Pediatric Skin Lesions with Predisposition to Cancer Mark A. Bechtel, M.D. Director of Dermatology The Ohio State University College of Medicine Pediatric Primary Malignant Skin Tumors В„ В„ В„ Melanoma В‰ Congenital nevi В‰ Xeroderma pigmentosa В‰ Nevus spilus В‰ Develop de novo В‰ Radiotherapy Squamous Cell Carcinoma В‰ Xeroderma pigmentosa В‰ Renal, bone marrow, other solid organ transplants В‰ Immunosuppressive therapy В‰ Immunodeficiency disorders В‰ Nevus sebaceous B Basal lC Cellll C Carcinoma i В‰ Gorlins syndrome В‰ Renal, bone marrow, other solid organ transplants В‰ Nevus sebaceous Skin cancers following gp pediatric organ g transplant. S Euvrard et.al. Dermatol g 2004;; 30: 616-621 Surg В„ В„ В„ Skin cancer is the most frequent malignancy following pediatric renal transplantation and the second most common after p pediatric nonrenal transplantation. Squamous cell and basal cell carcinoma, and rarely KaposiвЂ™s sarcoma Usually develop in early adulthood Pediatric Melanoma В„ В„ В„ В„ В„ В„ 2% of melanomas occur in patients younger than 20 years of age. 0.3% of melanomas occur in patients younger than 14 years of age. Risk factors for melanoma in children parallel those in adults adults. Predisposing factors В‰ Large congenital nevi В‰ Xeroderma pigmentosa Melanomas proportionately more common children В‰ Small cell melanomas В‰ Melanomas M l with ith ffeatures t off S Spitz it nevii with ith atypical t i l features Childhood melanomas histiologically resemble adult melanomas Pitfalls in Diagnosis & Management of P di t i M Pediatric Melanomas l В„ В„ В„ Low index of suspicion Atypical presentation В‰ Amelanotic В‰ Verrucous В‰ Pyogenic granuloma-like Delay in biopsy Melanoma in children and teenagers: an analysis of patients from the National Cancer Data Base. Lange JR et.al. J Clin Oncol 2007; 25: 1363-1368. В„ Evaluated 3158 patients ages 1-19 with malignant melanoma Age 1-4 5-9 10-14 15-19 % of study subjects 3.8% 5 7% 5.7% 17.3% 73 2% 73.2% Lange вЂ“ Pediatric Melanoma В„ В„ В„ Overall survival of patients aged 1-9 was significantly worse than those aged 10-24. Male patients aged 10-24 had worse outcome than females in this age group. In patients 1 1-19, 19 survival was not correlated with primary tumor thickness Congenital Melanocytic Nevi В„ В„ В„ В„ Nevomelanocytic proliferations that are present at birth Congenital nevus вЂњtardiveвЂќ вЂ“ develops during the first 2 years of life and is clinically and histologically indistinguishable from congenital melanocytic nevi Congenital nevi are present in 1% of newborns newborns. Large congenital nevi (> 20 cm) occur in 1:20,000 newborns. Congenital Nevi Classification В„ В„ В„ В„ < 1.5 cm вЂ“ small congenital nevus 1.5 cm to 20 cm вЂ“ medium congenital nevus > 20 cm вЂ“ large congenital nevus In the newborn or infant вЂ“ a CMN of 6 cm on the b d or 9 cm on th body the h head d will ill attain tt i a size i off 20 cm in adulthood Kopf p AW. J Am Acad Dermatol 1979;; 1: 123-130. Large g Congenital g Nevi вЂ“ Melanoma Risk В„ В„ В„ В„ В„ The lif Th lifetime ti risk i k off d developing l i melanoma l h has been estimated at 5-20%. Melanoma often develops during childhood childhood. Melanoma usually arises deep within the dermis where it is not easily detectable on clinical examination until it reaches an advanced stage. More than half of melanomas develop during the first 10 years of life life. The highest rate of malignancy occurs during the y first 5 years. Small and Medium Congenital Nevi вЂ“ Melanoma Risk В„ В„ В„ The lifetime risk of developing melanoma is not well established. Melanoma often develops in adulthood Melanoma usuallyy arises in the epidermal-dermal p junction and can be detected at an earlier stage by clinical examination A study of large congenital melanomcytic nevii and d associated i t d malignant li t melanomas. l DeDavid M et. al. J Am Acad Dermatol. 36: 409 416 1997 409-416, 1997. В„ В„ Reviewed 289 patients with large congenital nevi in NYU registry and the world literature. 34 patients (12%) developed primary cutaneous melanoma Results of DeDavid Study В„ В„ В„ В„ В„ В„ All the melanomas had congenital nevi in an axial location (32 вЂ“ torso, 2 вЂ“ posterior scalp). Satellite nevi were reported p in 91% of p patients with primary cutaneous melanoma. No melanomas developed on an extremity or within ithi a satellite t llit 50% of melanomas were diagnosed before 5 years (median вЂ“ 4.6). 62% of patients died from melanoma. Median age g of death was 7.1 yyears. Clinical appearance of the ulcerated nodule within the scalp giant congenital nevus of patient 1 Leech, S. N. et al. Arch Dermatol 2004;140:83-88. Copyright restrictions may apply. 5 yyear cumulative risk of developing p g melanoma in large congenital nevi В„ В„ Marghoob Egan g 4.5% 5.7% Marghoob et al, Arch Dermatol. 1996; 132: 170-175. Egan et al, J Am Acad Dermatol. 1998; 39: 923-932. Risk of melanoma in medium-sized congenital melanocytic nevi. Sahin S, et al. J Am Acad Dermatol. 1998; 39: 428-433. В„ В„ Followed a cohort of 230 p patients with CMN ((1.519.9 cm) for an average of 6.7 years (median 5.8 years). No melanomas observed. The risk of melanoma in patients with congenital nevi: a cohort study. Swerdlow AJ, et al. J Am Acad Dermatol. 1995; 32: 595-599. В„ В„ В„ Followed CMN involving less than 4% body surface (< 20 cm) in 232 patients. Observation period median of 25 years No melanomas developed Large g CMN May y Be Biologically g y Different From Small and Medium CMN В„ В„ Large CMN В‰ NRAS mutations (70%) В‰ BRAF mutations (15%) Small and medium CMN В‰ NRAS mutations (14-56%) В‰ BRAF mutations (70-94%) Dessars B B, et al al. J Invest Dermatol Dermatol. 2009; 129: 139-147 139-147. Management g of Large g Congenital g Nevi В„ В„ Treatment should be individualized Considerations for management В‰ Risk of melanoma В‰ Risks and functional impact of surgery В‰ Disfigurement of surgery В‰ Cosmetic concerns of lesion В‰ Ease of observation for changes in CMN Tromberg et al. Dermatol Ther 2005:;18 (2) : 144 Treatment options treatment benefits risks Full thickness excision i i 1. 2. 1. Reduces melanoma risk Cosmesis 2. 3. Partial-thickness excision 1. 2. Reduces melanoma risk Less potential for scarring than full thickness excision 1. 2. 3. 4. curettage 1. 2. Potential reduction of melanoma risk if done early May produce good cosmetic result 1. 2. 3. 3 4. 5. dermabrasion laser Chemical peel 1. 2 2. 3. Reduces melanoma risk May produce good cosmetic result Reduced pigmentation may allow for easier detection of developing melanoma 1. 1. 1. 2. 3. Unknown to what extent it may or may not reduce melanoma risk Low potential for scarring p recovery y time Improved 1. 2. May reduce melanoma risk cosmesis 1. 2. 2. 3. 2. Excision of large CMN may leave cosmetically disfiguring scar Often requires serial excisions, tissue expanders, skin grafts Requires general anesthesia Melanoma may develop from residual melanocytes Excision of large CMN may leave cosmetically di fi i scar disfiguring Requires general anesthesia Difficult to detect subcutaneous melanoma Melanoma may develop from residual melanocytes Requires general anesthesia Must be performed within the first few weeks of life Repigmentaiton of scarred skin Scarring may make it difficult to detect development of MM Case reports of melanoma development after dermabrasion Post-dermabraded skin is thin, fragile, tender, reduced hair density Melanoma may develop from residual melanocytes Repigmentation Unknown mutagenic g p potential Melanoma may develop from residual melanocytes Most effective in superficial CMN that are lightly pigmented Neurocutaneous Melanosis В„ В„ В„ Excessive proliferation of melanocytes within the CNS, including the leptomeninges as well as brain parenchyma h A congenital error in morphogenesis of embryonal neuroectoderm Risk factors include posterior axial location of a LCMN and the presence of multiple satellite nevi nevi. Neurocutaneous melanosis (cont.) В„ В„ В„ CMN typically involve the lumbosacral region, posterior thorax, and especially the head and neck. neck Patients with more than 20 satellite nevi have a 5 1 fold increased risk of neurocutaneous 5.1 melanosis. 34% of patients have multiple CMN rather than a single large CMN. Neurocutaneous Melanosis Symptoms В„ В„ В„ В„ В„ В„ Increased intracranial pressure Seizures Hydrocephalus Cranial nerve palsy Hemiparesis Developmental delays y Symptomatic Neurocutaneous Melanosis В„ В„ В„ В„ Most children present within the first 5 years of life Prognosis is poor with incidence of death of 79% with 50% dying before 5 years of age. Primary CNS melanoma occurs in over 50% with median age g of death of 3 yyears Treatment is only palliative. DeDavid M et al. J Am Acad Dermatol. 1996; 35: 529-538. MRI Findings in Neurocutaneous Melanosis В„ В„ Diagnosis established by MRI Characteristic hyper intense regions in T1 вЂ“ weighted images in the cerebellar hemispheres hemispheres, pons, and/or amygdala Spitz Tumors В„ В„ В„ В„ В„ В„ Usually acquired acquired, but may be congenital Majority develop in children, adolescents, and young adults, adults but may occur at any age Most often present as solitary asymptomatic, red/pink, hairless, dome-shaped, dome shaped, smooth nodule Some lesions are skin colored, tan, brown, or black Lesions are usually < 1 cm in diameter Predilection for face and extremities Spitz p Tumors - Histology gy В„ В„ В„ В„ В„ В„ В„ Large spindle вЂ“ shaped and/or epithelioid melanocytes Overall monomorphous population of cells Occasional striking pleomorphism in a minority of cells Symmetry Sharp p lateral demarcation Zonation in depth (maturation) Absent or rare mitoses in deep pp parts Spitz p Tumor with Atypical yp Features В„ В„ В„ В„ May be difficult distinguishing from conventional Spitz tumors and melanoma Diameter в‰Ґ 10 mm in diameter Ulceration may be present S Sometimes ti iinvolvement l t off subcutaneous b t fat f t Spitz Tumors with Atypical FeaturesHi t l Histology В„ В„ В„ В„ В„ В„ Poor circumscription Pagetoid melanocytosis over a large front Lack of zonation and maturation Asymmetry Significant mitotic rate, > 2-6/mm2 Deep p marginal g mitoses Assessment of Spitz Tumors for Risk of Metastasis Parameter Score Age (years) 0-10 11-17 0 1 Diameter (mm) 0-10 > 10 0 1 Involvement of subcutaneous fat absent present 0 2 Ulceration absent present 0 2 Mitotic activity (mm2) 0-5 6-8 >9 0 2 5 scoring Low risk вЂ“ 0-2 Hi h risk High i k вЂ“ 5-11 5 11 Management of Spitz Tumors В„ В„ В„ В„ В„ В„ В„ Examination of entire lesion Extensive histopathological and clinical evaluation Placement into risk category Complete excision of non atypical and low-risk Spitz tumors Excision of high risk and biologically indeterminate lesions with approximately 1 cm margins Sentinel lymph node biopsy may be considered for selected lesions > 1 mm in thickness Long g term follow up p The atypical Spitz tumor of uncertain biological potential potential. Ludgate et al al. Cancer 2009; 115 (3): 631-641. В„ В„ В„ В„ В„ Evaluated 67 patients with AST (median age 23.7 years) 57 had SLNB with 27 (47%) being positive Mean age SLNB positive was 17 17.9 9 years Mean age SLNB negative was 28.7 years All positive SLNB were alive and well with median follow up of 43.8 months Nevus Sebaceous В„ В„ В„ В„ В„ В„ Organoid hamartoma of appendageal structures usually evident at birth Seen in 0.3% of newborns Typical appearance is a pink-yellow pink yellow or yellow-orange yellow orange plaque with a velvety surface located on the scalp or face Circumscribed alopecia is common. Develops neoplastic growth вЂ“ most are benign appendageal tumors, such as syringocystadenoma papilliferum, tricholemmoma, trichoblastoma. Malignant tumors occur, including basal cell, squamous cell, apocrine, and sebaceous carcinoma. (Locally invasive, rarely metastasize). ) Management of Nevus Sebaceous В„ В„ В„ Prophylactic excision is controversial. Monitor for surface ulceration or development of a nodule Surgery should be individualized and may be performed in infancy or postponed until later in childhood or adolescence. Nevus Spilus В„ В„ В„ В„ В„ Present at birth with a speckled appearance Histology вЂ“ lentigo with junctional nevi Light brown patch patch, which may contain or acquire dark brown macules T k and Trunk d proximal i l extremities t iti mostt common location 2% d develop l melanoma l Xeroderma Pigmentosum В„ В„ В„ В„ В„ Autosomal recessive One per million newborns in Western countries 1 per 40,000 - 100,000 newborns in Japan M k d iincrease iin iincidence Marked id off cutaneous t malignancies at an early age photosensitivity h t iti it Xeroderma Pigmentosum вЂ“ Genetic Factors В„ В„ В„ В„ В„ Seven genetically different complementation groups (A to G) Defective global genomic nucleotide excision repair of ultraviolet radiation-induced DNA damage g ((such as pyrimidine dimers) Impairment in removal of DNA damage from any place in the genome XP-variant due to mutations that encodes DNA polymerase-n, p y , which results in insertion of erroneous residues during replication Cells are hypersensitive to killing by ultraviolet light Xeroderma Pigmentosum - Clinical Features В„ В„ В„ В„ В„ В„ В„ В„ Skin normal at birth, but sunburns easily Freckling and dryness on light-exposed surfaces are earliest manifestations, presenting by age 2. Actinic keratoses are frequent First cutaneous malignancies develop as early as 3-4 years of age with median onset of 8 years. Malignancies include basal and squamous cell carcinomas and d malignant li t melanoma l Patients up to age 20 have a 1000 times greater incidence of melanoma and non-melanoma skin cancers Approximately 20-30% of patients develop neurologic abnormalities. Ocular abnormalities occur in 40% Xeroderma Pigmentosum - Skin Malignancies В„ В„ В„ В„ Basal cell carcinoma is common in large numbers, often pigmented. Squamous cell cancer is common and may involve the anterior tongue. Melanomas may be multiple and lead to early death from widespread metastases. Di Disease often ft fatal f t l before b f the th age off 10 and d twot thirds die before 20 years of age Xeroderma Pigmentosum Treatment В„ В„ В„ В„ В„ Protect from sunlight by every means possible. Early and adequate excision of all cutaneous malignancies Topical 5-FU Oral retinoids Mi bi l enzyme T Microbial T-4 4 endonuclease d l applied li d regularly as a topical liposome lotion Nevoid Basal Cell Carcinoma Syndrome (Gorlins Syndrome) В„ В„ Autosomal dominant with 50% representing new mutations Caused by mutations in the tumor suppressor gene PTCH NBCCS вЂ“ Clinical Features В„ В„ В„ В„ В„ В„ В„ Numerous basal cell cancers Odontogenic keratocytes of the jaws Palmer and p plantar p pits Calcified dural folds Bifid ribs Macrocephaly medulloblastomas Management of NBCCS В„ В„ В„ В„ В„ В„ Radiation therapy is best avoided Excision Photodynamic therapy Imiquimod Sun avoidance Anti hedge hog therapy is experimental