Board Review The Dermatologist’s Board Review The content of these questions and answers are taken from the Galderma Pre-Board Slide Seminar. The course was most recently held June 24-26, 2011, at the Crowne Plaza Chicago O’Hare, Rosemont, IL.

Joseph B. Bikowski, JR, MD, FAAD, and Steven R. Feldman, MD, PhD

1. The earliest visible diagnostic findings in tuberous sclerosis are? a) Hypomelanotic macules. b) Lisch nodules. c) Cardiac rhabdomyomas. d) Angiofibromas. e) Lymphangiomyomatosis.

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2. Which of the following is true regarding the genetics of this condition? a) It is transmitted in an autosomal recessive manner. b) The majority of cases are transmitted via affected family members. c) TSC1 and TSC2 mutations occur with equal frequency in familial cases. d) Sporadic cases of tuberous sclerosis are more often caused by TSCI mutations e) Diagnosis can be made with one major diagnostic feature of the disease.

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3. Which of the following is true regarding the pregnant patient with this disease? a) Excision should be delayed due to the risk of lidocaine to the fetus. b) Epinephrine is Category B in pregnancy and can be safely used. c) Melanoma that metastasizes to the placenta affects the fetus 50% of the time. d) Melanoma diagnosed during pregnancy portends a worse prognosis. e) Women with 5 or more prior pregnancies may have better melanoma survival rates. 3

August 2011 | Skin & Aging | www.skinandaging.com 15 Board Review Answers

1 and 2. Tuberous Sclerosis Complex Confetti-like lesions are symmetrical and 1 mm to 3 mm in size. 1. The earliest visible diagnostic findings in tuberous sclerosis are? Facial angiofibromas are red/pink and located centrofacially. They a) Hypomelanotic macules. can be treated with cryosurgery, curettage, dermabrasion, chemical

2. Which of the following is true regarding the genetics of this condition? peels, excision or with pulsed dye laser and CO2 laser. Recurrence c) TSC1 and TSC2 mutations occur with equal frequency in familial cases. rates are high. Shagreen patches are common in lumbosacral areas and are connective tissue hamartomas with vessels, adipose, colla- Genetics: Transmitted autosomal dominant, but 2/3 of cases are gen, elastic tissue and smooth muscle. Periungual fibromas become sporadic. Germline mutations may also occur, where healthy par- evident around puberty to mid-twenties, are more common on ents have two or more affected offspring. TSC1 (chromosome 9, toes than fingers and must not be associated with trauma, as trau- encoding hamartin) and TSC2 (chromosome 16, encoding tuberin) ma can induce periungual fibromas in normal, non-TSC patients. are tumor-suppressor genes that cause TSC. They inhibit mTOR, Systemic Manifestations: Neurological sequellae from tubers, a cell proliferation regulator. 50% of cases are due to mutations of nodules and astrocytomas often cause intractable seizures. 90% to each gene in familial cases, but sporadic cases are four times more 96% of TSC patients suffer from seizures — 85% of them have a first commonly due to TSC2 mutations. TSC2 causes more severe dis- episode in first 2 years of life. Neurosurgical intervention may be- ease manifested by increased intellectual impairment, cortical tubers, come life-saving. Angiomyolipoma, the most common renal mani- retinal hamartomas and advanced facial angiofibromas. festation, increase in frequency with age and are treated based on Diagnosis: For diagnosis, two major features or one major plus two size/symptoms. Surgical removal and renal artery emoblization have minor features must be present. Major features include: facial angiofi- been used. Pulmonary involvement with lymphangiomyomoatosis, bromas, periungual fibroma, three or more hypomelanotic macules, which is rare (1% to 6% of patients), is the most common pulmo- shagreen patch, retinal nodular hamartomas, cortical tuber, subependy- nary manifestation and presents during third and fifth decades. It is mal nodule, subependymal giant cell astrocytoma, cardiac rhadomyoma, progressive and has a poor prognosis. Cardiovascular manifestations lymphangiomyomatosis and renal angiomyolipoma. Minor features are often the earliest diagnostic finding. Rhabdomyoma is the most include: dental enamel pits, rectal hamartomatous polyps, bone cysts, common tumor in infants/children; 80% to 95% of patients with white matter radial migration lines, gingival fibromas, nonrenal rhabdomyoma have TSC. Ocular retinal hamartomas usually remain hamartomas, retinal achromic patch, confetti skin lesions and mul- clinically stable and asymptomatic. tiple renal cysts. Diagnosis is often challenging earlier than age 2. Treatment: Surgical correction for specific lesions. In addition, the Dermatologic Manifestations: Hypomelanotic macules are often discovery of the involvement of the mTOR pathway has led to the the earliest visible sign of disease. Scalp involvement may cause use of rapamycin (sirolimus), which normalizes dysregulation in the poliosis. Melanocyte numbers are normal, but dopa reaction is re- mTOR pathway, induces regression of brain astrocytomas and ap- duced. One lesion may be present in 5% of normal population. pears to be promising for treating lymphangiomyomatosis.

3. Hormones, Nevi and Melanoma noma occurring within 5 years of pregnancy did not affect disease-free 3. Which of the following is true regarding the pregnant patient with this disease (melanoma)? interval or survival compared to patients diagnosed with melanoma e) Women with 5 or more prior pregnancies may have better melanoma survival rates. who did not become pregnant, the same result seen in a later study of 85 women who became pregnant. Counseling should be based on Nevi in Pregnancy: Changes in nevi during pregnancy are com- known prognostic factors such as tumor depth, ulceration, etc. In addi- mon. Some studies found many changing lesions in pregnant wom- tion, women with 5 or more pregnancies prior to diagnosis had better en to be dermatofibromas or skin tags. Of biopsied nevi in pregnant 8-year survival rates than those without prior pregnancy. No adverse women, one study showed no atypia in lesions biopsied, another effect on survival has been shown after pregnancy. showed mild increased melanocytic atypia thought to be minor/ Histology of Melanoma in Pregnancy: Some have shown that tu- insufficient. A prospective study showed 6% of nevi changing dur- mor thickness is increased in melanomas of pregnant patients, though ing pregnancy (most increasing in diameter, but a few decreasing). A it is unclear whether this is simply the result of a delay in diagnosis. study of pregnant patients with dysplastic nevus syndrome showed Treatment of Melanoma in Pregnant Patients: Prompt biopsy/exci- 3.9 times more changes during pregnancy compared to a non- sion should be performed and not delayed due to pregnancy. The use pregnant state. In general, nevi do not change during pregnancy; of lidocaine is generally accepted as safe during pregnancy (Category therefore changing melanocytic lesions should be biopsied. B); however, the use of epinephrine is less clear (Category C) and has Melanoma in Pregnancy and Prognosis: A diagnosis of localized the potential to decrease uterine blood flow. Epinephrine concentra- melanoma during pregnancy does not portend a worse prognosis. tion should be decreased, if possible. Sentinel node biopsy is controver- One study at Duke showed that pregnancy did significantly decrease sial since it requires the use of radioactive colloid or isosulfan blue dye. disease-free interval. Six case control studies have found no effect on Some centers use the radioactive colloid alone in pregnant women (the survival in pregnant women compared to non-pregnant women. radiation dose is thought to be far below the threshold for teratogenic- Twenty cases of melanoma that metastasized to the placenta have ity) because the risk of anaphylaxis to the blue dye is much greater. been reported and, though rare, melanoma is the most common Some centers avoid sentinel lymph node biopsy in pregnant patients cancer to metastasize to the placenta during pregnancy. From these, altogether. Evaluation for distant metastases is also controversial. Some approximately 25% of fetuses were affected. Fetal skin and liver are recommend ultrasonography of the liver and abdomen over CT scans most common sites of involvement. because of the radiation dose. MRI also is not favored during the first Melanoma Before and After Pregnancy: A review of 43 cases of mela- trimester due to heating of tissues. n

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