed notable success and appears to be a viable option in the treatment of BCC of the eyelid in selected patients.[82] PDT as an adjunct is a reasonable choice in the following cases: Tumor recurrence with tissue atrophy and scar formation Elderly patients or patients with medical conditions preventing extensive oculoplastic reconstructive surgery Tumor with poorly defined borders based on clinical examination Tumor requiring difficult or extensive oculoplastic surgery

Although its use is off label, PDT has been used for treatment and prevention of BCCs, including those patients with immunosuppression and nevoid BCC syndrome. Shallow tumors, such as superficial BCCs, respond most consistently. Surgical excision has been shown to be significantly more effective than ALAPDT in the treatment of nodular BCC.[83] The strongest support for PDT as a modality for BCCs comes with data on thin lesions treated with methylaminolevulinate (used outside the United States), but at least one long-term follow-up trial has also shown surgical excision to be superior.[84] Christensen et al reported a 10-year lesion complete response rate of 87% with two sessions of dimetylsulfoxide-supported topical 5aminolaevulinic acid-PDT and curettage for primary, small BCC. Favourable cosmetic outcomes also were reported for nearly all cases.[85] Various protocols have been followed to achieve varying levels of successincreasing incubation time, increasing occlusion time, and using longer and/or deeper-penetrating wavelengths of light (eg, red light or pulse-dye laser). Many patients continue to prefer PDT because of its short healing time, excellent cosmesis, and relative affordability. Also see the British Association of Dermatologists Therapy Guidelines and Audit Subcommittees clinical guidelines summary, Guidelines for topical photodynamic therapy: update.[80]

Systemic Retinoids
Although several clinical trials have shown some efficacy for available systemic retinoids in chemotherapy and chemoprevention, the long-term toxicity of these agents generally excludes them as treatment choices for most patients.[86] Studies are exploring their value as cancer preventive agents in patients at high risk for developing multiple tumors.

Hedgehog Pathway Inhibitors

Vismodegib Vismodegib (Erivedge) is the first FDA-approved drug for advanced forms of basal cell carcinoma. It selectively inhibits Smoothened (SMO), a key transmembrane protein involved in hedgehog signal transduction of cancerous epithelial cells. In a phase I dose-ranging study by Von Hoff et al, 18 of 33 patients showed an objective response. Two of the 18 had complete response, and the remaining 16 showed a partial response.[87] FDA-approval was based on a single, international, open-label trial (n=104). Of the 104 participants, 96 were evaluable. Of those with metastatic BCC (n=33), 30.3% had partial response, but none had complete

response. With locally advanced BCC (n=63), 22% showed a partial response and 20% showed complete response. [88]

Recurrence
The following is a list of treatments and their 5-year recurrence rates for primary BCCs: Surgical excision - 10.1% Radiation therapy - 8.7% Curettage and electrodesiccation - 7.7% Cryotherapy - 7.5% All non-Mohs modalities - 8.7% Mohs micrographic surgery - 1.0% These rates are probably affected by the fact that most clinicians use cryotherapy, curettage, and desiccation mostly on smaller and better-demarcated lesions.

Prevention
Avoid possible potentiating factors (eg, sun exposure, ionizing radiation, arsenic ingestion, tanning beds). The regular use of sunprotecting clothing (eg, wide-brimmed hat, long-sleeved shirts, sunglasses with ultraviolet [UV] protection) is recommended when outdoors. Instruct patients to avoid sun exposure particularly during the middle of the day (ie, 11:00 am to 3:00 pm), which is the most dangerous time. Also, the sun's rays are especially intense in sunny climates and at high altitudes, and UV radiation can also pass through clouds and water. Patients should be instructed to be careful on the beach and in the snow because sand, water, and snow reflect sunlight and increase the amount of received UV radiation. Researchers are investigating chemoprevention with systemic administration of retinoids as cancer preventive agents in patients at high risk for developing basal cell carcinoma; the efficacy of these agents will take several years to evaluate, however. The American Cancer Society recommends a dermatologic examination every 3 years for people aged 20-40 years and every year for people older than 40 years.

Consultations
Ideally, treatment options for the patient with basal cell carcinoma should be evaluated jointly with a surgeon, dermatologist, and radiotherapist and based on histologic diagnosis. Although early basal cell carcinoma can be treated adequately by means of local excision, advanced and recurrent tumors are best managed by a multidisciplinary approach involving head and neck surgical oncologists, Mohs micrographic surgeons, reconstructive plastic surgeons, pathologists, prosthetists, and radiation oncologists.

Long-Term Monitoring
Mc Loone et al found that patients who are diagnosed with BCC have a 35% chance of developing another tumor within 3 years and a 50% chance of developing another (not recurrent) BCC within 5 years.[41] The NCCN 2011 guidelines state that 30-50% of patients will develop another nonmelanoma skin cancer within 5 years. These patients are also at an increased risk of developing cutaneous melanoma.[59] Therefore, regular skin screenings are recommended.
[41, 59]

Less than 1% of BCCs spread to another site in the body; nevertheless, after treatment, which is curative in more than 95% of cases, BCC may develop in new sites. Recommend appropriate prolonged or lifelong follow-up care. Tumors occurring after radiotherapy tend to be more aggressive and infiltrative than other tumors. Metastasis is rare but has been reported with rates of 0.01-0.1%. Metastases most often originate from large, ulcerated tumors. Metastases usually occur in regional lymph nodes. Follow-up visits are scheduled 3 months after therapy and every 6 months to 1 year thereafter for the life of the patient. Proceed to Medication

Medications used for the treatment of basal cell carcinoma (BCC) include neoplastic agents such as 5-fluorouracil and imiquimod; the photosensitizing agent methyl aminolevulinate cream; and the acetylenic retinoid tazarotene.

Medication Summary

Antineoplastic Agents
Class Summary The most common chemotherapeutic agent used in superficial basal cell carcinoma is topical 5-fluorouracil.
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Fluorouracil 5-Fluorouracil is used topically for the management of superficial BCC. It interferes with DNA synthesis by blocking methylation of deoxyuridylic acid and inhibiting thymidylate synthetase and, subsequently, cell proliferation.
View full drug information

Imiquimod The precise mechanism of imiquimod for superficial BCC is unknown. It may increase tumor infiltration by lymphocytes, dendritic cells, and macrophages. It is indicated for biopsy-confirmed primary nonfacial superficial BCC in adults with normal immune systems. Additionally, tumors must not exceed 2 cm in diameter on certain

areas of the body. Imiquimod is indicated only when surgical methods are not appropriate.
View full drug information

Interferon alfa-2b Interferon alfa-2b is a protein product manufactured with recombinant DNA technology. The mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may be important. As an investigational drug for nodular BCC, interferon alfa-2b was used in a randomized, placebo-controlled multicenter study with 172 patients. Intralesional injections of 1.5 million U administered 3 times/wk for 3 wk yielded an 86% complete-response rate, compared with 29% for placebo. A similar study did not show efficacy for morpheaform or aggressive BCCs.
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Visomodegib (Erivedge) Visomodegib is a Hedgehog (Hh) pathway inhibitor. The Hedgehog signaling pathway is important in embryogenesis, but in adults, it is mostly inactive. Signaling is relayed by key proteins including Smoothened (SMO). Hh ligand-expressing cancerous epithelial cells that are activated by the Hh signaling pathway may cause growthpromotion. Vismodegib binds to and inhibits SMO, a transmembrane protein involved in Hedgehog signal transduction. This agent is indicated for treatment of adults with metastatic basal cell carcinoma or with locally advanced basal cell carcinoma that has recurred following surgery, or those who are not candidates for surgery or radiation.

Photosensitizing Agent, Topical

Class Summary Photodynamic therapy (PDT) for basal cell carcinomas is the process of using specific wavelengths of light to photoexcite porphyrins that have been applied to neoplastic and preneoplastic cells. This increased energy is rapidly absorbed by adjacent tissue oxygen, causing the formation of singlet oxygen radicals. These radicals rapidly react with adjacent tissue and destroy it. Methyl aminolevulinate cream Methyl aminolevulinate cream is a porphyrin precursor used in combination with narrow-band, red-light illumination for nonhyperkeratotic, nonpigmented actinic keratoses. When used with photodynamic therapy, the accumulation of photoactive porphyrins produces a photodynamic reaction that results in a cytotoxic process dependent upon the simultaneous presence of oxygen.

Receptor-Selective Acetylenic Retinoids

Class Summary These agents decrease cohesiveness of abnormal hyperproliferative keratinocytes and may reduce potential for malignant degeneration. It modulates keratinocyte differentiation.
View full drug information

Tazarotene Tazarotene is a retinoid prodrug with an active metabolite that modulates differentiation and proliferation of epithelial tissue; it also may have anti-inflammatory and immunomodulatory properties. It is not approved by the US Food and Drug Administration for treating basal cell carcinoma.

1.

PENDAHULUAN

Kejadian keganasan pada kulit semakin meningkat dari tahun ke tahun. Pada tahun 2006 di Amerika Serikat didapatkan lebih dari 1.000.000 kasus baru keganasan kulit dalam berbagai stadium klinis. Peningkatan angka kematian dari tahun 2005 sampai dengan tahun 2006 mencapai lebih dari 10.000 pasien. Kematian terjadi akibat keganasan primer pada kulit maupun komplikasi yang timbul dari keganasan tersebut.1 Secara garis besar keganasan pada kulit dibagi menjadi 2, yaitu keganasan melanoma dan non melanoma. Melanoma maligna merupakan salah satu jenis tumor ganas yang berasal dari melanocyt yang berfungsi menghasilkan Melanin, di mana dapat terjadi pada kulit (Cutaneus Melanoma) maupun pada mukosa (Mucosal Melanoma). Melanocyt sendiri pada kulit terdapat pada lapisan ektodermal kulit, yang berada di stratum basalis epidermis. Melanoma maligna muncul dari melanocyte yang berubah sifat menjadi ganas.2

Angka kejadian Melanoma Maligna bervariasi di dunia. Di Amerika Serikat, angka kejadian mencapai 15 per 100.000 orang atau mencapai 4% dari seluruh keganasan yang terjadi. Sedangkan di Australia, angka kejadian mencapai 45 per 100.000 orang dan di China angka kejadian < 1 per 100.000 orang. Di Indonesia, berdasarkan statistik WHO April 2011, angka kejadian 1,4 per 100.000. 1,2 Studi epidemiologi juga menunjukkan bahwa Melanoma Maligna memiliki kekhasan dalam umur, jenis kelamin, ras dan lokasi penyakit. Berdasarkan umur, rata rata usia penderita adalah 55 tahun. Melanoma Maligna sendiri lebih banyak diderita kaum pria (1,2:1). Berdasarkan penelitian oleh WHO, ras Kaukasian memiliki resiko terkena Melanoma Maligna lebih tinggi dibandingkan ras lain (ras Mongoloid, ras Negrito, ras Latin). Lokasi yang sering terkena penyakit ini adalah daerah tubuh yang terpapar langsung sinar UV yang berasal dari matahari. 2. FAKTOR RESIKO penelitian terdahulu, diketahui beberapa faktor resiko yang

Berdasarkan

mengakibatkan terjadinya Melanoma Maligna.1,3 1. Paparan Sinar Ultra Violet

Paparan Ultra Violet B (panjang gelombang 290-320 nm) yang berasal dari matahari merupakan faktor karsinogenik paling berpotensi. Seseorang dengan kulit putih dan jumlah rambut tipis menyebabkan sinar UV langsung terpapar pada kulit. Paparan UV menginduksi terjadinya melanoma dengan merusak DNA dari Melanocyte sehingga berubah sifat dan meningkatkan produksi radikal bebas dalam kulit. 2. Atypical Nevi Melanoma dapat terjadi dari Atypical Nevi atau Dysplastic Nevi yang berubah sifat menjadi ganas. Gambaran atypical nevi memiliki ciri khas bentuk yang asimetris dan warna coklat atau lebih muda. Pada penelitian oleh Tucker (1997), seseorang dengan Nevi > 5 buah memiliki resiko mengalami 10 kali lipat mengalami Melanoma Maligna. 3. Riwayat Keluarga Menurut Clark et al (1978), 10% dari penderita Melanoma Maligna merupakan Familial Melanoma. Apabila salah seorang anggota keluarga mengalami Melanoma, Keturunan pertamanya sering didapatkan Atypical Nevi yang juga merupakan faktor resiko melanoma maligna. 4. Perubahan Genetika Perubahan genetika yang menyebabkan terjadinya Melanoma Maligna erat berkaitan dengan faktor keturunan atau riwayat dalam keluarga. Menurut Serrano et al (1993) yang didukung penelitian Masback et al (2002), adanya gen CDKN2A merupakan tanda khas mutasi genetika yang terjadi pada penderita dengan Melanoma Maligna. CDKN2A sendiri mengkode kromosom protein p16, di mana p16 memiliki peranan vital dalam menghambat siklus sel. Selain perubahan genetika oleh CDKN2A, Melanoma Maligna juga dapat berhubungan dengan perubahan kromosom 9p21 yang terjadi pada Familial Melanoma. 3. KLASIFIKASI HISTOPATOLOGI

Melanoma Maligna secara histopatologi diklasifikasikan menjadi 4 tipe, antara lain:2 1. Superficial Spreading Melanoma Jenis ini merupakan jenis Melanoma yang paling sering terjadi yaitu 70% dari kejadian Melanoma. Umumnya muncul dari nevus atau dari kulit yang masih normal sebelumnya.

Gambarannya berupa plak dengan ukuran 0,5 3 cm dengan tepi ireguler dan meninggi. Permukaan sering berwarna kecoklatan. Meluas secara radial. Lesi ini sering regresi spontan dan meluas ke dalam. Predileksinya berbeda pada pria dan wanita. Pria sering pada badan dan leher sedangkan wanita sering pada tungkai bawah. 2. Nodular Melanoma Jenis ini merupakan Melanoma yang paling sering di Indonesia, kejadiannya terbanyak kedua setelah Superficial Spreading Melanoma. Umumnya muncul dari kulit normal sebelumnya dan jarang dari nevus.

Gambarannya berupa setengah bola atau polipoid dengan tepi simetris. Sering berwarna kebiruan. Meluas secara vertikal, sering menyebabkan perdarahan dan muncul lesi satelit. Predileksi paling banyak di punggung. 3. Lentigo Melanoma Maligna Jenis ini jarang ditemukan. ulserasi,

Gambarannya berupa lesi berbenjol dengan permukaan tengah lebih gelap dibanding tepi disertai hiperkeratotik pada ujung lesi, dengan tepi tak rata. Meluas secara radial. Melanoma jenis ini sering ditemukan pada daerah yang sering terpapar langsung sinar matahari. 4. Acral Lentigenous Melanoma

Melanoma paling jarang terjadi dan memiliki nama Palmar Plantar Subungual Melanoma karena predileksinya. Muncul dari kulit normal.

Gambarannya berupa nodul yang kadang disertai ulserasi pada tengah benjolan. Histopatologinya dikenali berdasarkan lokasinya yang khas. 4. STADIUM KLINIS

Terdapat beberapa klasifikasi klinis pada Melanoma Maligna. Klasifikasi klinis ini penting untuk menentukan penatalaksanaan pada Melanoma dan nilai prognosis. Klasifikasi yang paling sering digunakan adalah sistem TNM (AJCC,2002). Selain system TNM, klasifikasi lain berdasarkan kedalaman seperti Clarks Level dan Breslows Thickness juga sering digunakan dalam penentuan prognosis dari Melanoma Maligna. 1,2,3,4

(DIKUTIP DARI TMN ATLAS STAGING ONCOANATOMY 2008) Clarks Level

Level I Level II Level III Level IV Level V I II III IIV 5.

: Melanoma terdapat pada epidermis, membrane basalis utuh : Melanoma menembus membrane basalis sampai papilare dermis : Melanoma menembus sampai perbatasan papilare dan retikulare dermis : Melanoma mencapai stratum retikularie dermis : Melanoma menembus jaringan subcutan : Melanoma menginvasi sampai kedalaman 0,76 mm : Melanoma menginvasi sampai kedalaman antara 0,76 1,5 mm : Melanoma menginvasi sampai kedalaman antara1,5 4 mm : Melanoma menginvasi sampai kedalaman lebih dari 4 mm DIAGNOSIS

Breslows Thickness

Untuk menegakkan suatu diagnosis Melanoma Maligna, perlu melakukan pemeriksaan meliputi anamnesis, pemeriksaan fisik dan pemeriksaan penunjang, yang akhirnya sekaligus untuk menentukan klasifikasi klinis. 1. Anamnesis Pada Melanoma perlu untuk mengetahui awal dari benjolan apakah ada atau tidak ada sebelumnya, bentuk dan ukuran benjolan dan kecepatan pertumbuhan. Perlu ditanyakan juga rasa nyeri dan perdarahan pada benjolan. Selain mengenai perjalanan penyakit sendiri, perlu dicari faktor resiko terjadinya Melanoma. Mulai dari riwayat keluarga, pekerjaan sehari hari sampai dengan kebiasaan sehari hari. 1,5 2. Pemeriksaan Fisik Adanya suatu lesi kehitaman yang berubah sifat menjadi suatu Melanoma, memiliki gambaran perubahan sebagai berikut: 5

Pemeriksaan tidak hanya dilakukan pada bagian yang tampak mengalami perubahan sifat, tetapi perlu juga mencari kemungkinan tempat lain yang juga mengalami Melanoma Maligna. Selain mencari gambaran Melanoma, penting untuk mencari ada tidaknya Limfonodi regional yang teraba membesar pada saat melakukan pemeriksaan fisik. Hal ini penting pada penentuan staging keganasan ini. 3. Pemeriksaan Penunjang Pemeriksaan penunjang pada pasien dengan Melanoma, juga memiliki peranan dalam menentukan staging dari Melanoma itu sendiri. Yang harus dilakukan saat melakukan pemeriksaan penunjang meliputi2,3 a. Pemeriksaan Laboratorium Dilakukan pemeriksaan darah rutin untuk persiapan tindakan yang akan dilakukan. Selain pemeriksaan darah rutin, pada pasien dengan Melanoma perlu diperiksa status nutrisi pasien dan kadar LDH. Keduanya berhubungan sebagai faktor prediktif terhadap prognosis pasien.

b. Pemeriksaan Radiologis Pemeriksaan dilakukan untuk mencari adanya keterlibatan organ paru dan hati dalam proses keganasan. Pemeriksaan yang sering dilakukan meliputi pemeriksaan Ro Thorax dan USG Abdomen untuk mencari gambaran metastasis. Pemeriksaan PET (Positron Emission Tomography) pada negara maju sudah sering dilakukan untuk mencari limfonodi yang terlibat secara langsung dan lesi satelit pada Melanoma. c. Pemeriksaan Sitologi Biopsi Eksisi biopsi komplit lebih dipilih dan harus mencakup 1 2 mm jaringan sehat. Eksisi dilakukan untuk mendapatkan staging dari Melanoma yang diderita pasien. Apabila Melanoma terlalu luas, Incisi biopsi dilakukan untuk memastikan pasien menderita Melanoma. Selain biopsi pada Melanoma perlu dilakukan pengambilan limfonodi regional yang teraba membesar, untuk menentukan keterlibatan limfonodi dalam metastase. 6. PENATALAKSANAAN

Saat pertama kali menemukan suatu lesi berpigmen yang dicurigai sebagai Melanoma, perlu tata laksana bertahap untuk mencapai prognosis yang lebih baik. Berikut adalah algoritme tata laksana Melanoma sesuai dengan NCCN: 1,5,7

PEMBEDAHAN EKSISI LUAS DARI LESI PRIMER Setelah melakukan pengambilan lesi baik secara eksisi pada lesi yang kecil maupun incisi pada lesi yang besar, diketahui hasil histopatologi suatu Melanoma Maligna disertai ada maupun tidaknya gambaran pembesaran Limfonodi, eksisi luas dilakukan sampai daerah bebas tumor. Berdasarkan penelitian oleh Veronesi et al (1988), eksisi pada Melanoma dengan ketebalan 1 mm (Breslow 2) dilakukan hingga 1 3 cm dari tepi Melanoma Maligna yang tampak pada kulit. Penelitian lain oleh Barch et al (1993), Melanoma dengan ketebalan > 4 mm (Breslow 4) perlu dilakukan eksisi luas hingga 4 cm dari tepi lesi. Kedua penelitian menunjukkan angka rekurensi Melanoma yang sangat rendah disertai meningkatnya angka

harapan hidup pada penderita Melanoma. Namun, kelemahan pada penelitian ini adalah tidak memperhitungkan ada tidaknya Limfonodi yang terlibat. 6,7 MANAJEMEN LIMFONODI REGIONAL Keterlibatan Limfonodi pada Melanoma Maligna dimulai pada Melanoma Stage III (AJCC, 2002). Hal ini menandakan adanya penyebaran dari sel ganas ke tempat jauh. Penelitian terakhir merujuk pada hubungan ketebalan dari Melanoma Maligna terhadap kemungkinan keterlibatan Limfonodi regional. Pada pasien dengan Melanoma ketebalan < 1 mm, kurang dari 5%, ada keterlibatan dari Limfonodi regional, sehingga direkomendasikan untuk tidak dilakukan Limfadenektomi. Pada Melanoma dengan ketebalan 1 4 mm, 20 25% terjadi keterlibatan Limfonodi, sehingga perlu dilakukan limfadenektomi selektif dan apabila positif dilakukan lifadenektomi total. Untuk Melanoma dengan ketebalan > 4 mm, angka keterlibatan Limfonodi mencapai 96% sehingga perlu dilakukan limfadenektomi selektif, dilanjutkan limfadenektomi total. 1,2,3,7 NON PEMBEDAHAN Setelah dilakukan semua langkah pembedahan, survival rate dapat ditingkatkan dengan melanjutkan terapi menggunakan terapi sistemik dengan tujuan utama mencegah metastasis ke organ jauh. Sampai saat ini didapatkan 2 terapi sistemik yaitu kemoterapi dan immunotherapy dengan Interferon Alfa dan Vaksin Melanoma. KEMOTERAPI Dacarbazine merupakan agent kemoterapi sering diberikan pada penderita Melanoma Maligna. Selain Dacarbazine, agen kemoterapi berbahan dasar Platinum juga sering dipakai baik sebagai agen tunggal maupun dikombinasikan dengan Dacarbazine. Namun, banyak penelitian menyebutkan bahwa kemoterapi gagal meningkatkan survival rate sehingga saat ini sudah tidak banyak digunakan. INTERFERON ALFA Oleh Legha (1997), lebih dari 15% pasien dengan Melanoma memberikan respon baik untuk mengurangi kejadian metastasis. Interferon memiliki respon anti tumor dengan menghambat proliferasi dari Melanoma, meningkatkan fagositosis anti tumor dan mengubah permukaan dari sel tumor sehingga mudah ditangkap oleh anti tumor dan menurunkan angka metastasis. Namun, dosis pemberian dari Interferon masih diteliti, dikarenakan tidak ada persamaan pada setiap obyek penelitian dan memiliki efek toksik bila diberikan dalam jangka waktu panjang. 2,8 VAKSIN MELANOMA

Adanya kesulitan dalam mengendalikan dalam mengendalikan pertumbuhan Melanoma dan efek samping kemoterapi yang diberikan, memberi tempat untuk percobaan pemberian Vaksin Melanoma pada penderita Melanoma Maligna stadium lanjut. Vaksin ini berasal dari sel ganas dari Melanoma yang diubah sifatnya secara biomolekuler menjadi alat melawan Melanoma itu sendiri. Vaksin ini akan meningkatkan aktivitas dari Antigen Presenting Cell yang membuat sel imun dengan mudah mengenali Melanocyt yang akan berubah sifat menjadi ganas. Namun dari penelitian Demmiere et al (2006), kurang dari 10% penderita merespon baik terhadap pemberian vaksin ini dan vaksin ini belum terbukti bisa menghambat metastasis Melanoma ke organ jauh. Masih dibutuhkan penelitian lebih lanjut. 9 7. PROGNOSIS

Prognosis penderita dengan melanoma bergantung pada stadium klinis dari Melanoma itu sendiri. Penderita Melanoma stage 1, angka 5 years survival mencapai lebih dari 90%. Melanoma stage 2 mencapai 45 77%, stage 3 antara 27 70%. Bila telah didapatkan metastasis (stage 4) 5 years survival kurang dari 20%.7,9

PENDAHULUAN Kanker kulit merupakan kanker terbanyak di Amerika Serikat dengan angka kejadian 40% dari seluruh kanker.Angka ini cenderung meningkat dengan perubahan lingkungan hidup dan terutama peningkatan paparan sinar ultra violet matahari.Mayoritas kanker kulit adalah karsinoma sel basal (BCC), karsinoma sel skuamosa (SCC), dan Melanoma (ketiga jenis ini merupakan 95% dari seluruh kanker kulit). Karsinoma sel Skuamosa (SCC) adalah neoplasma kulit pada keratinosit.

FAKTOR ETIOLOGI Sebagian besar tumor kulit terjadi sebagai akibat kerusakan multikausal jangka panjang dari epidermis.Faktor yang paling dikenal adalah cahaya matahari.Terutama pada orang yang banyak terpapar cahaya matahari, seperti para pelaut, petani, dan orang yang banyak pergi ke daerah tropik, pada umur lanjut terjadi didaerah kulit yang terbuka (muka, kepala, punggung tangan) perubahan-perubahan aktinik.Dari spektrum cahaya matahari

terutama bagian ultraviolet yang memberi kerusakan terbesar.Terutama pembakaran oleh cahaya matahari dalam hal ini merupakan faktor penting. Penderita yang mempunyai kulit dengan sedikit pigmen, lebih cepat menderita pembakaran oleh cahaya matahari, sehingga mempunyai risiko terbesar. Faktor lain adalah mekanisme reparasi molekul DNA dalam inti sel. Jika mekanisme ini (sering familial) sedikit banyak terganggu maka kemungkinan terjadinya tumor kulit lebih besar. Kemungkinan reparasi yang mengalami defek ekstrem kita dapati pada penyakit kulit familial resesif xeroderma pigmentosum dengan terjadinya banyak tumor maligna mulai umur muda.Juga pada melanoma dipikirkan kemungkinan korelasi dengan pengaruh cahaya matahari, ditambah dengan pertahanan imunologik kulit terhadap sinar ultraviolet terhambat. Akhirnya diketahui juga bahwa radiasi sebelumnya, pembentukan sikatriks yang luas dan proses inflamasi kronik (misalnya sikatrises luka bakar, ulkus kruris, fistula), mempunyai peran juga. Kontak dengan zat-zat toksik, sering sebagai akibat dari pekerjaan, dapat menyebabkan timbulnya tumor kulit.Ter misalnya sering dipakai dalam onkologik eksperimental.'untuk menimbulkan tumor.Karena pengaruh terapi dengan arsenikum, dahulu sering digunakan, terjadi keratosis yang cukup karakteristik, yang dapat berkembang menjadi tumor maligna.

KANKER KULIT Kanker kulit dibedakan atas kelompok Melanoma dan kelompok Non Melanoma. Kelompok Non Melanoma dibedakan atas Karsinoma Sel Basal, Karsinoma Sel Skuamosa dan karsinoma adneksa kulit. Faktor-faktor yang berperanan dalam mekanisme karsinogenesis keganasan pada kulit diantaranya: sinar matahari: merupakan faktor utama terjadinya kanker. Sembilan puluh persen kanker pada bagian tubuh yang terkena sinar matahari karsinogen: arsenik, radiasi, batubara, obat immunosupresi

trauma dan inflamasi kronik : osteomielitis, dermatitis, lupus eritematosus faktor herediter: xeroferma pigmentosum, sindroma basal cell nevus infeksi: HPV tipe 5,8,16,18 onkogen: mutasi anti-oncogene p53

KARSINOMA SEL SKUAMOSA Karsinoma sel skuamosa adalah neoplasma maligna dari keratinizing cell dengan karakteristik anaplasia, tumbuh cepat, invasi lokal dan berpotensi metastasis Patogenesis karsinoma set skuamosa sama seperti karsinoma sel basal yaitu : adanya peran paparan sinar ultraviolet sinar matahari yang menyebabkan terjadinya mutasi gen supresor, disamping itu terdapat pula peran imunosupresi dan infeksi virus.Karsinoma sel skuamosa dapat pula terjadi pada parut/scar luka bakar, yang disebut sebagai Marjolin ulcer. Yang berisiko tinggi untuk mendapat kanker kulit adalah penderita kelainan pre kanker (xeroderma pigmentosum, keratosis senilis, compund nevus, multiple dysplatic nevi), bangsa kulit putih, terbakar sinar matahari, terpapar sinar pengion, arsen, jelaga, keloid luka bakar, penderita dengan fistula, immuno supresi, dsb. Insidens tertinggi pada usia 50 - 70 tahun, paling sering pada kulit berwarna di daerah tropik. Laki-laki lebih banyak dari wanita. Lesi dapat timbul dari kulit normal atau dari lesi prakanker, pada orang kulit kulit putih hal ini diduga akibat rangsangan sinar ultraviolet, karsinogen kimia (Coal tar, arsen, hidrokarbon polisiklik). Sedangkan pada kulit berwarna : predisposisi trauma, ulkus kronik, jaringan parut dan dapat pula terjadi dari fistel yang tidak sembuh-sembuh Predileksi : kulit yang terpapar sinar matahari, membrana mukosa, lokasi terbanyak (orang kulit putih : wajah, ekstremitas atas, kulit berwarna : ekstremitas bawah badan, dapat pada bibir bawah, dorsum manus).

Klasifikasi Histopatologi

Disamping itu perlu dilaporkan pula gradasi histopatologisnya, yaitu Gx : G1 : G2 : G3 : G4 : Gradasi diferensiasi tidak dapat diperiksa Diferensiasi baik Diferensiasi sedang Diferensiasi buruk Tidak berdiferensiasi (undifferentiated)

Stadium Klinis Klasifikasi TNM T - :Tumor Primer Tx :Tumor primer tidak dapat diperiksa T0 :Tidak ditemukan tumor primer Tis:Karsinoma in situ T1 : Tumor dengan ukuran terbesar <2 cm T2 :Tumor dengan ukuran terbesar >2 s/d <5 cm T3 :Tumor dengan ukuran terbesar >5 cm T4 :Tumor menginvasi struktur ekstradermal dalam, seperti kartilago, otot skelet atau tulang N -:Kelenjar getah bening regional NX:Kelenjar getah bening regional tidak dapat diperiksa N0: Tidak ditemukan metastasis kelenjar getah bening N1:Terdapat metastasis kelenjar getah bening regional M -: Metastasis jauh MX: Metastasis jauh tidak dapat diperiksa M0: Tidak ada metastasis jauh M1: Terdapat metastasis jauh Stadium Stadium 0 Stadium I Stadium II Stadium III Stadium IV Tis T1 T4 NO NO NO MO MO MO MO MO

T2,T3 NO Tiap T N1

Tiap T Tiap N M1

Prosedur Diagnostik A. Pemeriksaan Klinis 1. Anamnesis Penderita mengeluh adanya lesi di kulit yang tumbuh menonjol, mudah berdarah, dapat berbenjol-benjol, bagian atasnya terdapat borok seperti gambaran bunga kol 2. Pemeriksaan Fisik Didapatkan suatu lesi yang tumbuh eksofitik, endofitik, infiltratif, tumbuh progresif, mudah berdarah dan pada bagian akral terdapat ulkus dengan bau yang khas. Selain pemeriksaan pada lesi primer, perlu diperiksa ada tidaknya metastasis regional dan tanda tanda metastasis jauh ke paru-paru, hati.

B. Pemeriksaan Penunjang 1. Radiologi: X-foto toraks, X-foto tulang di daerah lesi, dan CTScan/ MRI atas indikasi 2. Biopsi untuk pemeriksaan histopatologi: -Lesi < 2 cm dilakukan biopsi eksisional (sekaligus merupakan terapi) -Lesi > 2 cm dilakukan biopsi insisional Prosedur Terapi Terapi untuk SCC hampir sama dengan.basalioma. Jenis tindakan tergantung dari ukuran lesi, lokasi anatomi, kedalaman invasi, gradasi histopatotogi dan riwayat terapi. Prinsip terapi yaitu eksisi radikal/ luas untuk lesi primer dan rekonstruksi penutupan defek dengan baik. Penutupan defek dapat dengan cara penutupan primer, tandur kulit atau pembuatan flap. Tindakan eksisi luas harus dengan batas aman 1 - 2 cm. Bila radikalitas tidak tercapai, diberikan radioterapi adjuvant. Untuk lesi di daerah cantus, nasolabiat fold, peri orbital dan periaurikular, dianjurkan untuk Mohs micrographic surgery (MMS). Untuk lesi di kepala dan leher yang menginfiltrasi tulang atau kartilago dan belum bermetastasis jauh, dapat diberikan radioterapi.

Untuk kasus inoperabel dapat diberikan radioterapi preoperatif dilanjutkan dengan eksisi luas atau MMS. Bila terdapat metastasis ke kgb regional, dilakukan diseksi kgb.

Peranan ultraviolet dalam pertumbuhan SCC Faktor yang mempengaruhi pathogenesis SCC adalah paparan ultraviolet, mutasi genetic, imunosupresi, dan infeksi virus. Ultraviolet memediasi perkembangan SCC melalui beberapa mekanisme. Paparan UVB mempengaruhi kemampuan dan densitas antigen sel langerhans dan interferon . Paparan Ultraviolet menyebabkan terjadinya mutasi tumor supresor gen p53 dengan memproduksi pyrimidine DNA yang dianggap sebagai mutasi akibat ultraviolet. Fungsi normal protein p53 adalah untuk menginduksi ekspresi beberapa protein untuk regulasi siklus sel dan menginduksi apoptosis. Di epidermis, p53 mudah diinduksi oleh ultraviolet dan aktivasi nya menyebabkan berhentinya siklus sel pada fase G1, dimana pada fase tersebut terjadi perbaikan DNA yang rusak, induksi ultraviolet pada p53 di epidermis tersebut juga menyebabkan matinya p53 yang seharusnya berfungsi untuk mengatur apoptosis sel apabila terjadi gangguan pada DNA dan fungsi seharusnya P53 untuk mengeliminasi sel yang mengalami kerusakan DNA yang tidak dapat diperbaiki akibat ultraviolet tersebut. Apabila fungsi p53 ini hilang akibat mutasi karena ultraviolet, terjadi pembelahan secara kontinu pada sel mutan dan terjadi akumulasi mutasi tambahan. Pada keadaan ini ultraviolet berperan sebagai inisiator dan promotor.

Jawaban Permasalahan Peranan lingkungan ( ultraviolet) dalam pertumbuhan SCC Melalui mekanisme pathogenesis terrpaparnya kulit (di epiermis terdapat sel langerhans dan interferon ) oleh ultraviolet B menyebabkan terjadinya mutasi gen p53 yang menyebabkan gangguan fungsi apoptosis dan eliminasi sel mutan sehingga proses siklus sel berlanjut dengan keadaan DNA mutan yang tidak dapat diperbaiki.proses ini berlanjut terus secara kontinu.

Tumor kulit dapat dibagi menjadi: 1. Tumor Jinak (Benign tumor ) Cysts (Epidermal, Dermoid, Trichilemmal) Kista epidermal Jenis yang paling umum dari kista kulit dan dapat terjadi di mana saja di tubuh sebagai nodul tunggal dan tegas. Kista epidermal memiliki epidermis yang benar-benar matang berisi lapisan granular. Kista dermoid Timbul pada saat lahir dan dapat hasil dari epitel terperangkap selama penutupan garis tengah pada perkembangan janin. Kista dermoid yang paling sering ditemukan di garis tengah wajah (misalnya, hidung atau dahi) dan juga umum di alis. Kista dermoid memiliki epitel skuamosa, kelenjar ekrin, unit pilosebaceous, dan kadang-kadang, tulang, gigi, atau jaringan saraf. Ahli bedah sering menyebut kista sebagai kista sebasea karena seperti memuat sebum, bagaimanapun juga ini adalah sebuah ironi karena sebenarnya substansi tersebut adalah keratin. Tumor jinak Tumor Ganas

Kista Trichilemmal (pilar) Terjadi lebih sering pada wanita dan biasanya di kulit kepala. Ketika pecah, kista ini memiliki bau yang kuat yang khas. Dinding kista Trichilemmal tidak mengandung lapisan granular tetapi memiliki lapisan luar yang khas menyerupai selubung akar luar folikel rambut (trichilemmoma). Pada pemeriksaan, sulit untuk membedakan satu jenis kista dari yang lain. Mereka semua nodul subkutan, dinding tipis berisi pusat putih, krem. Pemeriksaan histologi diperlukan untuk membedakan. Dinding kista ini terdiri dari lapisan lapisan basal epidermis berorientasi dengan lapisan superfisialis dan profunda lebih dewasa (yang mengatakan, dengan kulit mendorong Pusat kista). Sel Desquamated (keratin) berkumpul di tengah dan membentuk substansi kental kista. Kista biasanya asimptomatis, dan menghilang sampai kista tersebut ruptur dan menyebabkan inflamasi lokal. Daerah tersebut menjadi terinfeksi dan membentuk abses. Insisi dan drainase disarankan untuk infeksi kista akut. Nevi (Acquired, Congenital)

Nevus adalah tumor yang paling sering dijumpai, merupakan tumor yang berasal dari sel-sel melanosit. Nevus umumnya muncul saat lahir atau segera setelah lahir, terbanyak pada dewasa muda. Jenis-jenis nevus : Junctional nevi Sel-sel nevus terdapat diantara lapisan epidermis dan dermis. Intradermal nevi Sel-sel nevus terdapat di lapisan dermis. Compound nevi Sel-sel nevus terdapat diantara lapisan epidermis dan dermis, serta di lapisan dermis. Nevi melanositik acquired diklasifikasikan sebagai junctional, senyawa, atau kulit, tergantung pada lokasi sel nevus. Klasifikasi ini tidak mewakili berbagai jenis Nevi tetapi tahap yang agak berbeda dalam pematangan Nevi. Awalnya, sel-sel nevus terakumulasi di dalam epidermis (junctional), beberapa bermigrasi ke dermis (compound), dan akhirnya sisanya benar-benar dalam dermis (dermal). Nevi Congenital lebih jarang terjadi, hanya 1% dari bayi yang baru lahir. Lesi ini lebih besar dan mungkin berisi rambut. Secara histologi, menyerupai nevus acquired. Lesi kongenital raksasa (nevus berbulu raksasa) biasanya terjadi di dada dan punggung. Selain itu, nevi kongenital berlanjut menjadi melanoma maligna dari 1 - 5% dari kasus. Eksisi nevus adalah pengobatan pilihan, tetapi sering cedera yang begitu besar sehingga penutupan luka dengan cangkok kulit autologus tidak mungkin karena kurangnya donor yang memadai. Excisions serial untuk beberapa tahun dengan penutupan primer atau pencangkokan kulit dan perluasan jaringan di kulit sekitarnya yang normal adalah mode saat terapi. Pada umumnya tidak memerlukan terapi, kecuali bila pasien menginginkan nevus diangkat atau dokter mencurigai metaplasia ke arah keganasan. Keratosis (seboroik, solar)

Keratosis seboroik merupakan suatu tumor jinak yang berasal dari hiperplasia epidermis. Biasanya terjadi di dada, punggung, dan perut pada lansia. Gejala klinis : sering multiple, diameter jarang lebih dari 3 cm, berbatas tegas sedikit meninggi, warna kecoklatan, permukaan seperti beludru sampai verukos, konsistensi lunak. Diagnosa : berdasarkan gejala klinis, dengan kaca pembesar ditemukan tanda khas berupa sutura-sutura halus pada permukaannya. Bisa juga dilakukan pemeriksaan histopatologi. Soft-Tissue Tumors (Acrochordons, Dermatofibromas, Lipomas)

Acrochordons (skin tags) adalah massa berdaging, pedunkulata terletak di ketiak, batang dan kelopak mata. Mereka terdiri dari epidermis hiperplastik batang jaringan ikat fibrosa. Lesi ini biasanya kecil dan selalu jinak.2

Dermatofibroma berupa nodul soliter atau multiple yang keras, tidak nyeri. Biasanya terdapat di ekstremitas. Ukuran kira-kira 1-2 cm, warna merah tau kecoklatan, bisa juga biru kehitaman karena deposisi hemosiderin. Dimple sign (+), yaitu bila kulit sekitar lesi dicubit maka benjolan akan melekuk ke dalam. Dermatofibromas dapat didiagnosis dengan pemeriksaan klinis. Ketika lesi membesar 2 - 3 cm, biopsi eksisi dianjurkan untuk menilai terhadap keganasan. Lipoma adalah tumor jinak jaringan lemak yang dikelilingi kapsul fibrosa tipis. sebagian besar ditemukan di bagasi tetapi dapat muncul di mana saja. Etiologi lipoma belum diketahui pasti, akan tetapi kecenderungan mendapat lipoma dapat diturunkan. Beberapa lipoma dapat terjadi akibat trauma tumpul. Kadang-kadang dapat tumbuh hingga ukuran besar. Pemeriksaan mikroskopis menunjukkan sel-sel tumor lobulated mengandung lemak yang normal. Eksisi dilakukan untuk diagnosis dan untuk mengembalikan kontur kulit normal. Vascular Tumors Hemangiomas (Capillary, Cavernous)

Hemangioma adalah neoplasma jinak pembuluh darah dengan ciri proliferasi endotel yang meningkat pesat pada waktu bayi (1 tahun pertama), dan dapat mengalami involusi secara perlahan pada masa anak-anak melalui proses kematian sel secara progresif atau terjadinya fibrosis (sampai usia 6 7 tahun). Patogenesis Merupakan suatu tipe angiogenesis murni, yaitu meningkatnya faktor angiogenesis dan berkurangnya faktor supresi sel-sel. Hemangioma yang berproliferasi terdiri atas kumpulan sel-sel endotel yang membelah dengan cepat. Saat mengalami involusi, aktivitas endotel berkurang, dan sel-selnya menjadi lebih rata dan matur. Bekas hemangioma yang telah involusi berupa kulit yang agak tipis, pigmen bisa berkurang, atau ada bagian yang sedikit lebih gelap, dengan permukaan yang tidak terlalu rata. Lesi papular dengan batas yang tegas, sebagian besar terletak di bahu, wajah, dan kulit kepala. hemangioma memiliki konsistensi kenyal. Secara histologi, hemangioma kapiler terdiri dari sel endotel terlihat terutama pada pembuluh darah janin. Lesi mengandung sebuah gua yang besar, ruang diisi darah yang dibatasi oleh sel-sel endotel tampak normal. Pengobatan akut terbatas pada lesi yang mengganggu fungsi, seperti penglihatan, makan, dan buang air kecil, atau yang menyebabkan masalah sistemik, seperti trombositopenia dan gagal jantung-output tinggi. Pertumbuhan lesi yang cepat membesar dapat dihentikan dengan obat prednison atau interferon alfa-2a. Hemangioma yang tetap setelah awal masa remaja umumnya tidak akan sulit, karena eksisi bedah dianjurkan. Neural Tumors (Neurofibromas, Neurilemomas, Granular Cell Tumors) Neurofibroma merupakan kelainan yang diturunkan secara autosomal dominan ditandai dengan pigmentasi kulit (bercak cafe au lait) dan tumor tumor pada sistem saraf berupa

perubahan-perubahan pada kulit, tulang, otot, serta sistem endokrin. Kelainan ini dibedakan dalam dua tipe, dimana kasus terbanyak (85%) adalah neurofibroma tipe 1. Gejala klinis : Bercak cafe au lait yang multiple. Axillary freckling (Crowes sign) Neurofibromas Bercak pseudoatrofik warna merah-biru. Manifestasi pada mata : nodula Lisch pada iris Manifestasi sistemik : pada sistem saraf, tulang, dan endokrin. Penatalaksanaan Untuk tumor-tumor yang mengganggu fungsi atau mudah infeksi/trauma dapat dilakukan bedah eksisi. Pemeriksaan fisik lengkap secara periodik untuk mendeteksi kelainan-kelainan sistemik. Konseling genetik dan edukasi. Neurilemomas adalah tumor soliter yang ditemukan di sepanjang saraf perifer kepala dan ekstremitas. Berupa nodul diskrit yang mungkin menyakitkan atau secara lokal memancarkan sepanjang distribusi saraf. Mikroskopis, tumor mengandung sel Schwann dengan inti palisading dikemas dalam baris. Tumor sel granular biasanya lesi soliter dari kulit atau, lebih umum, pada lidah. terdiri dari sel granular berasal dari sel Schwann yang sering menyusup otot lurik sekitarnya. 2. Tumor Ganas (Malignant Tumors) Yang paling sering ditemukan Kanker kulit yang timbul dari sel-sel pada lapisan epidermal dan dalam urutan frekuensi, Karsinoma sel basal (Basal sel karsinoma) Karsinoma sel skuamosa (Skuamous sel karsinoma), dan Melanoma maligna. Keganasan yang timbul dari sel-sel dermis atau struktur adneksa jarang ditemukan. Pengaruh lingkungan dan penyakit bersamaan dikaitkan dengan peningkatan kejadian keganasan epidermis. Faktor-faktor ini telah dipelajari secara ekstensif dan beberapa bentuk terbaik dari pemahaman tentang penyebab kanker. Basal Cell Carcinoma Karsinoma sel basal mengandung sel-sel yang menyerupai sel-sel basal epidermis. Merupakan jenis yang paling sering ditemukan pada kanker kulit dan dibagi menjadi beberapa jenis berdasarkan morfologi dan histologis. Jenis nodulocystic atau noduloulcerative sebesar 70% dari karsinoma sel basal. Karsinoma sel basal biasanya lambat tumbuh, dan pasien sering mengabaikan lesi ini selama bertahun-tahun.

Metastasis dan kematian dari penyakit ini sangat jarang, tetapi lesi ini dapat menyebabkan kerusakan lokal yang luas. Sebagian kecil (kurang dari 2 mm), lesi nodular dapat diobati oleh ahli dermatologi dengan kuretase dan electrodesiccation atau penguapan laser. Sebuah kelemahan dari prosedur ini adalah bahwa tidak ada spesimen patologis diperoleh untuk mengkonfirmasikan diagnosis atau mengevaluasi margin tumor. Tumor yang lebih besar, lesi yang menyerang tulang atau struktur di sekitarnya, dan tipe histologis lebih agresif (morpheaform, infiltrasi, dan basosquamous) paling baik diobati dengan eksisi bedah dengan 2 4 mm margin jaringan normal. Kejadian BCC meningkat menurut usia dan lebih sering terjadi pada orangtua. Lebih dari 90 % dari BCC yang terdeteksi terdapat pada pasien yang berusia 60 tahun atau lebih. Gambaran klinik basal cell karsinoma bervariasi. Terdapat 5 tipe dan 3 sindroma klinik, yaitu: 1. Tipe Nodular-Ulseratif (Ulkus Rosdens) Jenis ini dimulai dengan nodus kecil 2-4 mm, translusen, warna pucat seperti lilin (Waxy-nodule). Dengan inspeksi yang teliti, dapat dilihat perubahan pembuluh darah superficial melebar (telangiektasis). Permukaan nodus mula-mula rata tetapi kalau lesi membesar, terjadi cekungan ditengahnya dan pinggir lesi menyerupai bintil-bintil seperti mutiara (pearly border). Nodus mudah berdarah pada trauma ringan dan mengadakan erosi spontan yang kemudian menjadi ulkus yang terlihat di bagian sentral lesi. Kalau telah terjadi ulkus, bentuk ulkus seperti kawah, berbatas tegas, dasar irreguler dan ditutupi oleh krusta. Pada palpasi teraba adanya indurasi disekitar lesi terutama pada lesi yang mencapai ukuran lebih dari 1 cm, biasanya berbatas tegas, tidak sakit atau gatal. Dengan trauma ringan atau bila krusta diatasnya diangkat, mudah berdarah. 2. Tipe Pigmented Gambaran klinisnya sama dengan nodula-ulseratif, pada jenis ini berwarna coklat atau berbintik-bintik atau homogeni (hitam merata) kadang-kadang menyerupai melanoma. Banyak dijumpai pada orang dengan kulit gelap yang tinggal pada daerah tropis. 3. Tipe Morphea-Like atau Fibrosing Merupakan jenis yang agak jarang ditemukan. Lesinya berbentuk plakat yang berwarna kekuningan dengan tepi yang tidak jelas, kadang-kadang tepinya meninggi. Pada permukaannya tampak beberapa folikel rambut yang mencekung sehingga memberikan gambaran seperti sikatriks.

Kadang-kadang tetutup krusta yang melekat erat. Jarang mengalami ulserasi. Tapi ini cenderung invasive kearah dalam. Tepi ini menyerupai morphea atau skleroderma. 4. Tepi Superficial Berupa bercak kemerahan dengan skuama halus dan tepi yang yang meninggi. Lesi dapat meluas secara lambat, tanpa mengalami ulserasi. Umumnya multiple, terutama dijumpai pada badan, kadang-kadang pada leher dan kepala. 5. Tipe Fibroepitelial Berupa satu atau beberapa nodul keras dan sering bertangkai pendek, permukaannya halus dan sedikit kemerahan. Terutama dijumpai dipunggung.Tipe ini sangat jarang ditemukan. Sindrom klinik yang merupakan bagian penting dari Basal Cell Karsinoma, yaitu: Sindrom Karsinoma Sel Basal Nevoid Dikenal sebagai sindrom Gorlin Goltz. Merupakan suatu sindrom yang diturunkan secara autosomal dan terdiri dari: Kelainan kulit : Berupa nodul kecil yang multiple yang terdapat pada masa kanak-kanak atau akhir pubertas, terutama dijumpai pada muka dan badan. Selama stadium nevoid, ukuran dan jumlah nodul bertambah. Sering setelah umur dewasa, lesinya mengalami ulserasi dan kedalam stadium neoplastik dimana terjadi invasi, destruksi dan mutilasi. Kematian dapat terjadi karena invasi ke otak terdapat cekungan (pits) pada telapak tangan dan kaki. Kelainan tulang : Berupa kista pada rahang, kelainan pada tulang iga dan tulang belakang (skoliosis,spina bifida) Kelainan mata: berupa katarak, buta congenital.

Sindrom Linear and Generalized Follicular Basal Cell nevi Merupakan jenis yang sangat jarang ditemukan pada lesi yang linear, berupa nodul yang disertai komedo dan kista epidermal, tersusun seperti garis dan unilateral, akibat kerusakan folikel rambut akibat pertumbuhan tumor.

Sindrom Bazex : atrophoderma dengan multiple karsinoma sel basal Disamping itu ada juga tipe-tipe klinis yang jarang dijumpai, yaitu: Fibroepitelioma, giant pore KSB,wild fire KSB, angiomatous KSB, Lipoma like KSB, giant exophytic KSB, hiperkeratotic KSB dan intra oral KSB. Diagnosis

Ditegakkan berdasarkan anamnesis, pemeriksaan fisik (gejala klinis) dan pemeriksaan histopatologis. Dari anamnesis terdapat kelainan kulit terutama dimuka yang sudah berlangsung lama berupa benjolan kecil, tahi lalat, luka yang sukar sembuh, lambat menjadi besar dan mudah berdarah. Tidak ada rasa gatal/sakit. Pada pemeriksaan fisik terlihat papul/ulkus dapat berwarna seperti warna kulit atau hiperpigmentasi. Pada palpasi teraba indurasi. Tidak terdapat pembesaran kelenjar getah bening regional. Pemeriksaan penunjang berupa pemeriksaan histopatologi yaitu dengan dilakukannya biopsi. Tumor (T) Tx T0 Tis T1 T2 T3 T4 Primer Tumor primer

tidak dapat dinilai Tidak ada bukti tumor primer Karsinoma in situ Diameter tumor 2 cm Diameter tumor 25 cm Diameter tumor > 5 cm Tumor menginvasi struktur extradermal dalam (yaitu: atau tulang. tulang rawan, otot rangka

Limfonodus Regional (N) Nx Kelenjar bening N0 getah regional

tidak dapat dinilai Kelenjar getah bening regional tidak metastasis Kelenjar getah bening metastasis regional

N1

Metastasis (M) Mx

Metastasis

jauh

M0 M1 Stadium Stadium 0 Stadium I Stadium II Stadium III Stadium IV

tidak dapat dinilai Metastasis jauh tidak ada Metastasis jauh Tis T1 T2 T3 T4 Semua T Semua T N0 N0 N0 N0 N0 N1 Semua N M0 M0 M0 M0 M0 M0 M1

Banyak metode pengobatan Basal Cell Carcinoma, yaitu: a. Bedah Eksisi Bedah eksisi atau bedah scalpel pada Basal Cell Carcinoma dini memberikan tingkat kesembuhan yang tinggi. b. Radioterapi Penyinaran lokal diberikan lapangan radiasi meliputi tumor dengan 1-2 cm jaringan sehat disekelilingnya. Penyinaran dilakukan dengan dosis 200 cGy perfrasaksi, 5 fraksi dalam 1 minggu dengan total dosis 4000 cGy c. Kuretasi dan elektrodesikasi Dilakukan pada tingkat yang dini, cara yang terbaik dengan cara memotong dan koagulasi dibantu dengan curettage. Jika hendak mengambil spesipik jaringan untuk pemeriksaan histopatologis, dilakukan dengan elektro section (pure cutting). Terlebih dahulu diberi marker 3 5 mm diluar tumor. d. Bedah Beku (Cryosurgery) Bedah beku adalah Suatu metode pengobatan dengan menggunakan bahan yang dapat menurunkan suhu tubuh jaringan tubuh dari puluhan sampai ratusan derajat celcius dibawah nol (Subzero). e. Bedah Mikrografi Mohs Evaluasi Histopatologi pada tepi irisan mendekati 100 % dibandingkan dengan tekhnik seksi vertikal tradisional. Dengan analisa tepi irisan yang lengkap dapat diketahui dan ditelusuri semua fokus-fokus tumor yang masih tertinggal. Reseksi hanya pada daerah tumor, sehingga dapat menghemat jaringan atau meminimalkan jaringan yang hilang. f. Terapi Fotodinamik Fotodinamik terapi (PDT) dilakukan dengan aplikasi topikal dari asam 5aminolaevulinic prodrug (ALA) atau Aminolaevulinic (MAL). g. Imiquimod

Imiquimod merupakan modifikasi respon imun, mengikat reseptor permukaan sel toll 7 dan atau 8. Ikatan ini mengaktifkan produksi sitokin pro inflamasi dan selanjutnya kematian sel T sitotoksik sel diperantarai. Prognosis umumnya baik dengan five year survival rate mencapai 99 %. Basal Cell Carcinoma mempunyai rekurensi tinggi, terutama bila pengobatan tidak adekuat. Biasanya rekurensi terjadi 4 bulan pertama sampai 12 bulan setelah pengobatan Squamous Cell Carcinoma Merupakan keganasan yang berasal dari lapisan sel skuamosa berkeratin pada permukaan kulit. Keganasan kulit terbanyak kedua setelah karsinoma sel basal. Faktor resiko : Radiasi UV Pajanan zat kimia : beberapa pestisida, tar, bahan bakar minyak, parafin, arsen Infeksi virus : HPV, herpes simpleks Radiasi Ulkus marjolin : terjadi pada luka kronik, dimana perubahan seluler terjadi karena inflamasi kronik. Gangguan imunitas : imunosupresan, AIDS Genetik : kulit putih, albino, xeroderma pigmentosum. Patofisiologi Karsinoma sel skuamosa umumnya muncul di daerah yang terpajan sinar matahari. Inflamasi dan indurasi yang terjadi menandai perubahan lesi prekanker menjadi karsinoma sel skuamosa. Klasifikasi Tipe karsinoma sel skuamosa : Verukosa : tumbuh lambat, eksofitik, jarang bermetastasis. Ulseratif : tumbuh cepat, invasif lokal. Penatalaksanaan Eksisi dengan tepi yang sehat sejauh kurang lebih 20 mm. Pembedahan Mohs : eksisi horizontal Terapi adjuvan radioterapi dilakukan pada karsinoma sel skuamosa dengan faktor resiko tinggi. Prognosis Sebanyak 5 10% karsinoma sel skuamosa bermetastasis. Karsinoma sel skuamosa yang terjadi dari ulkus marjolin atau xeroderma pigmentosum memiliki kemungkinan metastasis lebih tinggi. Melanoma maligna Lebih dari 90% melanoma terjadi di kulit, tetapi melanoma juga dapat terjadi pada sel berpigmen di retina (ocular melanoma) dan membran mukosa seperti pada nasofaring, vulva, dan anal canal. Kira-kira 2% dari kasus melanoma disertai metastasis kelenjar limfe nodus regional atau metastasis jauh tanpa diketahui tumor primernya. Etiologi a) Sinar Ultraviolet

Paparan sinar matahari, terutama radiasi ultraviolet (UV) merupakan faktor resiko utama terjadinya melanoma. Radiasi UVB paling berbahaya (panjang gelombang : 290-320 nm), tetapi UVA (320-400 nm) juga dapat bersifat karsinogenik. Resiko terjadinya melanoma akan meningkat seiring dengan terjadinya sunburn. Diduga insidensi melanoma lebih sering dijumpai pada penduduk atau populasi di daerah sekitar ekuator. Paparan sinar matahari mungkin merupakan faktor risiko lingkungan yang paling relevan untuk melanoma. Ambang paparan sinar UVA dan UVB yang diperlukan untuk meningkatkan resiko melanoma masih belum diketahui. Kerentanan genetik untuk radiasi UV sangat bervariasi antar individu dan ini tidak sepenuhnya berkorelasi dengan jenis kulit, karena itu faktor genetik lain yang berperan perlu diperhatikan. b) Jenis dan Tipe Kulit Jenis kulit dan respon terhadap paparan sinar matahari mempunyai peran penting dalam terjadinya melanoma.

Tipe jenis kulit menurut Fitzpatrick Resiko terbesar melanoma terjadi pada tipe kulit 1 dan 2, yaitu pada jenis kulit putih, sedangkan, pada tipe kulit gelap yaitu tipe 5 dan 6 jarang ditemui melanoma maligna. c) Nevi

Nevi adalah tumor jinak melanosit yang mulai muncul di masa kecil, terus berkembang di masa dewasa awal, dan menurun secara bertahap pada usia 40-50 tahun dan seterusnya. Nevi dipengaruhi oleh jenis kelamin. Pada anak perempuan, nevi lebih banyak ditemukan di anggota badan sedangkan pada anak laki-laki sering ditemukan pada batang badan. Alasan mengapa gender mempengaruhi distribusi pada melanoma belum diketahui. Nevi merupakan faktor risiko terkuat untuk melanoma, jauh lebih besar daripada resiko relatif yang berhubungan dengan paparan sinar matahari.4 Benign moles, disebut juga melanocytic nevi : Ukuran kecil (< 6 mm) Bulat

Hanya satu warna coklat atau coklat tua Simetris Pasien dengan melanocytic nevi >25 meningkatkan resiko terkena melanoma.

Atypical nevi atau dysplastic nevi : Lebih besar (>6 mm) Asimetris Biasanya berwarna coklat namun dapat bervariasi. Bila terdapat 1 tanda klinis dari atypical nevi memiliki kemungkinan terkena melanoma sebesar 6%. d) Faktor Biologis Trauma mekanis yang berkepanjangan merupakan resiko terjadinya keganasan ini, Selain itu juga dilaporkan adanya hubungan antara oral melanoma maligna dengan merokok konsumsi alkohol dan iritasi karena oral appliances lain. Keadaan lainnya yang mempengaruhi adalah berkurangnya ketahanan imunologik, misalnya pada penderita pengangkatan ginjal dan juga M. Hodgkin akan meningkatkan kejadian melanoma maligna. 4,6 Trauma mekanis dari protesa dan infeksi rongga mulut merupakan faktor kausatif yang mungkin menyebabkan melanoma rongga mulut. 1

e)

Faktor Genotip Riwayat keluarga terhadap melanoma akan meningkatkan resiko terjadinya melanoma terhadap seseorang. Kira-kira sebesar 10% melanoma terjadi pada pasien dengan riwayat melanoma pada keluarga. Beberapa penelitian mengatakan adanya faktor autosomal dominan, pada kasus sering terlihat pada kromosom 1p atau 9p. Mutasi gen yang ditemukan di keluarga dengan kecenderungan terjadi melanoma memiliki kontribusi tinggi tetapi prevalensinya rendah di populasi umum dan pada kelompok risiko tinggi ditemukan mutasi cyclin-dependent kinase inhibitor 2A (CDNK2A). Tes mutasi pada gen CDNK2A mengungkapkan alasan mengapa melanoma dapat menurun pada keluarga, lebih banyak gen yang dikaitkan dengan melanoma mempunyai kontribusi yang rendah dan biasa di populasi umum, dimana sebagian besar tidak akan menyebabkan melanoma. Mutasi pada beberapa lokus genetik, CDNK2A (p16INK dan p14ARF) dan melanoma. Cyclindependent kinase 4 CDK4, telah diidentifikasi dalam keluarga dengan riwayat

Keragaman faktor molekuler penyebab melanoma dan penelitian yang ada menemukan bahwa pigmentasi, jenis kulit, dan kebiasan (paparan sinar matahari) memegang peranan penting sebagai penyebab terjadinya melanoma pada populasi keluarga tertentu. Patofisiologi Secara sederhana, pertumbuhan radial menunjukkan kecenderungan awal dari suatu melanoma untuk tumbuh horizontal di dalam epidermis (in situ) dan lapisan dermal yang dangkal, seringkali ini terjadi untuk waktu yang lama. Selama tahap pertumbuhan ini, sel-sel melanoma tidak memiliki kemampuan untuk bermetastasis, dan tidak ada bukti angiogenesis. Dengan berjalannya waktu, pola pertumbuhan menjadi vertikal, tumbuh ke bawah ke lapisan dermal yang lebih dalam sebagai massa yang meluas dan kurang pematangan selular. Terdapat 4 jenis melanoma maligna, yaitu:2,6 1. Superficial spreading melanoma (SSM) Merupakan jenis melanoma terbanyak yang ditemukan di Indonesia (70%). Subtipe ini paling sering terlihat pada individu usia 30-50 tahun. Pada umumnya SSM timbul pada kulit normal (de novo), berupa plak archiformis berukuran 0,5 - 3 cm dengan tepi meninggi dan irreguler. Pada permukaannya terdapat campuran dari bermacam-macam warna, seperti coklat, abu-abu, biru, hitam dan sering kemerahan Lesi ini meluas secara radial. Pada umumnya mempunyai ukuran 2 cm dalam waktu 1 tahun, untuk melanjutkan tumbuh secara vertikal dan berkembang menjadi nodula biru kehitaman. Dapat mengalami regresi spontan dengan meninggalkan bercak hipopigmentasi. Predileksinya pada wanita sering dijumpai di tungkai bawah, sedangkan pada pria di badan dan leher. Secara histologis, ditandai buckshot (pagetoid) melanosit pada epidermis.

Superficial spreading melanoma pada kulit. 2. Nodular melanoma (NM) Merupakan jenis melanoma kedua terbanyak (15-30%), sifat lesi ini lebih agresif. Terjadi paling sering di kaki dan badan. Nodular melanoma adalah lesi berupa nodul berbentuk setengah bola (dome shaped) atau polipoid dan eksofitik, berwarna coklat kemerahan atau biru sampai kehitaman. Pertumbuhannya secara vertikal, pertumbuhan pesat terjadi beberapa minggu sampai bulan, subtipe ini bertanggung jawab untuk kebanyakan melanoma yang dalam. Dapat

mengalami ulserasi dan mudah terjadi perdarahan hanya dengan trauma ringan. Metastase dapat secara limfogen dan hematogen. Secara histologis, lesi ini tidak memiliki fase pertumbuhan radial.2,6

Nodular melanoma pada kulit. 3. Lentigo Maligna Melanoma (LML) Merupakan kelainan yang jarang ditemukan (4-10%). Pertumbuhan lesi ini secara vertikal, terjadi sangat lambat bisa sampai 5-20 tahun. Biasanya sering ditemukan di kepala, leher, dan lengan pada individu yang lebih tua dengan rata-rata umur 65 tahun. Lesi precursor in situ biasanya besar, berdiameter lebih dari 1-3 cm dengan tepi tidak teratur, telah terjadi minimal 10-15 tahun, dan menunjukkan pigmentasi makula dari coklat tua sampai kehitaman, namun pada beberapa area dapat tampak hipopigmentasi. Invasi pada dermal berkembang menjadi lentigo maligna melanoma yang ditandai nodul biru-kehitaman dalam lesi in situ.2,6 Secara histologis ditandai dengan proliferasi melanosit yang predominan dan meluas sepanjang struktur adneksa kulit. Lesi ini terjadi terutama pada wanita usia lanjut. Perbandingan antara pria dan wanita 1: 2-3. 4. Acral Lentiginous Melanoma (ALM) Sering dijumpai di telapak tangan, ibu jari kaki, daerah subungul, dan membran mukosa. Biasanya berawal dari pigmentasi hitam, makula batas tidak teratur, yang kemudian berkembang menjadi papula yang invasif. Sering terjadi didekade ke-5 sampai ke-7 dari hidup seseorang. Pertumbuhan lesi makula meluas kearah lateral dan ke arah vertikal berupa penebalan lesi.2,6

Acral lentiginous melanoma Diagnosis 1. The ABCDE checklist from the American Cancer Society's Sistem ABCDE (A untuk asimetri, B ketidakteraturan tepi lesi, C untuk variasi warna, D untuk diameter yang lebih besar dari 6 mm, dan E untuk elevasi, pembesaran)

mudah diingat dan digunakan untuk mendiagnosa melanoma, meskipun tidak mencerminkan perubahan yang terjadi pada lesi berpigmen.2,4,6 A: Asimetry

Bentuk tumor yang tidak simetris B: Border irregularity

Garis batas yang tidak teratur C: Colour variation

D: Diameter

Diameter tumor lebih besar dari 6 mm E: Evolution Terdapat perubahan lesi yang dapat diperhatikan sendiri oleh keluarganya. penderita dan

Pemeriksaan Penunjang a) Biopsi Pemeriksaan laboratorium dimulai dengan dilakukannya biopsi pada lesi. Biopsi eksisi dilakukan jika tidak memacu perkembangan terhadap metastase lesi. Tindakan biopsi eksisi dilakukan dengan mengambil marginal jaringan normal secukupnya yang dapat dilakukan jika lesi berukuran kecil, namun pada lesi yang cukup besar dengan keterbatasan anatomi, maka biopsi insisi sangat memadai. b) Pemeriksaan Mikroskopis Pemeriksaan mikroskopis dilakukan setelah biopsi dengan preparat didapat. Pada pemeriksaan mikroskopis didapat gambaran histopatologis berupa sel-sel yang ganas, dan tersusun rapat yang mempunyai variasi dalam bentuk dan ukuran. Penatalaksanaan 1. Eksisi Bedah Tindakan eksisi bedah diindikasikan pada melanoma stadium I dan II.

2. Elective Lymph Node Dessectio (ELND) Biasanya ELND dilakukan pada melanoma stadium III, dimana telah terdapat metastase ke kelenjar lymph. Hal ini dibuktikan dengan terabanya pembesaran kelenjar lymph. ELND masih merupakan terapi yang kontroversial. Cara yang lebih dianjurkan adalah dengan intraoperatif lymphatic mapping. 3. Interferon Dapat digunakan sebagai terapi adjuvan pada melanoma yang berukuran lebih dari 4 mm atau menyebar ke limfe nodus regional (stadium V), tetapi harus dipertimbangkan tingkat toksisitasnya yang masih tinggi. 4. Kemoterapi Dikatakan tidak terlalu bermanfaat pada terapi melanoma. Jenis kemoterapi yang paling efektif dacarbazine (DTIC= Dimethyl Triazone Imidazole Carboxamide Decarbazine). 5. Terapi Radiasi Digunakan hanya sebagai terapi simptomatis pada melanoma dengan metastase ke tulang dan susunan saraf pusat (SSP). Meskipun demikian hasilnya tidak begitu memuaskan.