Melanocytic Nevi and Neoplasms Andrew’s chapter 30 Michael Hohnadel, D Melanocytic Nevi and Neoplasms Andrew’s chapter 30 Michael Hohnadel, D.O. 4/20/04

Nevus Spilus Pigmented, light brown or tan macule, varied diameter, speckled with smaller, darker-colored macules or papules. Lower extremity & trunk frequently. When these nevi follow a dermatomal distribution they may be referred to as a zosteriform, or sometimes a speckled lentiginous nevus. Usually do not cross the midline.

Nevus Spilus Syndromes: Phakomatosis pigmentovascularis - nevus spilus is present with a nevus flammeus. Phakomatosis pigmentokeratotica- Organoid nevus with sebaceous differentiation, hemiatrophy with muscular weakness & other neurologic findings & speckled lentiginous nevus. The darker speckles usually contain nevus cells. Melanoma might arise with greater frequency than in normal skin. TX: Removal is not necessary. Q-switched ruby laser has been reported effective.

Lentigo Simplex Sharply defined, rounded, brown or black macules found anywhere on body or mucosa. No predilection for sun exposed regions. Usually arise in childhood but can arise anytime. Histologically: Elongation of rete ridges, increase in number of melanocytes in basal layer, increase of melanin in both melanocytes, and basal keratinocytes, and melanophages in the upper dermis. No therapy is needed/ there is no predisposition to neoplastic change.

Solar Lentigines Discrete hyperpigmented macules in areas of sun exposure. May evolve into sk’s or lichenoid keratoses. Possibility of lentigo maligna or lentigo maligna melanoma. Tx: liquid nitrogen, laser. Peels. Hydroquinones ect. Photochemotherapy or frequent tanning salons may develop lentigines on non-sun-exposed areas and these may show cellular atypia

Solar Lentigines Hyperpigmented elongated rete ridges with diffuse increase in non-nested melanocytes, and solar elastosis.

Penile and Vulvar Melanosis Localized pigmentary alterations Most often show basilar hyperpigmentation May appear in large patches or in smaller, well-demarcated lesions Present on the penis or in women on the labia majora

Bannayan-Riley-Ruvalcaba Syndrome Rare, AD disorder that manifests in childhood. 80% of the pts are male Characterized by genital lentiginosis, macrocephaly, motor and speech delay, mental retardation, lipomas, hemangiomas, verruca vulgaris, and many types of facial papules.

Multiple Lentigines Syndrome Multiple lentigines which are dark brown macules, 1-5 mm. in diameter. Preponderance on the trunk Multiple generalized lentigines may occur with a number of associated signs as an dominantly inherited syndrome. l

Multiple Lentigines Syndrome LEOPARD Syndrome: lentigines electrocardio abnorm. ocular hypertelorism pulmonary stenosis abnormalities of genitalia retardation of growth deafness

Centrofacial Lentiginosis Moynahan Syndrome Multiple lentigines, Congenital mitral stenosis, Dwarfism, Genital hypoplasia and Mental deficiency Centrofacial Lentiginosis Characterized by lentigines on the nose, and adjacent cheeks Sometimes associated with status dysraphicus, multiple skeletal anomalies, and CNS disorders Spares the mucous membranes Onset is first years of life

Inherited Patterned Lentiginosis in Blacks A.D. syndrome. Ten, light-complexioned black patients who developed numerous lentigines in infancy or early childhood Distribution is central face, lips, with variable involvement of dorsal hands and feet, elbows, and buttocks Sparing of mucous membranes and no internal abnormalities

Carney’s Syndrome Carney syndrome (2+ of following) AKA: NAME syndrome or LAMB syndrome Carney syndrome (2+ of following) Cardiac Atrial Myxoma (79%) Can be life threatening. Cutaneous myxomas (45%) <1 cm flesh colored papules which develop by the age of 18 and occur on ears, eyelids and nipples. Mammary myxoid fibromas (30%) Spotty mucocutaneous pigmentation (blue nevi) (65%) or lentigines Prim. Pig. Nodular adrenocortical disease. (45%) Testicular tumors (56%) Pituitary G.H. secreting tumors. (10%)

Peutz-Jeghers Syndrome A.D. Pigmented macules on the lips, oral mucosa, perioral acral areas Associated with gastrointestinal polyps, especially prominent in the jejunum.

Melanoacanthoma Uncommon, benign epidermal melanocytic neoplasm, occurring on the head Resembles a pigmented sk or a pigmented BCC. Predominantly seen in white men > 60 yrs

Cellular Nevi Appear in first yrs of life, increases in number over the next 2-3 decades, after which there is a steady decline. F>M Less common in sun-protected areas Maximum number is at age 20- 25 yrs, the average number is 40 Sun exposure increases the number of nevi in the exposed skin. Eruptive nevi are rare, but may occur after severe bullous disease such as TEN, EM, or severe sunburn, Addison’s disease or immunosuppresion

Junctional Nevi A smooth, hairless, light to dark brown macule, varying in size from 1 –6 mm. Occurs on any site, especially on palms, soles, scrotum. It is characterized by single melanocytes, or nest of melanocytes, in the lower epidermis. During adolescence some will become compound or intradermal.

Compound Nevus The compound nevus is one that is still manifesting so-called junctional activity (accumulation of melanocytes in the epidermis) but has formed structure of a cellular nevus in the dermis as well

Compound Nevus Nests of nevus cells in the epidermis overlying a dermal component of orderly nevus cells

Intradermal Nevus A compound nevus in which junctional activity has ceased, and all the nevus cells are in the dermis.

Intradermal Nevus Nevus cells that are recognized at this power by tendency to be arranged in nests At the base of this dermal nevus the melanocytic cells resemble neural structures -neurotization

Treatment of Nevi Signs of malignant degeneration ABCDE changes. Thickening, ulceration, pain, ugly duckling sign. Dot extensions. New lesion in patient over 35 years. Changes may occur during pregnancy or with oral contraception. Biopsy if you think melanoma. Treatment: Andrews recommends biopsy and removal of scalp nevi if atypical due to difficulty in following. Single oral or vaginal lesions – biopsy.

Balloon Cell Nevus A pigmented nevus, varying in size from 1 –5 mm, usually occurring on the head, neck, and trunk. Clinically indistinguishable from ordinary pigmented or nonpigmented nevus Histologically: Composed of peculiar vesicular cells that appear to be foamy and form large pale polyhedral balloon cells that may be multinucleated giant cells in addition to nevus cells. Not considered potentially malignant, and treatment is same as other nevi

Halo Nevus AKA: Sutton’s nevus, perinevoid vitilgo, & leukoderma acquisitum centrifugum Pigmented nevus with surrounding depigmented zone. Immune response to melanin. No tx indicated - central nevus disappears with time, leukodermic area will usually repigment with time A search for melanoma should be done.

Halo Nevus The nevus architecture is obscured by a dense lymphocytic infiltrate Lymphocytes infiltrate among the dermal nevus cells, which eventually degenerate and disappear

Giant Pigmented Nevus Presentation: Characterized by a large, darkly pigmented hairy patch in which smaller, darker patches are interspersed or present as small satellite lesions. Skin may be thickened or verrucous By definition >20cm. Has a tendency to follow a dermatome distribution Trunk favored site.

Giant Hairy Nevi Present at birth and grow proportionally to the site of the body where they are located. When a large congenital nevus involves the axial skin, there may be an associated neurocutaneous melanocytosis Hydrocephalus, leptomingeal melanoma Incidence of melanoma: Overall risk is 3% to 7%. (40% of melanoma in children.) Risk is greatest in axial lesions. Seldom in satellites. Only 1/3 of melanoma arise from epidermal sites (makes) for more difficult surveillance.

Giant Hairy Nevi Treatment: Most recommend total surgical excision and resurfacing autografts. Alternative treatments: dermabrasion, curettage, and laser ablation. These eliminate some of the nevus cells, with theoretic lowering of the risk of melanoma Monitoring. Serial MRI’s for neurocutaneous melanosis

Small and Medium-sized Congenital Nevocytic Nevus Small - < 1.5 cm in greatest diameter. Medium- > 1.5 cm but < 20 cm. Found in 1% of newborns. Half eventually become hairy. Data indicates that those which do progress to melanoma occur in Pts older than 18 yrs and in the epidermis (Hence monitoring is effective) Treatment: Excision is recommended for lesions of the hairy scalp, or those of great cosmetic concern or nevi with unusual clinical features. Otherwise, observation.

Epitheliod and Spindle-Cell Nevus (Benign Juvenile Melanoma, Spitz Nevus) Firm, 3–10 mm diameter, rosy papule on the face, especially on the cheek. Lesion has distinctive pink, brownish red, or purplish red color. Female predominance. 2/3 in first two decades of life. Should be completely excised and examined histologically. Full excision recommended to prevent confusion with melanoma at future date.

Spitz Nevus A variant of the compound nevus Epidermal irregular acanthosis, pseudoepitheliomatous hyperplasia, and thinning of the epidermis Nevus cells are pleomorphic, but mostly spindle-shaped (fusiform), or polygonal (epithelioid) cells

Spitz Nevus Immunohistochemical staining for MIB-1 and bcl-2 will distinguish most Spitz nevi from melanoma: Melanomas are immunoreactive Spitz nevi not reactive.are not Differential diagnosis: Pyogenic granuloma, mastocytoma, juvenile xanthogranuloma, or melanoma.

Dysplastic Nevus Variegated tan, brown, pink coloration with pink hues seen in macular portion. Macular portion always present, frequently surrounds a papular center. Generally larger than are common nevi, usually 5–12mm, with irregular borders. Develop new lesions over a lifetime. Sun protected areas.

Dysplastic Nevus Occurrence: 5% -20% of pts have at least one clinically dysplastic nevus. Importance: Careful history and evaluation of family members. DNs provide another risk factor for melanoma predisposition. >3 lesions increases the risk of melanoma from 3 to 43 times. Increased risk of melanoma in the DN AND in the rest of epidermis

Dysplastic Nevus Histologic features as per an NIH consensus: Basilar melanocytic hyperplasia with elongation of rete ridges. Spindle-shaped or occasionally, epithelioid melanocytes arranged horizontally and aggregating in nests that fuse with adjacent rete ridges. Lamellar and concentric superficial dermal infiltrate. Cytologic atypia, usually present but not essential for diagnosis.

Dysplastic Nevus Elongated rete ridges, bridging between rete ridges, fibroplasia, and sparse lymphocytes are features. Cytologic atypia is usually mild.

Dysplastic Nevi Treatment: Patients with dysplastic nevi and a positive family or personal history of melanoma, physician examination every 3 – 6 months Excision of those nevi that change clinically or are located in difficult to monitor locations such as the scalp. Photographs with measured scale is useful Sunscreens and Pt self exam are critical.

Dysplastic Nevus Syndrome Around 1978 Lynch et al recognized an autosomal dominant inheritance pattern in families with unusual nevi and multiple melanomas-initially described by Clark et al as B-K mole syndrome. Now called dysplastic nevus syndrome (DNS). Criteria: Melanoma in 1st or 2nd degree relative Often >50 melanocytic nevi some AN DN on histologic exam.

Dysplastic Nevus Syndrome Risk of melanoma: Normal = 1 %. DN, no family with MM = 6% lifetime risk. DN, (+) family history of MM = 15 % DN, (+) two or more 1st degree relatives with MM, lifetime risk approaches 100%.

Dysplastic Nevi

Melanoma Originate from melanocytes at epidermal-dermal junction 50% will develop in pre-existing nevi. Prolonged, non invasive, horizontally oriented growth phase. When tumor nodule develops the vertical growth phase is occurring and the risk of metastatic disease increases dramatically. One in 80 Americans will develop melanoma. Incidence is low until after puberty. During pregnancy pigmented nevi may enlarge in size uniformly 2nd to hormones. If changes of irregular pigmentation or asymmetrical growth occur ect, then a biopsy should be performed.

Melanoma Risk Factors Light complexion, blonde or red hair, childhood blistering sunburns, heavy freckling. Other factors: >50 benign nevi or family history of melanoma, dysplastic nevi. > 50 benign nevi Presence of large congenital nevus Presence of clinically dysplastic nevus Mutations in the p16-CDK4 (DNS) Immunodeficiency syndromes-acquired or genetic PUVA treatments Xeroderma pigmentosum Use of tanning lamps

Melanoma Types. There are four recognized clinicohistologic types: 1.) Lentigo maligna (melanoma in situ, noninvasive melanoma) 2.) Superficially spreading melanoma 3.) Acral-lentiginous melanoma 4.) Nodular melanoma

Lentigo Maligna (melanoma in situ, noninvasive melanoma) Begins as a tan macule that extends peripherally, with gradual uneven darkening, over several years. At this stage called lentigo maligna After a radial growth of 5 to 20 years, a vertically growing component melanoma usually develops within it. A palpable nodule within the original macule is the best evidence that a lentigo maligna melanoma has occurred. 60-70 yrs. M=F Usually on chronically sun-damaged skin, most often on the face Accounts for 5% of all melanomas.

Lentigo Maligna (melanoma in situ, noninvasive melanoma)

Superficially Spreading Melanoma Most common, 70% of melanoma. Adults of all ages. Median age 50 yrs. No preference for sun damaged skin.. Lesion has tendency for multicolored appearance with notched borders and areas of regression. Faster growing than lentigo maligna. In a study by Bolognia et al 5% of lesions with an eccentric foci of hyperpigmentation(a roundish area of brown or black 3mm or less and located peripherally) are melanomas arising from within a nevus . It is necessary to ensure that the pathologist sections through the black dot to make this early diagnosis

Superficially Spreading Melanoma

Acral-lentiginous melanoma Subungual and mucosal lesions are in this category. Account for 10% of all melanomas. The most common type among Japanese, African American, Hispanics, and Native Americans. Due to lower incidence of other melanoma types. Most common site in blacks is the foot - 60%. Median age is 50 yrs with equal sex distribution.

Acral-lentiginous melanoma

Nodular Melanoma 15 % of melanomas. Pigmented papule or nodule of varying size. No apparent radial growth phase. Histologically, lesion extends several rete ridges past the apparent margin. Polypoid Variant: Does not appear to extend into dermis yet behaves like clark level IV or V. 42% vs 57% five year survival.

Nodular Melanoma

Other Melanoma Types. Desmoplastic Melanoma: Deeply infiltratiing, spindle cell type. Most are amelanotic. Occur within lentigo maligna often. Neurotropic spread. Inflammatory melanoma: Inflammation surrounding melanoma = poor prognosis. Amelanocytic melanoma – pink or flesh colored. Mistaken for PG. Seen in Albinos.

Diagnosis of Melanoma Surgical excision is the best method. A shave may be better for less suspicious or broad, thin lesions. For larger lesions an incisional or punch biopsy is the standard. When melanoma is suspected in a melanotic freckle or a giant pigmented nevus, biopsy should be done through the thickest and most atypical area and multiply sectioned to find thickest area of involvement

Histologic Diagnosis of Melanoma Pinkus criteria: Presence of mitoses Inflammatory reaction composed of lymphocytes and possibly plasma cells Dermoepidermal junctional activity. (Except in giant nevus) Absence of dermal stroma

Histologic Diagnosis of Melanoma Increased number of melanocytes with atypical nuclei not only in the basal zone, but also at the upper levels of the epidermis

Histologic Diagnosis Inflammatory cells surrounding atypical melanocytes.

Histologic Diagnosis of Melanoma Neoplastic melanocytes extend into the dermis. Absence of maturation at deeper levels of the dermis

Melanoma Metastasis Metastasis-usually manifested by pigmented nodules appearing around the site of the excision Early remote metastases occur via lymphatics and regional lynphadenopathy may be the first sign Sites of mets: Skin most common. Lungs, CNS also common. Any organ possible. Usually occurs with in 5 years of diagnosis.

Melanoma Workup and Treatment Establish a family history, thorough review of systems and physical exam for all patients. A consensus conference in 1992 concluded that a staging workup (including E.L.N.D.) was not indicated for melanomas below 1.0 mm thickness. Many physicians obtain a CXR and an LDH. Consultation with an oncologist is worthwhile for advanced cases. Sentinel node / ELND. Still evolving criteria. Recommended for tumors >1.0 mm thick or with ulceration.

Melanoma Excision Margins

Melanoma - Other Treatments High-dose interferon alfa-2b therapy. Efficacy is equivocal and toxicity high. May diminish the occurrence of mets and prolong disease free survival with melanoma > 1.5 mm thick Chemotherapy is not effective. Adoptive immunotherapy with lymphokine-activated killer cells + interleukin-2, or high dose interleukin-2 alone. Some patients are responsive. Perfusion chemotherapy has been used for extremity melanoma and has almost eliminated the need for amputation. Aldara and Tazorac for M.I.S. recently published.

Survival Indicators 5 Year Survival Rates Based on Lesion Thickness: In situ ……= 100% <0.76 mm. = 2-4% 0.76 to 1.49 = 90% 1.50 to 3.99 = 70% > 4 mm ….. = 50 %

Dermal Melanocytic Lesions At birth, melanocytes may be present in the dermal portion of the skin of the scalp, the backs of the hands, and the sacrum. These are large ameboid cells that normally disappear shortly after birth.

Mongolian Spot Bluish gray macule of varying size from 2-8 cm. Typically in the sacral area of the newborn. 80-90% of Asians, Southern Europeans, American blacks, and Native Americans. Multiple spots may be situated in other locations and if associated with a nevus flammeus called phakomatosis pigmentovascularis Most resolve with by adulthood.

Nevus of Ota (Nevus Fuscocerulleus Opthalmaomaxillaris) Brown, slate gray, or blue-black macules grow slowly larger and deeper in color around eye. May have involvement of the conjunctiva and the skin about the eye. Usually present at birth, esp if the patient is going to have ocular involvement. 80% occur in women; 5% are bilateral Usually benign. Malignant melanoma may occur with choroid most commonly. Glaucoma may occur. Nevus of Ota (Nevus Fuscocerulleus Opthalmaomaxillaris)

Nevus of Ito (Nevus Fuscoceruleus Acromiodeltoideus) Same features as nevus of Ota except that it occurs in the distribution of the posterior supraclavicular and lateral cutaneous brachial nerves. It involves the shoulder, side of the neck, and supraclavicular areas TX: Q-switched ruby laser.

Blue Nevus 2 types: Blue nevus of Jadassohn-Tiche (common blue nevus) Cellular blue nevus

Blue Nevus of Jadassohn-Tiche Common blue nevus or nevus ceruleus Steel-blue nodule that begins early in life Slow growing. Rarely reaches 2-10mm. Occurs most frequently on the dorsal hands, feet, forearms, shins, face, and the buttocks.

Blue Nevus Within the dermis there is a poorly defined but symmetric spindle cell proliferation that is dark brown in color No significant change in the overlying dermis

Blue Nevus The spindled, heavily pigmented cells encircle collagen bundles in the reticular dermis. The lesion is composed of elongate cells that are heavily pigmented and show prominent pigmented dendrites

Cellular Blue Nevus Large, firm, blue or blue-black nodule. Frequently seen on the buttock and sacrococcygeal region. Multilobulated, well circumscribed tumor. Women 2.5 times > Men. Occasionally present at birth Average age is 40. Uncommonly, these invade underlying structure such as the skull in scalp lesions.

Cellular Blue Nevus Frequently large and involve a good part of the dermis and extending deeply as tonguelike aggregates of tumor cells at the base of the lesion Involvement of the subcutaneous fat is common and does not imply a malignant diagnosis

Cellular Blue Nevus The cellular areas are composed of uniform spindled melanocytic cells with more cytoplasm and larger nuclei than what is seen in common blue nevus. There are irregularly distributed collections of course melanin pigment within the cells

Epithelioid Blue Nevus Newly described lesion with strong association with Carney’s complex (myxomas, spotty skin pigmentation, endocrine over activity, and schwannomas) Occur frequently on the head and neck, and are at times multiple They are darkly pigmented, domed, and less than 1 cm.

Malignant Blue Nevus Cellular blue nevus may rarely undergo malignant transformation into malignant melanoma Clinically sudden increase in size and ulceration. Histologically: Pleomorphism of nuclei, mitotic figures, and invasion of clusters of malignant cells into the deep dermis and fatty tissue. Treatment: Benign lesions - Excision has been mainstay of treatment. Q-switched ruby laser. Malignant variety is the same as M.M.