ETAS_06 ben mal_neoplasms
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    ETAS_06 ben mal_neoplasms ETAS_06 ben mal_neoplasms Document Transcript

    • 6 Benign and Malignant Neoplasms Keyvan Nouri, MD Sonal Choudhary, MD Maria Patricia Rivas, MD Voraphol Vejjabhinanta, MD L. Magaly Villafradez-Diaz, MD George W. Elgart, MD C o n t e n t s 6.1 Seborrheic Keratosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 221 6.2 Actinic Keratosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 6.3 Bowen’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 6.4 Non-melanoma Skin Cancer . . . . . . . . . . . . . . . . . . . . 226 6.5 Basal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . 226 6.6 Squamous Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . 229 6.7 Keratoacanthoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 6.8 Malignant Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 6.9 Merkel Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . 238 6.10 Cutaneous T-Cell Lymphoma . . . . . . . . . . . . . . . . . . . 240 6.11 Angiosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 6.12 Desmoplastic Trichoepithelioma . . . . . . . . . . . . . . . 242 6.13 Dermatofibrosarcoma Protuberans . . . . . . . . . . . . . 243 6.14 Microcystic Adnexal Carcinoma . . . . . . . . . . . . . . . . 245 Benign and Malignant Neoplasms  219
    • Committed to Your Future For practice exam questions and interactive study tools, visit the Dermatology In-Review Online Practice Exam and Study System at DermatologyInReview.com/GaldermaSponsored by
    • 6.1 SEBORRHEIC KERATOSISEpidemiology • Frequently found in individuals older than 30 years of age • Lesions are usually multiple and can occur in any location except mucosa, palms and solesEtiology The etiology of SKs is unknown. 1 Risk factors: Genetic propensity may play a role, as patients with multiple lesions commonlyhave a positive family history. According to Kennedy et al , aging remains the strongest factor 1,2 3associated with the development of SKs; whereas, painful sunburns and a lifetime of sun exposurewere not associated with an increased risk. 3Clinical Presentation The lesions may begin as well-defined brown macules. Later on they become waxy, hyper-keratotic and hyperpigmented plaques with a stuck-on appearance. The surface has a “warty”appearance with multiple plugged follicles. Colors range from brown to black and may be locatedanywhere with the face, trunk and upper extremities being the predilected sites (Figure 6-1). 1,2 Dermoscopic features: comedo-like openings, milia-like cysts, fissures (brain-like appearance),fingerprinting, lack of true pigment network, and telangiectasias arranged in regular loops (hair-pin-like vessels). The absence of pigment network, branched streaks, and pigment globules arethe key features that differentiate SKs from melanocytic neoplasms. 4,5 Figure 6-1. Hyperpigmented plaque with “stuck-on” appearance typical of seborrheic keratosisHistopathology There are several clinicopathological variants: 1,2 • Common SK: The classic lesion is histologically characterized by a mushroom-like appearance, with sharply demarcated hyperplastic epidermis overhanging the surrounding skin. The tumor consists of uniform masses of keratinocytes or baseloid cells with tunnels filled with keratin that look like cysts when seen in cross-section. The number of keratinocytes present determines the color of the lesion (Figure 6-2 and Figure 6-3) • Reticulated SK: Histologically shown as thin cords of basaloid cells descending from the base of the epidermis. These cords may be surrounded by eosinophilic collagen stroma making up much of the lesion. Keratin cysts are also present (Figure 6-2 and Figure 6-3) Benign and Malignant Neoplasms  221
    • Figure 6-2. SK, lower magnification. Figure 6-3. SK, higher magnification. Benign neoplasm of keratinocytes confined Keratin filled invaginations surrounded to the epidermis, composed of basaloid by strands of uniform basaloid uniformed cells that shows no signs of proliferations cellular atypia. The neoplasm is sharply circumscribed and has numerous invagina- tions that are filled with keratotic plugs called “pseudo-horn cysts” • Stucco Keratosis: Also known as hyperkeratotic or verrucous SKs. Typically appear as multiple, skin colored papules or plaques, located symmetrically on the lower extremities. Histologic evaluation shows “church-spire” like projections of epidermal cells around a collagen core thrusting upward into a basket-weave type of hyperkeratosis. Vacuolated keratinocytes are not present in this type of lesion, thus differentiating it from verruca vulgaris • Irritated SK: Presents as a typical SK with eczematous and erythematous changes around it, usually due to trauma. Histologically, inflammation is seen, with eosinophilic flattened squamous cells arranged in onion-like pattern. This may resemble poorly differentiated keratin pearls seen in squamous cell carcinoma, but can be differentiated by their large number, small size, and circumscribed configurations. Keratinocytes in irritated SKs show a high degree of keratinization or maturation compared to the common SK • Pigmented SK: Also known as melanoacanthoma, characteristically presents as a dark colored SK. Dendritic melanocytes engorged with pigment are prominent within the lesion. The surrounding keratinocytes barely contain any melanin. The melanocytes proliferate as nests from the basal layer into the superficial layer of the epidermis. There is no malignant potential associated with this type of SK • SK with Squamous Atypia: Characterized by the presence of cellular atypia and dyskeratosis of unknown cause. The lesion mimics Bowen’s disease or invasive SCC. Therefore, complete removal is recommended • Dermatosis Papulosa Nigra: Multiple, small, hyperpigmented, sessile SKs typically found on the face of African American individuals. Except for the smaller size, there’s no difference found on histology compared to common SK Sign of Leser-Trélat It is defined as a sudden appearance and increase in size of multiple SKs. The eruption is classically described to appear in a “Christmas tree” pattern and may occur anywhere in the body; however; the most common location is the back and the chest. Its association with an internal malignancy remains controversial. Adenocarcinomas of the colon, rectum, stomach and 222  2011/2012 Dermatology In-Review l Committed to Your Future
    • breast, among others, are the most common malignancies associated with this phenomenon.Therefore, depending on the clinical findings, further evaluation should include complete bloodand chemistry studies, chest X-ray, endoscopy of the gastrointestinal tract, mammogram, cervi-cal cytology, and prostate specific antigen.6 Malignant acanthosis nigricans is commonly seen inapproximately 35% of patients with the sign of Leser-Trélat. 1,6Treatment SKs are usually treated only in those cases when the lesion is not a typical SK, when theybecome symptomatic or cosmetically unacceptable for the patient. Surgical excision should be considered the treatment for those cases when the lesion is not atypical SK and histologic verification is needed. Other treatment alternatives include cryotherapy,electrodessication, laser therapy, topical 5-FU and dermabrasion. 5,76.2 ACTINIC KERATOSISEpidemiology Actinic keratoses (AKs) are very common, premalignant lesions, with the potential ofbecoming invasive squamous cell carcinomas (SCC). It accounts for the third most commonreason why individuals consulta dermatologist. Risk factors: Individual susceptibility (older age, male gender, fair skin phenotype, and lighteye color), immunosuppression, lifetime sun exposure, and some genetic syndromes such as albi-nism and xeroderma pigmentosum. 8,9Etiology Ultraviolet radiation B (UVB) from sunlight is responsible for AK development. It triggers theformation of thymidine dimers both in DNA and RNA, resulting in mutated keratinocytes. Themutations occur on the tumor suppressor gene p53 within the keratinocytes resulting in impair-ment of the mechanism of apoptosis. Therefore, clonal expansion of mutated keratinocytes mayoccur leading to the formation of AKs.10-12Clinical Presentation Patients are usually elderly with fair complexion and evident solar elastosis due to a history ofchronic sun exposure. Therefore, lesions are commonly found on sun-exposed areas (head, neck,forearms, dorsal hands) with 60% found on upper extremities.13 Typical AKs appear as erythem-atous, flat, rough macules or papules that are better felt than seen.9,13 Other clinical subtypes include hypertrophic AK, cutaneous horn and actinic cheilitis. Thehypertrophic AK (HAK) lesions are thicker, scaly, skin colored or erythematous plaques. The cuta-neous horn is defined as a type of HAK that presents as a conical hypertrophic protuberanceemanating from an erythematous base (Figure 6-4). Actinic chelitis develops from the confluenceof several AKs on the lips (usually the lower lip). The patient presents with red, scaly or chappedlips with erosions and fissures.13 (Figure 6-5)Histopathology The keratinocytes appear atypical, pleomorphic and disordered in arrangement. Foci of atypi-cal keratinocytes are located in the basal layer protruding as buds into the papillary dermis. Theepidermis also shows irregular acanthosis with columns of parakeratosis and hyperkeratosis.Changes due to solar elastosis and inflammatory infiltrate can be found in the dermis.9 (Figure 6-6and 6-7) Benign and Malignant Neoplasms  223
    • Treatment • Cryotherapy: The most common treatment for AKs with a cure rate of 98.8%. Curettage and Electrosurgery: for those patients with very few AKs, hyperkeratotic AKs, or recalcitrant lesions • Topical 5-Fluorouracil (5-FU): Blocks the methylation reaction of deoxyuridylic acid to thymidylic acid, thus interfering with the synthesis of DNA and RNA with cure rates up to 93% when patients sustain treatment until adequate endpoint Figure 6-4. Cutaneous Horn Figure 6-5. Hypopigmented, scaly plaque with fissures involving the lower lip of a male patient Figure 6-6. AK, lower magnification. Focal Figure 6-7. AK, higher magnification. parakeratosis alternating with orthokerato- Marked parakeratosis and absence of the sis. The neoplasm is confined to the epider- granular layer. Pleomorphism of the mis. There is prominent solar elastosis in atypical keratinocytes within the basal layer the subjacent papillary dermis. The tumor of the epidermis spares the hair follicles • Imiquimod: Is an immune response modifier that stimulates the innate and cell mediated immune pathways. It induces the synthesis and release of cytokines such as interferon, tumor necrosis factor, and interleukins 1,5,6,8,10, and 12, among others • Photodynamic therapy (PDT) with aminolevulinic acid hydrochloride (ALA) has been reported for the treatment of AKs 17 • Other treatments include: Dermabrasion, chemical peels and laser224  2011/2012 Dermatology In-Review l Committed to Your Future
    • Prevention • Sun avoidance • Low fat diets have been reported as useful in decreasing the incidence of AKs 18 • Retinoids in transplant patients may also reduce the formation of AKs 19Prognosis The risk of AK progression into invasive SCC ranges from 0.025% to 16% per year. Glogau 10concluded that the average rate of risk of progression of AK to SCC is approximately 8% amongthe studies reviewed. 206.3 BOWEN’S DISEASEEpidemiology Bowen’s disease (BD) is a form of squamous cell carcinoma (SCC) in situ than may occurboth in skin and mucous membranes. The exact incidence of BD is unknown. It affects elderly adults of both sexes, with a slight pre-dominance in the female gender.13,21,22Etiology Multiple etiologic factors have been associated with the development of BD including chronicsun exposure, arsenic exposure, ionizing radiation, immunosuppression and the human papillomavirus (HPV).13,21Clinical Manifestations BD typically appears as a slowly enlarging, well-demarcated, often scaly, erythematousplaque. It may be located on any sun-exposed or non-sun-exposed areas of the skin, includ-ing mucous membranes.13,21-23 However, the most common locations include the head and neckregions as well as the extremities (Figure 6-8). BD arising on the lower limbs is frequently foundin women; whereas lesions located on the ears and scalp are more common in men.23 BD on thenail bed presents as a periungual erythematous scale, onycholysis, or an erosion with crusting andnail discoloration.13,21 Intertrigenous BD appears as an acute oozing, erythematous dermatitis or asa pigmented plaque.13,21 Mucosal BD may appear as a verrucous or polypoid plaque, as an erythro-plakic patch or as a velvety red plaque.13,21Histopathology Epidermal dysplasia and keratinocytic disorganization is seen through the entire thicknessof the epidermis, from the stratum corneum down to the basal layer. However, the basementmembrane remains intact. Hyperkeratosis and parakeratosis is also present. Within the entire epi-dermis, pleomorphic keratinocytes show loss of polarity, atypia and mitosis, producing a “wind-blown” appearance. Chronic inflammatory infiltrate composed of lymphocytes, plasma cells andhistiocytes is commonly found in the upper dermis. Other histologic variants have been reportedincluding psoriasiform, atrophic, verrucous, acantholytic and pigmented BD.13,24 (Figure 6-9)Diagnosis and Differential Differential diagnosis include superficial BCC, chronic dermatitis, psoriasis, lichen planus, andactinic keratosis, among others. Histologically, BD must be differentiated from Paget’s disease,melanoma, bowenoid papulosis, and podophyllin-induced changes in a wart. 13 Benign and Malignant Neoplasms  225
    • Treatment • Simple excision(Recurrence rates of 5%) • Mohs micrographic surgery: in areas where there is an increased incidence of sub-clinical spreading, or when tissue sparing is a priority (e.g., face, genitals) 25,26 • Cyosurgery, 5-FU, and imiquimod have been reported with conventional excision 13,21Prognosis It is estimated that approximately 5% of patients with BD develop invasive SCC. Of these,about 30% have an increased risk of developing metastases.13,24 Figure 6-8. Pink, scaly well-demarcated Figure 6-9. BD. Neoplasm confined to plaque located on the lower extremety of the epidermis. The proliferation of atypi- a white, female patient cal keratinocytes is present in all layers of the epidermis. The hyperchromatic pleomorphic cells exhibit atypical mitotic figures within the whole thickness of the epidermis. Some dyskeratotic cells with pyknotic nuclei are observed in the upper layers of the epidermis. The white line is pointing at a multinucleated tumor cell6.4 NON-MELANOMA SKIN CANCER Non-melanoma skin cancer (NMSC) is the most common cancer in the United States. Basalcell carcinoma (BCC) accounts for approximately 80% of NMSC, whereas 20% corresponds tosquamous cell carcinoma (SCC).226.5 BASAL CELL CARCINOMAEpidemiology BCC is more common in men, with a male to female ratio of approximately. 2:1. 30,31 Risk factor: UVR exposure, fair skin phenotype, immunosuppression, family history of skincancer, genetic syndromes (e.g., nevoid basal cell carcinoma syndrome, and xeroderma pigmen-tosa, among others), and radiation therapy.30-33226  2011/2012 Dermatology In-Review l Committed to Your Future
    • Etiology When UVB damages the DNA it produces C-T transition mutations, better known as “UVB signature” or “fingerprinting.” The p53 and PTCH (patch) genes are the major targets of UVB for the development of BCC. The p53 is a tumor-suppressor gene, that regulates the cell cycle and apoptosis, and has been found to be mutated in approximately 56% of human BCC. Furthermore, the “UVB signature” is present in about 65% of them. The PTCH gene (located on chromosome 9q22) is involved in the Hedgehog signal transduction pathway and is found to be mutated in 30-40% of sporadic BCC, with 41% incidence of “UVB signature.” It is also responsible for the genetic defect in Gorlin syndrome. In approximately 50% of BCCs isolated from xeroder- ma pigmentosa both p53 and PTCH genes are mutated.11,32,34 On the other hand, UV radiation induces a state of relative immunosuppression (by alter- ing antigen-presenting mechanisms and producing immunosuppressive cytokines) that ulti- mately compromises tumor rejection.11,32 Other genes involved in the development of BCC include smoothened-activating mutations and PTCH2 mutation.34 Clinical Manifestations Sun-exposed areas are the most frequent location of BCCs, but it can be found in anywhere in the skin. There are several subtypes of BCC:31,33 The nodular BCC initially presents as a small, translucent, pearly papule with telangiectasias on its surface. As the lesion progresses, the center may become ulcerated and the borders become indurated, rolled and pearly. (Figure 6-10) This classic lesion is better known as “rodent ulcer.” This variant is frequently found on the face. The superficial BCC is commonly located on the thorax and limbs, and appears as a pink, scaly plaque with a slight elevation pearly border. (Figure 6-11) Crusting and ulceration may sometimes be present. Pigmented BCCs may appear as the nodular or superficial variant, with central black or brown pigmentation in the form of specks, dots or globules. (Figure 6-12) The morpheaform BCC, also known as sclerosing BCC, presents as a skin-colored, pink or whitish, indurated plaque that resembles a scar. (Figure 6-13) This variant has ill-defined borders and an aggressive growth pat- tern. It represents approximately 5% of all BCCs. The fibroepithelioma, or Pinkus, BCC appears as pedunculated, pink, dome-shaped papule, frequently located on the back (lumbosacral area). Gorlin syndrome (i.e., Nevoid Basal Cell Carcinoma syndrome) is characterized by the appearance of multiple BCCs during childhood, odontogenic keratocysts of the jaw and skel- etal defects (e.g., macrocephaly, hypertelorism, frontoparietal bossing, spina bifida, or rib abnormality, among others). Tumors associated with this disease include medulloblastoma and meningioma. It is inherited in an autosomal dominant pattern.31 Histopathology Several histologic patterns have been described: nodular, superficial, micronodular, infiltrative, or morpheaform.31 • The nodular pattern is the most common, and shows large, well defined, tumor masses with peripheral palisading • Superficial BCCs are characterized by the presence of tumor buds (Figure 6-14) or prolif- erations originating in the epidermis and extending towards and into the dermis. Palisading is also evident • The micronodular variant shows small tumor masses surrounded by fibrous stroma. Palisading is not prominent • Infiltrative BCCs appear as tumor masses of variable size, with irregular, spiky outlines and scarce evidence of palisading Benign and Malignant Neoplasms  227
    • • Morpheaform BCCs present with elongated strands of tumors cells within an abundant, sclerotic stroma • The Pinkus tumor shows long, branched, thin strands of tumor embedded in a fibromyx oid stroma, and connected to the overlying epidermisDiagnosis and Differential Some suggest that for morpheaform-appearing BCC a punch biopsy of the central, induratedarea of the lesion should be done to establish the diagnosis. Whereas, for all other types of BCC, ashave biopsy is usually enough to confirm the diagnosis. Differential diagnosis include ulcerative SCC, amelanotic melanoma, and fibrous papule fornoduloulcerative BCCs. Bowen’s disease, AK, psoriasis, and eczema for superficial BCCs. Whereaspigmented BCC can be confused with malignant melanoma or melanocytic nevi. MorpheaformBCCs must be distinguished from a scar or an isolated plaque of morphea.21,33Treatment Conventional excision (margin of about 4 mm, has 5-year cure rates of 89.9% and 82.6%, forprimary and recurrent BCC, respectively. 31,35) Figure 6-10. Nodular BCC. Notice the Figure 6-11. Superficial BCC appearing asa translucent appearance and pearly pink plaque with pearly borders and cen- surface with telangiectasias tral ulceration on an upper extremity Figure 6-12. Multiple pigmented Figure 6-13. Morpheaform BCC. BCCson the scalp of a white, elderly Atrophic plaque with raised, pearly individual borders and center crust228  2011/2012 Dermatology In-Review l Committed to Your Future
    • u TIP a  ohs micrographic surgery is indicated for large lesions (equal or greater M than 1 cm on the face or 2 cm on the trunk), located on high-risk anatomic areas (ear, eyelid, lips, genitals, nose, and temples), of the morpheaform subtype, recurrent, and with an aggressive growth pattern (the 5-year cure rate for primary and recurrent BCCs is 99% and 96%) a Curettage and electrodessication: the 5-year recurrence rate for primary BCC has been reported to be approximately 7.7%Figure 6-14. BCC. Nests of basal cells • Other methods: Cryosurgery, radiotherapy, topical 5-FU or imiquimod36,37 for superficial BCC are less often used techniquesPrognosis BCCs are characterized by their slow, indolent growth and progressive invasion of adjacenttissues. However, the metastatic potential is very low with rates ranging from 0.0028 to 0.1%.31,33,38Those BCCs that do metastasize tend to be large, ulcerated, neglected lesions, with an aggressivegrowth pattern. Metastases commonly occur in the lymph nodes and lungs. These tumors typi-cally recur regardless of multiple treatments.33,386.6 SQUAMOUS CELL CARCINOMAEpidemiology • SCC is the second most common skin cancer and accounts for approximately 20% of all NMSC • It is more common in the male gender (a lifetime risk 9-14% in men vs. 4-9% in women) • The incidence also increases with age (35 times higher in individuals older than 75 years of age when compared to ages 50-55 22,39) • The incidence of SCC doubles for each 8 to 10 degree decline in latitude; therefore populations living closer to the equator have a greater risk Risk factors: Chronic sun exposure, skin types I and II, chemical carcinogens (arsenic, tobacco,coal, tar), immunosuppression (due to immunosuppressive treatment in transplant patients, orimmunodeficiency syndromes such as HIV), chronic ulcers, burn scars, and genetic syndromes(e.g., xeroderma pigmentosa).Etiology Actinic keratosis (AK) is the precursor u TIPlesion of SCC. There is a sequence or continuum a VB radiation is the major causative agent for the Ubetween actinic keratoses, SCC in situ (Bowen’s development of SCC. It produces specific mutations disease) and invasive SCC. However, some SCCs (C to T transitional mutations) in the tumor suppressordevelop de novo and do not form from a previ- gene pg. 53ous AK. Keratinocytes with one mutation in p53after UV radiation may undergo apoptosis. However, if these keratinocytes with mutated p53 suf-fer a second hit or mutation, then they become resistant to further apoptosis and instead experi-ence clonal expansion, which is clinically evident as actinic keratoses. Uncontrolled proliferationof these abnormal keratinocytes leads to the development of SCC in situ and ultimately invasiveSCC.11,22 Benign and Malignant Neoplasms  229
    •  Human papilloma virus (HPV) infection has been linked with cutaneous SCC. Lesions on the genitals have been associated with HPV 6 and 11, whereas HPV 16 has been found in periungual lesions.40 Clinical Manifestations SCCs usually present as firm, skin-colored to pink, papules or plaques, commonly found on the head and neck region of elderly individuals (Figure 6.15). Other locations include the trunk, arms, dorsal hands and legs. Hyperkeratosis, ulceration or crusting may be found on its surface. Symptoms such as itching, pain and bleeding may be associated with the lesion.22,40 Histopathology Histopathologic evaluation of SCC reveals a proliferation of atypical keratinocytes that extends beyond the basement membrane into the dermis. The proliferation of cells can be seen as slender, long strands or as bulky masses. Individual cells have a glassy eosinophilic cytoplasm, with large nuclei. Mitotic figures (Figure 6-16) and horn pearls are also seen. Various degrees of differentiation may be seen and is usually described as well-, moderately-, or poorly-differentiated. Increasing degrees of malignancy show less demarcation between the tumor masses and the stroma, greater atypia, less keratinization, and loss of intercellular bridges. Other histologic vari- ants include acantholytic, adenosquamous, spindle-cell, verrucous, and desmoplastic SCC. 21,40,41 Treatment • Conventional excision for low risk SCCs (less than 2cms in diameter, well differentiated pattern, located on the trunk or extremities) • Mohs micrographic surgery (Overall cure rates are estimated to be as high as 98.1% for lesions less than 2cms, but drop to 74.8% for those larger than 2cms. Well differentiated SCCs have a 97% cure rate with Mohs, this rate drops to 67.4% for poorly differentiated lesions35). • Curettage and electrodessication • Radiation therapy used in combination with other modalities to treat aggressive, recurrent, or large, inoperable tumors or elderly patients that may not tolerate surgical procedures22 • Cryotherapy for small, superficial, low-risk lesions • Overall cure rates with non-Mohs modalities for tumors greater than 2 cms is 58.3%, for well-differentiated SCCs is 81%, and 46.4% for poorly differentiated lesions35 Prognosis u TIP The 10-year survival rate for individuals with a etastasis from a primary SCC is 0.3 to 16%.35,42-45 M regional and distant metastases is 20% and less than 10%, respectively.  he risk of metastatic disease increases with tumor T When metastases occur, regional lymph nodes size (>2cms), location (lips, ear, and eyelid, among others), depth of invasion, degree of differentiation, are more commonly affected. Furthermore, hema- perineural invasion, immunosuppression, recurrent togenous spread usually involve lungs, liver, brain, tumors, and SCCs arising in areas of chronic inflam- skin, and bone.22 mation (i.e., osteomyelitis, burn scars, ulcers)35 Management of the patients with high-risk cuta- neous SCC and no clinical nor radiological evidence of regional metastasis remains controversial. Some advocate the “watchful waiting” approach, while others prefer elective lymph node dissection. Recently, studies evaluating the usefulness of sentinel lymph node biopsy for the management of these patients have been reported.46,47 230  2011/2012 Dermatology In-Review l Committed to Your Future
    • Figure 6-15. High-risk SCC Figure 6-16. SCC. Typical explosive located on the lower lip mitotic figures, necrotic keratinocytes, and highly pleomorphic cells of invasive SCC are observed6.7 KERATOACANTHOMAEpidemiology Keratoacanthomas (KAs) are rapid growing cutaneous tumors believed to arise from the hairfollicles. There is much controversy as to whether or not KAs are benign lesions or well differenti-ated variants of SCC capable of spontaneous degeneration. KAs usually present as a crateriformnodule in fair-skinned, elderly individuals. It is commonly found as a solitary lesion; however, otherKA variants have been reported and consist of multiple lesions.41,48Etiology The origin of KAs has not been established. Due to its usual location on sun-exposed areas,ultraviolet exposure has been proposed as an important etiologic factor. Exposure to chemicalcarcinogens such as tar and pitch, as well as smoking, has also been linked to the development ofKAs. A viral etiology, specifically the human papilloma virus, has also been proposed but its role inthe origin of KAs remains unclear.41,49Clinical Manifestations KAs usually appear as solitary, firm, dome-shaped papules with an eroded or crateriformcenter. (Figure 6-17) Occasionally, KAs may be multiple. Patients are commonly fair-skinned, withhistory of sun-exposure, and pick incidence between 50 and 69 years of age.50 The lesion canbe located on any sun-exposed area, but the majority occurs on the face, forearms and hands.Typical of this tumor is its rapid growth, reaching a size of 1 to 2 cms within a few weeks. Figure 6-17. Dome-shaped nodule with cratiform center typical of keratoacanthoma Benign and Malignant Neoplasms  231
    • KAs have three clinical stages: Proliferative, mature and resolving. The first stage (prolifera-tive) is characterized by the sudden appearance of a firm, smooth, papule with fine telangiecta-sias. The papule may be skin-colored or erythematous. As stated before, the tumor grows rapidlyduring 2 to 4 weeks until reaching a size of approximately 2 cms. During the mature phase, thenodule acquires a dome-shaped or bud-shaped appearance with central, umbilicated, keratinouscore. Its consistency is firm; however, fixation to underlying tissue is not present when palpatingthe nodule. Tumor reabsorption occurs within 4 to 6 months (involution stage), ultimately result-ing in a slightly depressed, and hypopigmented scar.49 Usually, the process from origin to sponta-neous resolution takes place within four to six months.50 KA progressions to SCC with metastaticspread is rare but frequently seen in immunosuppressed patients.50 There are several types of KAs including: • KA centrifugum is an unusual subtype of solitary KA that may reach a size of up to 20 cms in diameter. Enlargement and extension of the border with simultaneous central healing are characteristic of this type of KAs.52 It affects both men and women and usually occurs on the face, trunk or extremities. Spontaneous resolution may or may not occur.49 50 Diagnosis: foresee difficulties due to clinical similarities and histological to lesions such as halogenoderma, verrucous tuberculosis or deep fungal infections51 • The giant KA is characterized by rapid growth reaching a diameter of 9 cms or more. This type of tumor can invade underlying structures including cartilage49 • The subungual KA originates in the nail bed and is locally destructive to the underlying bone. It presents as a painful, umbilicated, red and swollen lesion, commonly located on the thumb and little finger. It is persistent, thus spontaneous involution is rarely seen 49, 50 • The Ferguson-Smith variant is characterized by the sudden appearance during childhood or adolescence, of multiple eruptive KAs that slowly resolve and re-appear later on. These may be located on any sun-exposed surface; however, face and extremities are the most common location. This condition is apparently inherited in an autosomal dominant pattern49 and seems to be a result of a single mutation that occurred in Scotland in the 1700’s.50 There is a 3:1 male predominance50 • Grzybowski type is typically diagnosed during adulthood, with the sudden appearance of hundreds to thousands of lesions in a disseminated fashion. Diameter of the lesions is usually 2-3 mm and can be found anywhere in the body including palms, soles, larynx and oral mucosa.49 Similar incidence between men and woman50 • Intraoral or Mucosal Membrane KAs: Extremely rare. Appears as a painless ulcer particularly difficult to differentiate from SCC, especially in the tongue, where the malignancy is a common site. Negative history of exposure to known risk factors may light towards the KA52 • Multiple Persistent50 • KA in special situations: Occupational (tar-induced), immunosuppressed patients (rapid progression to SCC), xeroderma pigmentosum, in Muir-Torre syndrome (AD, associated with a defective DNA mismatch repair gene)50Histopathology During the proliferative stage the tumor appears as a well-defined, keratin-filled invaginationof the epidermis arising from contiguous hair follicles. Hyperkeratosis and acanthosis are alsoseen. Epidermal strands consisting of atypical squamous cells with mitotic figures extend into thedermis. A sparse dermal inflammatory infiltrate is usually found surrounding the tumor. Perineuraland vascular invasion may be present and should not be considered a sign of malignancy, inopposition to SCC, where it is a sign of metastatic disease.50 Once the tumor progresses into the232  2011/2012 Dermatology In-Review l Committed to Your Future
    • mature phase, the atypical squamous cells become less prominent. The fully developed crateri-form nodule has a central depression filled with hyaline keratin. Irregular epidermal proliferationsmay be seen protruding into and around the base of the crater. Keratinization of the squamouscells is prominent, producing a glassy appearance. During involution, the lesion becomes flattenedwith a dense lichenoid infiltrate, fibrosis, and granulation tissue. The crater heals slowly, ultimatelyresulting in an irregularly shaped, atrophic scar.21,41,48,49Diagnosis and Differential The most important differential diagnosis for KA is SCC. Other differential diagnosis are:Seboacanthoma (sebaceous adenoma + KA), exophytic pilomatricoma, cutaneous metastaticdisease, verrucous carcinoma, deep fungal infection, and giant molluscum contagiosum. Clinically,the rapid growth of an exophytic, crateriform tumor is suggestive of KA. These distinctive fea-tures may sometimes be enough for the initial diagnosis of KA. Histological features such as thepresence of a compact tumor, with a central crater filled with keratin, along with protruding epi-dermal proliferations surrounding the crater, pronounced keratinization and neutrophilic microab-scesses further confirm the diagnosis. SCCs even when well-differentiated, show great pleomor-phism, scarce keratin production, and ulceration is sometimes present.48,49 It is important to obtain a biopsy of the specimen down to the subcutaneous fat. This can beachieved either by complete excisional biopsy, full-thickness shave biopsy or fusiform incisionthrough the entire KA including its center and sides.48,49,50 Even despite the fact that there are noadequately sensitive and specific criterion to distinguish KA from SCC, the five more significantare “epithelial lipping and sharp demarcation between tumor and stroma favoring KA and ulcer-ation, numerous mitosis, and marked pleomorphism/anaplasia favoring SCC.”50 Sometimes it isdifficult to differentiate KA from SCC, both clinically and histologically. Therefore, management ofthe tumor as an invasive SCC should be done when clear distinction between the two tumors hasnot been achieved. 21,48,49,50Treatment Even though KAs resolve spontaneously, biopsy and treatment is usually undertaken to con-firm the diagnosis and prevent further growth and discomfort, discomfort and scarring. Solitary KAs are usually treated by complete excision, which also provides an ideal specimento confirm the diagnosis by histological evaluation. Mohs micrographic surgery is used in KAswhen in critical anatomic areas and for large tumors. Recurrence after excision is seen in 4% to8% and does not imply change in malignity. In multiple KAs, another options should be consid-ered, but close follow up and excision if cases of non respondent lesions after four to six weeks.Radiotherapy or laser surgery has been successful in small solitary KAs located in difficult to treatbody areas. In early and small either solitary or multiple KAs, cryosurgery with liquid nitrogen isindicated.48,49,50 Amputation of digits should be considered when bone involvement or failure toother therapies, specially in subungual lesions. Intralesional and topical therapies are also available. Intralesional 5-fluorouracil (5-FU) andmethotrexate are widely used; nonetheless methotrexate is favored over 5-FU because fewertreatments are required.48,49,50 Corticosteroids were commonly considered in the 70s and 80s dueto the rapid control of the inflammation and discomfort with minimal scarring and regression ofabout 70% of the KAs. In selected cases, such as multiple or recurrent KAs, consideration of thisold therapeutic agent could benefit these patients.53 Intralesional bleomycin and interferon α-2aare other options. Topical 5% imiquimod every other day in solitary facial KAs for 4 to 12 weeks isan available treatment option.48,49,50 Benign and Malignant Neoplasms  233
    • Systemic treatments are reserved for multiple lesions including the Ferguson Smith variant,the Grzybowski type and the centrifugum marginatum. Retinoids, methotrexate, 5-FU, and cyclo-phosphamide have been used. However, retinoids are the most widely used due to its less toxicprofile. Prophylactic retinoid regimen in the Ferguson Smith variant is necessary to reduce out-breaks and minimize scarring.506.8 MALIGNANT MELANOMAEpidemiology Cutaneous malignant melanoma (MM) is a potentially fatal tumor that originates from malig-nant melanocytes. The incidence of MM has risen over the past decade. It was estimated that thelifetime risk for the development of melanoma in aperson born in the year 2000 is 1 in 75. u TIPThe incidence between males and females in the a isk factors for the development of MM include RUnited States is equal. MM affects younger population sun exposure with tendency to freckle and sun- burn, fair skin complexion, light colored eyes andin comparison with NMSC, with a peak incidence in hair, presence of large number of nevi, family andages 20-45 years old.30 The most common locations personal history of melanoma 3,30,54are the back, chest, and upper extremities for men.However in women, the most common locations are u TIPthe back, lower legs, and upper extremities.54 antermittent sun exposure (weekends and vacations) I with painful sunburns during childhood and adoles-Etiology cence may be the major predisposing risk factor for The etiopathogenesis of MM has not been clearly the development of melanocytic and atypical nevi, which could ultimately lead to MMdetermined. UV radiation causing DNA mutations hasbeen associated with the development of MM. It has ahe most important mutated gene associated with Tbeen reported that the risk is higher than twofold with a predisposition to develop MM is the CDKN2A (located on chromosome 9p21) 54,55a history of five or more episodes of sunburn duringadolescence.3,55Clinical Manifestations There are four types of melanoma: superficial spreading, acral lentiginous, nodular, and lentigomaligna melanoma. Superficial spreading melanoma (SSM) accounts for approximately 70% of all melanomasin the white population. It may be located anywhere, but the back and lower legs are the mostcommon sites for men and women, respectively. It is usually diagnosed in individuals during theirfourth or fifth decade of life. It may evolve from melanocytic nevi. It usually arises as a dark pig-mented macule or slightly raised plaque. Mixed colors may be seen, such as dark brown or black,with shades of pink, blue or gray. The lesion is found to be well-demarcated and asymmetrical,with indented borders.54,56 Acral lentiginous melanoma (ALM) is the predominant type of melanoma in dark-skinnedindividuals. It is usually located on the soles, palms, and subungual region of older patients (fifthto sixth decade of life). It presents as a flat, brown to black, lesion with irregular borders. 54,56 Nodular melanoma (NM) is the second most common type of melanoma in persons of faircomplexion (15%). This type of melanoma may be located anywhere on the body site of individu-als with ages ranging from 40 to 50 years old. The lesion is characterized by the sudden appear-ance and growth of a dark brown, black or blue nodule, with well-defined and regular borders.54,56234  2011/2012 Dermatology In-Review l Committed to Your Future
    • Lentigo maligna melanoma (LMM) is the least common (approximately 5%) and arises from the precursor lesion, lentigo maligna (melanoma in situ). It usually affects older individuals (sixth to seventh decade of life) and involves sun-exposed regions, with cheeks, nose and temples being the predilected sites. LMM appears as a flat lesion with nodular areas, and different shades of brown and black colors. The borders are sharply demarcated and very irregular.54,56 Histopathology Histologic findings such as diameter greater than 6 mm, asymmetry, poor circumscription, and the presence of single melanocytes (especially pagetoid, see Figure 6-18) at and above the dermal-epidermal junction on sun-damaged skin are diagnostic for melanoma. Atypical melano- cytes may also be distributed in the adnexal epithelial structures. MM has two growth phases, horizontal and vertical. During the horizontal growth period, atypical melanocytes are mainly located within the epidermis and may be singly seen infiltrat- ing the papillary dermis. This phase is followed by a vertical growth period, in which large nests of malignant melanocytes invade the dermis and obtain the potential of metastasizing. Nodular melanomas exhibit mainly a vertical growth phase and become thick lesions in a short amount of time.54,56 Figure 6-18. Pagetoid Melanoma. Neoplastic prolif- eration of melanocytes forming irregular nests in the basal layer. Single atypical melanocytes are spread- ing within all the layers of the epidermis. The cells have large atypical nuclei and abundant eosinophilic cytoplasm and a surrounding halo resembling cells of Paget disease Diagnosis Identification of melanoma is initially done through visual examination of suspicious lesions. The ABCD rule should be used, where A stands for asymmetry, B is for irregular borders, C is for diversity of colors, and D is for diameter larger than 6 mm. Dermoscopy or epiluminiscence microscopy is another non-invasive technique used for the evaluation of pigmented lesions and diagnosis of MM. A more objective assessment of the lesion is made through identification of pigment network and patterns. Several dermoscopic diagnostic algorithms have been proposed including the ABCD rule of dermoscopy, the Menzies’ method, the seven-point checklist and more recently the three-point checklist. In general, the following dermoscopic features are suggestive of MM: 1.) asymmetry; 2.) multicomponent pattern; 3.) parallel-ridge pattern (for acral melanocytic lesions); 4.) atypical pigment network (charac- terized by black, brown or gray network, irregularly distributed within the lesion that usually ends abruptly in the periphery); 5.) uneven arrangement of streaks (radial streaming) through- out the lesion; 6.) blue-whitish veil; 7.) localized irregular and diffuse pigmentation; 8.) irregu- larly distributed or isolated globules (dark or slate blue); and 9.) regression structures seen as white (scar-like) or blue-gray areas; among others.57-59 Once clinical examination and dermoscopic features lead to the initial diagnosis of MM, a biopsy must be performed for histologic confirmation. Excisional biopsies provide adequate tissue specimen for histologic diagnosis and staging of the lesion. Incisional biopsies may be considered Benign and Malignant Neoplasms  235
    • when the suspicion for melanoma is low, when the lesion is large, located in cosmetic areas suchas the face, or when it is unfeasible to perform an excision.60 Immunohistochemistry, using S-100 or HMB-45, may also be used for the diagnosis of MM.Staging Table 6-1 shows the final version of the American Joint Committee on Cancer Staging Systemfor cutaneous melanoma. 61 Table 6-1. Proposed Stage Groupings for Cutaneous Melanoma American Joint Committee on Cancer Staging System 2001 Stage TNM Criteria 0 Tis melanoma in situ IA† T1a N0M0: tumor ≤1.0 mm without ulceration and mitosis <1/mm2 IB† T1b N0M0: tumor ≤1.0 mm with ulceration or mitoses ≥1/mm2 T2a N0M0: tumor 1.01-2.0mm without ulceration IIA† T2b N0M0: tumor 1.01-2.0 mm with ulceration T3a N0M0: tumor 2.01-4.0 mm without ulceration IIB† T3b N0M0: tumor 2.01-4.0 mm with ulceration T4a N0M0: tumor >4 mm without ulceration IIC† T4b N0M0: tumor >4 mm with ulceration IIIA* T1-4a N1aM0: non-ulcerated tumor of any size with micrometastasis in 1 node T1-4a N2aM0: non-ulcerated tumor of any size with micrometastasis in 2-3 nodes IIIB* T1-4b N1aM0: ulcerated tumor of any size with micrometastasis in 1 node T1-4b N2aM0: ulcerated tumor of any size with micrometastasis in 2-3 nodes T1-4a N1bM0: non-ulcerated tumor of any size with macrometastasis in 1 node T1-4a N2bM0: non-ulcerated tumor of any size with macrometastasis in 2-3 nodes T1-4a/b N2cM0: tumor of any size ulcerated or not with in transit met(s)/satellite(s) without metastatic nodes IIIC* T1-4b N1bM0: ulcerated tumor of any size withmacrometastasis in 1 node T1-4b N2bM0: ulcerated tumor of any size with macrometastasis in 2-3 nodes T1-4a/b N3M0: any tumor with 4 or more metastatic nodes, or matted nodes, or in transit met(s)/satellite(s) with metastatic nodes IV† AnyT AnyN M1a: with distant skin, subcutaneous or nodal mets AnyT AnyN M1b: lung metastases AnyT AnyN M1c: all other visceral or any distant metastasis, plus elevated serum LDHAdapted from Balch et al. AJCC Cancer Staging Manual, 7th edition. 54 97† The stage I and IV subgroups are based on both, clinical and pathologic staging.* The stage III subgroups are based on pathologic staging only. 236  2011/2012 Dermatology In-Review l Committed to Your Future
    • Treatment The treatment of choice for MM is surgery, and the goal is complete removal of the lesion his- tologically confirmed with negative margins. The current surgical margins recommended by the American Academy of Dermatology are: 0.5 cm for melanoma in situ, 1 cm for melanomas that measure <2 mm in thickness, and 2 cm for lesions ≥2 mm in thickness.60 Mohs micrographic surgery has been suggested for the treatment of MM. However, its use remains controversial and the current guidelines do not recommend this method as a treatment option.60 The management of patients with melanoma and clinically negative nodes is controversial. Elective lymphadenectomy is performed by removing all the clinically negative regional nodes that drain the site where the primary melanoma is located. However, this procedure carries a great morbidity and has failed to establish an improvement in survival of these patients. Within the last decade, sentinel lymph node biopsy has gained acceptance for the treatment of inter- mediate thickness MM (1-4 mm, or lesions less than 1 mm deep showing ulceration). The sen- tinel lymph node is the first node that receives lymphatic drainage from the primary tumor. Histological evaluation of the sentinel node may depict the status of the remainder nodes in the basin. If the sentinel node is negative for micrometastasis then the rest of the basin may be con- sidered free of malignancy, and a complete lymphadenectomy might be considered unnecessary and avoided. Even though it has been widely accepted due to its low morbidity and high fea- sibility, the role of sentinel lymph node biopsy in survival has not been established. It is mainly being used for a more accurate staging and prognosis, and to determine if further treatment, such as adjuvant therapy, is necessary.54,55,63 Adjuvant therapy with interferon-alpha has been used for patients with high risk of recurrence(primary melanoma with tumor thickness ≥4.0 mm or level V invasion, primary melanoma with in-transit metastases, primary melanoma with regional lymph node metas- tases that are clinically apparent or detected at elective lymph-node dissection, regional lymph node recurrence, involved nodes were excised but there was no known primary mel- anoma, American Joint Committee on Cancer stage IIB, IIC and III). It has shown to improve disease-free and overall survival.54 Treatment options for distant metastases include surgical excision of isolated metastases (skin, subcutaneous tissue, lung, brain), radiation therapy, chemotherapy, and biologic therapy (interferon-alpha, interleukin-2), among others. However, the outcome for patients in stage IV remains unsatisfactory with an average survival of 6 months.54 Prognostic Factors Increasing age and male gender have a negative effect on survival. Patients with primary lesions located on the extremities have a better prognosis than those with tumors located on the head, neck or trunk. Increasing tumor thickness, invasion and ulceration are considered poor prognostic factors. In stage III melanoma, the fewer the number of nodes involved the better the prognosis. Furthermore, there is a significantly lower survival for those patients with palpable metastatic nodes (macrometastasis) when compared to those with micrometastatic nodes (non- palpable). For stage IV melanoma, patients with non-visceral metastases (skin, subcutis, distant lymph nodes) have a better prognosis compared to those with visceral metastases.54,64 Benign and Malignant Neoplasms  237
    • 6.9 MERKLE CELL CARCINOMAEpidemiology Also known as cutaneous neuroendocrine carcinoma, this tumor is an unusual malignant neo-plasm that arises from neuroendocrine cells with features of epithelial differentiation. Merkel cellcarcinoma (MCC) is a biologically aggressive tumor that is difficult to diagnose and even moredifficult to treat in advanced stages. It usually affects elderly individuals, but there have been reports of MCC in children and youngadults.65Etiology The origin of this neoplasm is unknown. UV radiation has been postulated as a risk factor.66 Anewly identified virus, the Merkel cell polyomavirus, appears to be associated with the develop-ment of Merkel cell carcinoma.98Clinical Manifestations Caucasians older than 50 years of age are typically affected, with no gender predominance.The tumor usually appears as a solitary, 1 to 2 cms, dome-shaped nodule, most frequently locatedon the head and neck region and extremities. The nodule is commonly found to be dark red orviolaceous with a shiny surface that often has telangiectasias. The overlying skin may be intact orulcerated.65,66Histopathology • Light microscopy: There are three histologic patterns of MCC: trabecular, intermediate- cell type, and small-cell type. The trabecular variant consists of interconnecting trabeculae separated by strands of connective tissue. Also pseudorosettes may be found. The majority of MCCs belong to the intermediate-cell type, characterized by large, solid nests of cells of intermediate size, with a trabecular pattern in the periphery. The least frequent variant is the small-cell type, which consists of diffusely infiltrating sheets of small neoplastic cells that may be mixed with intermediate cells. The tumors involve the dermis and spread into the subcutaneous fat, usually sparing the overlying epidermis. (Figure 6-19) The neoplastic cells are round and uniform in size, with a round to oval nucleus, small nucleoli, and evenly dispersed chromatin. A “ball-in-mitt” pattern is said to be typical, with one or two crescentic tumor cells wrapped around one central round tumor cell. Numerous mitotic figures, necrotic areas, in addition to neural and vascular invasion is often seen.65-67 Figure 6-19. Merkel Cell Carcinoma. Basophilic aggregates of small-round cells are seen in the upper and mid-reticular dermis extending towards the deeper portions of the dermis. There is an uninvolved Grenz zone of papillary dermis. The tumor cells have prominent round vesicular nuclei and scant ill-defined cytoplasm. Occasional mitoses are present. The neoplastic cell islands tend to connect each other via anastomosing cords238  2011/2012 Dermatology In-Review l Committed to Your Future
    • • Electron microscopy: The main ultrastructural features of MCC include dense core granules concentrated in cytoplasmic processes and paranuclear aggregates of intermediate filaments (cytokeratins, neurofilaments) which parallel or have a whorled arrangement near the nucleus. These characteristics are essential when making the diagnosis of MCC and differentiating it from other other neoplasms such as metastatic oat cell carcinoma, SCC, metastatic adult neuroblastoma, and malignant melanoma, among others65 • Immunohistochemistry: MCC exhibits both epithelial and neuroendocrine markers. The most commonly used markers for MCC are monoclonal antibodies to cytokeratins 8, 18 and 20; neuron specific enolase (the most constant marker); chromogranin A/B, and synaptophysin. This neoplasm may sometimes contain several neuropeptides including vasoactive intestinal peptide (VIP), calcitonin, ACTH, gastrin and somastatin, among others. Leukocyte common antigen, vimentin, desmin, glial fibrillary acidic protein, and S-100 are consistently absent in MCC 65,66 Diagnosis and Differential Both clinical and histopathological (light microscopy, electron microscopy and immunohisto- chemistry) evaluation are required for the diagnosis of MCC. A correct diagnosis of MCC may be confirmed by positive juxtanuclear labeling of tumor cells with anti-cytokeratins, cytoplasmic reactivity to neuron specific enolase, and focal pres- ence of neurofilaments proteins in paranuclear location. Differential diagnosis include SCC, BCC, pyogenic granuloma, keratoacanthoma, amelanotic and melanotic malignant melanoma, adnexal tumors, lymphoma, metastatic oat cell carcinoma, undifferentiated anaplastic carcinomas, and neuroblastomas, among others.69 Treatment There is no standard protocol for the treatment of Merkel cell carcinoma. However, treatment modalities include wide local excision or Mohs micrographic surgery, with or without adjuvant therapy. • Surgical Treatment: Wide local excision with 2-3 cms margins has long been advocated as the treatment of choice. However, currently, Mohs micrographic surgery has successfully been used for the treatment of MCC yielding the lowest local recurrence rates.65, 67-69 Compared to conventional excision, Mohs surgery allows evaluation of all margins (including the deep sections) as well as maximal sparing of adjacent normal tissue • Adjuvant Therapy: MCCs are sensitive to radiation and chemotherapy. Controversy exists regarding the usefulness of radiation as adjuvant therapy for the treatment of MCC.61,63,66 Boyer et al concluded that radiation may be an option when tumor free margins are not achieved, complete excision is not feasible, or for large or recurrent tumors70 For patients with systemic disease, multiple cytotoxic agents have been employed including: cyclophosphamide, methotrexate, 5-FU, cisplatin, etoposide, and doxorubicin, among others. However, a standard regimen has not been established, and a combination of drugs that are usually used to treat small cell carcinoma of the lung is usually recommended65-67 Benign and Malignant Neoplasms  239
    • • Sentinel Lymph Node Biopsy: Intraoperative mapping and sentinel lymph node biopsy has recently gained advocates for the treatment and prognosis of MCC. It is considered a low morbidity technique that can successfully identify micrometastatic or clinical occult disease in the regional lymph nodes of patients with MCC. The presence of metastatic disease in the sentinel node may be used as rationale for complete node dissection and additional adjuvant therapy67,71 Prognosis As stated before, MCC displays an aggressive behavior and has a high incidence of local recurrence, regional and systemic spread. The overall survival rates have been estimated to be 88% for one year, 72% for two years, and 55% for three years.65,66 The incidence of regional lymph node metastases has been reported to be between 50 and 60%.61,62 Distant or hematogenous metastases occur in 30-40% of patients, and usually involve the liver, bone, brain, or lung.65,66 6.10 CUTANEOUS T-CELL LYMPHOMA Epidemiology Cutaneous T-cell lymphoma (CTCL) is a neoplasm of helper T-cells (CD4+) that originate in the skin. There are many variants of CTCL but Mycosis Fungoides (MF) and Sezary syndrome (SS) are the most common. The annual incidence of MF and SS in the United States is approxi- mately 4.5 cases per million people.72 The male to female ratio for CTCL is 2:1. It is more commonly diagnosed in the adult black population. Furthermore, black race and advanced aging are associ- ated with a worse prognosis. MF acquired its name due to the mushroom-like appearance of the tumor. Sezary syndrome is considered the leukemic variant of MF. Etiology The etiopathogenesis of CTCL has not been established and several causative factors have been proposed. It has been postulated that patients with atopic dermatitis have an increased risk of developing CTCL due to chronic stimulation of T-cells that may induce its clonal proliferation. Other etiologic factors such as viral infections (HTLV-1) and chemical exposure have also been suggested.73 Clinical Manifestations CTCL is a chronic and slowly progressive disease that initially manifests in the skin and may ultimately involve other organs. There are three main skin lesions: Patches, plaques and tumors. The earliest lesion is usually a flat, scaly, erythematous or violaceous patch. Lesions may be single or multiple and usually occur in areas not exposed to the sun (lower abdomen, upper thighs, but- tocks, breasts). The patches may be pruritic or asymptomatic. During this stage, histologic evalu- ation may not be diagnostic for CTCL.73-74 The plaque stage starts to develop as the malignant T-cells invade and infiltrate the skin. Plaques may arise de novo or from existing patches. This phase is characterized well demarcated, irregularly shaped, elevated lesions that are red-brown or violaceous in color. An asymmetric distribution is usually present and pruritus remains a common complaint.73-74 The tumor stage represents a more aggressive period of vertical growth. It appears as expanding nodules arising from previous patches, plaques or non-affected skin. The tumors are initially dome-shaped with a smooth surface, and may later undergo necrosis and ulceration.73-74 240  2011/2012 Dermatology In-Review l Committed to Your Future
    •  Sezary syndrome, the leukemic variant of MF, is characterized by the triad of pruritic erythro- derma, generalized lymphadenopathy, and the presence of Sezary cells (abnormal, large hyper- convoluted lymphocytes) in peripheral blood. The number of Sezary cells that must be present for the diagnosis remains controversial. However, the most common cutoff point is more than 1,000 cell/mm3. Other manifestations include scaling and fissuring of palms and soles, alopecia, pruritus, peripheral edema, and nail dystrophy.73-75 Histopathology Histologic evaluation may show scanty superficial dermal infiltrate of normal lymphocytes appearing. In more advanced stages, histologic evaluation shows a thickened epidermis and a dense infiltrate of lymphocytes in the dermis. Epidermal involvement with uTIP single-cell exocytosis of lymphocytes (epidermotropism) is often seen. The aarly lesions usually do E lymphocytes may also aggregate in the epidermis forming the Pautrier not show characteristic microabscesses. The cells look larger than normal and have a characteristic findings for the diagnosis of CTCL cerebriform nuclei.73-75 (Figure 6-20) Figure 6-20. F. Plaque lesion. Mild epidermal hyperplasia is observed. M The papillary dermis bears a band-like mononuclear cell infiltrate com- posed of hyperchromatic cerebriform cells with hyperchromatic cere- briform nuclei which are called mycosis cells. Some of the mycosis cells are seen also on the epidermis forming Pautrier microabscesses. The neoplastic cells have epidermothrophism not only in the form of Pautrier abscess, but single lymphocytes are present in the basal layer Diagnosis The accurate diagnosis of CTCL requires the combination of both clinical and histopatho- logic findings. Immunophenotyping and molecular techniques may also be used for the diagnosis of CTCL. The CD4+ T-helper cells typically express alpha/beta T-cell receptors CD2 and CD3, but lack the T-cell antigens CD7 and Leu-8. These features are useful in the diagnosis of CTCL. Another option for the diagnosis of CTCL is the determination of monoclonal rearrangement of T-cells gene receptors through PCR or Southern blotting techniques.73-75 Treatment Management of the patient with CTCL can be done through skin-directed or systemic therapy. Skin-directed therapies include topical corticosteroids, PUVA, UVB therapy, topical chemotherapy with mechlorethamine (nitrogen mustard), or topical bexarotene gel. Localized radiotherapy may be considered for lesions resistant to other treatments. Total skin electron beam therapy may be indicated for patients with widespread skin lesions or for those that did not respond to more conservative therapies. Photopheresis is usually reserved for patients with erythrodermic MF. Systemic therapy is indicated for patients that do not respond to topical therapy or more advanced disease. Treatment options include methotrexate, interferon-alpha, retinoids (such as Bexarotene), denileukin diftitox (a diphtheria fusion toxin that targets the interleukin-2 receptor), and systemic chemotherapy (cyclophosphamide + doxorubicin + vincristine + prednisone is the most widely used combination chemotherapy).72-75 Benign and Malignant Neoplasms  241
    • 6.11 ANGIOSARCOMA u TIPEpidemiology a utaneous AS appear in three different clinical settings: C Angiosarcoma (AS) is a very rare and 1.) diopathic, arising in the head and neck region of white, elderly Iaggressive tumor of endothelial origin. individualsMen are more commonly diagnosed with 2.) On the limbs in association with lymphedema the idiopathic form of this neoplasm.77 3.) In areas previously exposed to radiation therapy (latency 3-40 years) 76Clinical Manifestations The lesion initially arises as a painless, purple macule-patch or plaque on the scalp or face.Later on it becomes an elevated, bluish or purple nodule that may ulcerate. Tumors may be singleor multiple. Common symptoms include bleeding, edema, and ultimately pain. Cervical lymphnode and hematogenous metastasis commonly occur.77 The lungs, spleen, and liver are the mostcommon organs where distant metastasis occur.78,79Histopathology Angiosarcomas are commonly seen infiltrating the dermis, but may also invade the fas-cia and subcutis. Multiple anastomosing vascular spaces are found. The cells lining the vesselsare large, pleomorphic and hyperchromatic with atypia. (Figure 6-21) Hemorrhage may alsobe seen.78,80 Immunohistochemistry markers such as CD31, CD34 and factor VIII are positive inangiosarcomas. These neoplasms are vimentin negative and cytokeratin positive.80 Figure 6-21. Angiosarcoma. Ill-defined neoplastic proliferation of plump-cuboidal mostly pleomor- phic endothelial cells intermingled with slit-like spaces with many erythrocytesTreatment Wide surgical excision remains the treatment of choice. However, this tumor’s ability ofsubcutaneous spreading make the achievement of true free margins very difficult. Therefore,radiation therapy is usually employed after surgical excision.79,806.12 DESMOPLASTIC TRICHOEPITHELIOMAEpidemiology Desmoplastic trichoepithelioma is a variant of trichoepithelioma, an uncommon adnexal tumorwith differentiation towards hair structures. It is three times more common in the female genderand usually occurs in young adults.21,81 Trichoepitheliomas are benign tumors arising from the undifferentiated germinative cells ofthe follicular-sebaceous-apocrine unit. Multiple trichoepithelioma (MT) and giant solitary tricho-epithelioma (GST) are other variants of Trichoepithelioma. MT is an autosomal dominant trait242  2011/2012 Dermatology In-Review l Committed to Your Future
    • that first manifests in puberty and occurs primarily in the facial area. The GST is not hereditary, appears later in life, and affects the perianal region.82 Clinical Manifestation It presents as a small, firm, umbilicated papule on the face.21,81 Histopathology The tumor is seen as a well circumbscribed lesion located in the upper dermis. Strands or columns of basaloid cells are seen surrounded by fibrotic or desmoplastic stroma. Horn cysts may also be seen, as well as foci of sebaceous cells, calcification and ossification.21,81 (Figure 6-22) Figure 6-22. Desmoplastic Trichoepithelioma. Observe the sclerotic stroma, small aggregations and cords of baseloid neoplastic cells within the reticular dermis. The neoplastic cells have round to oval basophilic nuclei and scant cytoplasm Diagnosis and Differential Differentiation from BCC can be challenging. Also SCC and microcystic adnexal carcinoma should be considered.83 Treatment Local surgical excision.81 6.13 DERMATOFIBROSARCOMA PROTUBERANS Epidemiology Dermatofibrosarcoma protuberans (DFSP) is more common in individuals 30-50 years old, with a higher incidence in males with a 3:2 male-to-female ratio.88 It accounts for approximately 0.1% of all skin neoplasms. Etiology The histogenesis of DFSP has been proposed to be fibroblastic, histiocytic, or neuroec- todermal.85 However, general agreement on its origin has not been determined. Chromosomal abnormalities are present in the vast majority of cases. A chromosomal reciprocal transloca- tion t(17;22)(q22;q13), and supernumerary ring chromosome have been reported as cytogenetic characteristics of DFSP.87 More than 90% of DFSP present a translocation in different regions of chromosomes 17 and 22. Other translocations such as t(2;17), and t(9;22) have also been pro- posed.87 In the translocation t(17,22), an exon of the platelet-derived growth factor-B (PDGFB) in chromosome 22 is fused with the collagen 1 alpha 1 (COL1A1) in chromosome 17. The final Benign and Malignant Neoplasms  243
    • COL1A1 –PDGF-B fusion oncogene produced mature and fully functional PDGFB protein. Theidentification of this deregulated expression of PDGFB provided new solid theoretical basis forthe use of inhibitors of PDGFB receptors (PDGFRB), such as Imatinib, as an alternative therapy inthis disease.89,92,93Clinical Presentation DFSP is an uncommon monoclonal cutaneous soft tissue neoplasma, characterized by a slow,infiltrative growth pattern. DFSP has considerable morbidity because of its aggressive local inva-siveness. It is typically located on the trunk, followed by extremities. Initially it arises as an asymp-tomatic, reddish or skin colored indurated plaque. Some telangiectasia may be present in the sur-rounding skin. (Figure 6-23) It may slowly enlarge, and become raised, firm, and multinodular untillate in its course. (Figure 6-24). It is usually fixed to overlying skin but remains freely movablefrom deep tissue. At this stage, it may ulcerate, bleed, or become painful.85,88 Distant metastasesoccurred in 1 to 4 % of DPSP.81 Palpation of lymph nodes is necessary to detect rare cases of lym-phatic (1%) or hematogenous dissemination (4%), predominantly to the lungs.86,90 Figure 6-23. DFSP located Figure 6-24. Large multinodular DFSP on the right clavicle area of located on the left hip of a female a female patient patientHistopathology DFSP is histologically characterized by the presence of monomorphic spindle cells arrangedin a “storiform” or “cartwheel” pattern. The cells may show slight atypia. At later stages, the cellsinfiltrate the subcutaneous adipose tissue, resulting in a honeycomb pattern of entrapped adi-pocytes.84,85,88 (Figure 6-25) Figure 6-25. DFSP. Neoplasm composed of ill- defined, dense, spindle cells within the reticular der- mis extending towards the subcutaneous fat. The tumor cells are monomorphic and in some areas arranged in a whorl-like pattern. In the subcutane- ous tissue the neoplastic cells are invading subcuta- neous fat lobules in a lace-like fashion244  2011/2012 Dermatology In-Review l Committed to Your Future
    • Diagnosis and Differential The final diagnosis of DFSP is done histologically by evaluation of the biopsy specimen. Immunohistochemistry of the specimen may also be done to confirm the diagnosis. Typically DFSP is CD34 positive and factor XIIIa negative, allowing its differentiation from dermatofi- broma.84,85,88 Magnetic resonance imaging (MRI) is useful to determine deep tumor invasion, especially in recurrent lesions.86 Other differential diagnosis include scar, keloid, morphea plaque, fibrous histiocytoma, and morpheaform BCC, among others.84,85,86 Treatment DFSP is characterized by an overall high recurrence rate after wide local excision. The tumor shows a subclinical growth pattern through finger-like projections. Accurate removal with the least recurrence requires careful and extensive evaluation of all the margins. Therefore, Mohs micrographic surgery has become a favorite treatment alternative for DFSP. Recently, a review by Snow et al91 reported 136 patients with DFSP treated with Mohs surgery. Long term follow up of these patients showed a 6.6% (9/136) recurrence rate after the first Mohs procedure. However, in all of the recurrent cases there were extensive infiltration or discontinuous tumor growth. Treatment of the recurrent DFSPs with a second Mohs surgery yielded a 98.5% cure rate.83 Adjuvant radiotherapy (RT) reduces local recurrence in patients who have close or posi- tive margins and patients with unresectable macroscopic disease.86,90 6.14 MICROCYSTIC ADNEXAL CARCINOMA Epidemiology Microcystic adnexal carcinoma (MAC), also known as sclerosing sweat duct carcinoma, is an uncommon locally aggressive adnexal tumor. Patients diagnosed with MAC are usually 40-60 years old. Sex distribution seems to be equal. It usually affects middle aged to elderly individuals of both sexes.21,94,95 Etiology The origin of this tumor is unknown. Eccrine, follicular, apocrine or sebaceous differentiation has been reported.21,94,95 Clinical Presentation The most common tumor locations include the perioral, lip, nasolabial, or periorbital areas.21,94,95 Clinically MAC appears as a solitary, skin colored, indurated plaque or nodule. It is usually asymptomatic, but symptoms such as paresthesia, numbness and burning sensation may be pres- ent when perineural invasion has occurred.21,94,95 (Figure 6-26) Histopathology Histologically it presents with poorly demarcated tumor cells invading the dermal and sub- cutaneous tissue. Islands of basaloid keratinocytes, horn cysts and duct structures are also seen within a desmoplastic stroma. Cytologic atypia and mitotic figures are rarely observed.21,94,95 (Figure 6-27) Benign and Malignant Neoplasms  245
    • Diagnosis and Differential Clinical and histological evaluation is required to diagnose MAC. A deep biopsy specimen isrequired for complete architectural examination.21,94,95 Differential diagnosis include desmoplastic trichoepithelioma, syringoma, and morpheaformBCC, among others. MAC shows deep subcutaneous and perineural invasion, as well as CEA posi-tive staining, all features that may help differentiate it from desmoplastic trichoepitheliomas.94Treatment Due to the high recurrence rate after conventional excision (approximately 47%), and its infil-trative and aggressive growth pattern, Mohs micrographic surgery has become the preferredtreatment option for MAC.21,94,96 Figure 6-26. MAC arising in Figure 6-27. MAC. Irregular island perioral area, clinically of neoplastic baseloid cells with prominent oval resembling morpheaform BCC nuclei. The small aggregations of cells are sur- rounded by fibrotic desmoplastic stroma. The white line is pointing at neural invasion246  2011/2012 Dermatology In-Review l Committed to Your Future
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