MELANOMA AND INCIDENTALOMA
| MODERN MELANOMA MANAGEMENT ----- David J. Cole, MD, McKay Rose Professor of Surgery and Head, Division
of General Surgery, Medical University of South Carolina, Charleston
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| Epidemiology: ≈47,000new cases and almost 8000 melanoma-related deaths in United States in 2005; high cost
and economic impact; incidence increasing ≈10% per year (faster than that of any other tumor); 5-yr case fatality
rate decreasing (89% in 1925 vs 20% in 1995)
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| Risk factors: genetic—history of dysplastic nevus; dysplastic nevus syndrome; family history of melanoma;
environmental—history of severe sunburn or multiple sunburns (especially at young age); decreasing latitude or
increasing altitude of residence (intense exposure to sun); increased exposure to sun (work-related or recreational);
race—lower incidence among blacks
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| Anatomic classification: superficial spreading—most common; typically has irregular border, pigmentation, and
surface; usually arises from preexisting nevus; commonly seen on trunk and extremities; grows radially and vertically
and has central areas of regression; nodular—represents 15% to 30% of cutaneous melanomas; exhibits most
aggressive growth (vertical growth predominates); typically arises de novo; deeply pigmented; lentigo maligna—
progresses most slowly (radial growth predominant); typically occurs on areas exposed to sun; acral-lentiginous—
relatively rare; typically occurs on palms, soles, and subungual areas (work up subungual hematomas that occur
without explanation)
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| ABCs of diagnosis: asymmetry; border irregularity; color variation; diameter \>6 mm; using these criteria, experienced
observers can identify 90% of clinically significant melanomas; early diagnosis important; thin lesions associated
with better prognosis; biopsy—excisional and incisional techniques; microstaging requires full-thickness
biopsy into subcutaneous tissue; shave or curette biopsies contraindicated (prevent accurate measurement of thickness);
full-thickness punch or excisional biopsy appropriate for lesions ≤2 cm; punch biopsies of larger lesions may
not accurately reflect thickness
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| Microstaging systems: Clark—levels 1 through 5 reflect extent of dermal invasion (eg, epidermal, dermal, subdermal);
Breslow—measures absolute thickness; more reliable than Clark; note—ideally, Clark and Breslow
stages correlate (ie, thin lesions have low Clark’s level); thin lesions with high Clark’s level treated as intermediate
thickness; prognostic factors—tumor thickness; level of invasion; ulceration; anatomic location (may have impact);
age, sex, and race also should be considered
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| Local excision: former recommendation of 5-cm margins based on anecdotal evidence; World Health Organization
(WHO) trial found 1-cm margins sufficient for lesions <1 mm thick (no recurrences over ≈5 yr); multi-institutional
trial found no statistically significant differences in rates of local recurrence between 2-cm and 4-cm margins; current
recommendations for excisional margins—0.5 to 1.0 cm for in situ (preinvasive) lesions; 1 cm for lesions <1
mm thick; 2 cm for lesions of intermediate thickness; some controversy about larger lesions (risk for distant metastasis
may exceed risk for local recurrence); special sites—for lesions on head, neck, or ear, Mohs’ surgery best
option to achieve adequate margins with minimal disfigurement; excision of lesions on breast based on standard
factors of prognosis (ie, site does not affect prognosis)
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| Lymph node dissection: rationale—provides information for staging and treatment decisions; may aid in regional
control and cure (no randomized controlled trials); sentinel lymph node biopsy provides important prognostic
information; therapeutic dissection—15% to 20% of patients with clinically positive nodes who undergo
dissection have 10-yr disease-free survival; lymphadenectomy therefore considered in otherwise healthy patients,
but clinician should discuss risks with patient; 50% to 60% of patients with microscopically positive nodes
have 10-yr disease-free survival (strong indication for therapeutic dissection); elective dissection—prospective
multicenter randomized controlled trial found no survival benefit
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 | Sentinel lymph node: first lymph node encountered in lymphatic basin that receives lymph from region of primary
lesion; biopsy—generally performed in patients with lesions of intermediate thickness (\>1 mm); associated with
false-negative rate of 5% to 6% and negative predictive value of 98%; also recommended for patients with thin
lesions with negative modifier (eg, ulceration) and when discrepancy occurs between Clark and Breslow staging
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| Systemic therapy: interferon—significantly prolongs disease-free and overall survival; commonly used for
younger patients with positive sentinel nodes; associated with significant adverse effects and decreased quality of
life (duration of treatment typically 1 yr); interleukin 2 (IL-2)—response rate relatively low, but 82% of responsive
patients have disease-free survival of 39 to 148 mo; dacarbazine (DTIC; imidazole carboxamide)—common chemotherapeutic
agent associated with response rates of 15% to 20%; soft-tissue disease more likely to respond; effect
lasts 3 to 6 mo; <5% of patients have complete remission
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| Immunotherapy (experimental): vaccine against melanoma-associated antigen elicits immunologic response;
treatment may be combined with IL-2; research ongoing; excellent response in some patients; spontaneous
regression—immunologic responsiveness of melanomas leaves open possibility of partial or complete regression
without therapy
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| MANAGEMENT OF ADRENAL INCIDENTALOMA ----- David R. Farley, MD, Professor of Surgery, Mayo Clinic
College of Medicine, Rochester, MN
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| Adrenal tumors: functional tumors may secrete aldosterone, cortisol, androgens or estrogens, or epinephrine and
norepinephrine; assessment of functionality important before attempting resection; anatomy—right adrenal
gland located directly posterior to inferior vena cava; left adrenal gland located behind pancreas, directly posterior
to splenic vessels
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| Imaging: computed tomography (CT) measures density in Hounsfield units (H); water (0 H) important reference
point; contrast may increase density; benign cysts generally have density near 0 H; benign myelolipomas less
dense than water (eg, -50 H); cortical adenomas (functional or nonfunctional), 10 to 20 H; increasing density
(\>30 H) suggestive of malignancy; benign tumors—typically small (1-3 cm), homogeneous, with friendly borders;
malignancies—typically larger (\>10 cm on average), heterogeneous, with irregular borders
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| Differential diagnosis: aldosteronoma; neuroblastoma; pheochromocytoma; metastasis; cortical adenoma; adrenocortical
carcinoma; incidentaloma
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| Presentation: 2% to 4% of hospitalized patients have adrenal masses (incidence increases with age); adrenal masses
discovered incidentally by various imaging modalities (eg, ultrasonography, angiography, magnetic resonance imaging),
depending on initial presentation (eg, recurrent urinary tract infections, hypertension); history and physical
examination—look for signs and symptoms suggestive of functionality (eg, headaches, hypertension, change in
weight, malaise, diabetes, hirsutism); ask about family history (eg, conditions suggestive of multiple endocrine neoplasia);
laboratory studies—include cortisol level, catecholamines, and potassium level
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| Diagnosis: Conn’s syndrome—primary aldosteronism results in hypertension, hypokalemia, and slight hypernatremia;
serum levels of potassium and aldosterone important for diagnosis; renin level in urine also useful; small mass
visible with abdominal CT; laparoscopic adrenalectomy may cure; pheochromocytoma—95% of patients have hypertension
(episodic or chronic); diaphoresis and flushing may occur; family history important; urinary levels of
fractionated catecholamines diagnostic; restriction of expanding adrenal medulla by cortex results in round or egg-
shaped mass visible on CT; metastasis—prostate, breast, and lung cancers commonly metastasize to adrenal
glands; if history of cancer, may need to perform imaging to rule out recurrence of primary; neuroblastoma—
relatively common in young children, but rare in adults; large painless abdominal mass; prognosis partly depends
on age; CT and catecholamine levels important for diagnosis and for directing intervention; primary malignancy—
adrenocortical carcinomas typically produce high dehydroepiandrosterone (DHEA), but low level does not rule
out; CT shows large mass; benign adrenocortical adenoma—hypercortisolism may result in hypertension, obesity,
and diabetes; removal of mass may correct comorbidities; uncommon; incidentaloma—diagnosis of
exclusion; incidental radiologic finding; asymptomatic nonfunctional adrenal mass
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| Management of incidentalomas: experience at Mayo Clinic included \>61,000CT scans (patients with mass <1
cm or history of cancer excluded); 342 adrenal masses ≥1 cm found (more common in women; average age, 62 yr);
average size of adrenal mass, 2.5 cm (range 1-11 cm); 55 patients underwent surgery for concerning lesions; 5 had
pheochromocytomas, 4 had adrenocortical carcinomas, 2 had cortisol-secreting adenomas, and 1 had metastasis of
unidentified primary cancer; 287 patients diagnosed with incidentaloma; 251 of these followed for 1 yr (no changes
seen); conclusion—risk for malignancy increases with size of incidentaloma; recommendations—work up all adrenal
nodules \>1 cm (looking for functionality); resect all incidentalomas \>3 to 4 cm; reassess smaller incidentalomas
at 3 to 6 mo, looking for changes; long-term follow-up—87 patients followed for \>4 yr; CT repeated to assess
changes; 4 patients underwent surgery for growth (≥1 cm) of incidentaloma; no cancers or functional tumors found
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| Resection: laparoscopy gold standard, but open surgery recommended if malignancy suspected; surgical intervention
appropriate for functional tumors and those \>3 cm (other factors, eg, “cancer phobia,” considered);
approaches—anterior approaches more common than posterior; speaker prefers open approach via subcostal incision
for adrenocortical, renal cell, or hepatocellular cancers, for large tumors (\>8 cm if confirmed benign; \>5-6 cm
if possibility of malignancy), in patients with coagulopathy, and in those undergoing reoperation; laparoscopic
technique (anterior or posterior approach) good for smaller benign tumors
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| NOVEL THERAPEUTICS AND DIAGNOSTICS IN MELANOMA ----- Richard Essner, MD, Assistant Director,
Surgical Oncology, John Wayne Cancer Institute at Saint Johns Health Center, Santa Monica, CA
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| Treating patients with late-stage disease: improvements in surgical techniques and intensive care unit (ICU)
practices have led to increased survival (median of 22 mo for patients undergoing surgery vs 9 mo for patients undergoing
nonsurgical treatment); staging—accuracy of staging improved by newer imaging techniques; whole-
body positron emission tomography (PET) provides 3-D imaging and identifies sites of fluorodeoxyglucose (FDG)
uptake not seen with conventional imaging
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| Cytoreductive surgery: shown to reduce tumor volume (evidenced by semiquantitative reverse transcriptase
polymerase chain reaction [RTPCR]); tumor volume—reduction through resection and other methods important
for immunologic management
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| Disease progression: review of \>4000 patients managed by variety of methods; 1574 patients underwent surgical
treatment for stage IV melanoma; 26% of patients with early-stage disease (and 14% of patients with lesions <1
mm thick) developed distant metastases; resection—most patients had single metastasis (rarely, \>4 sites resected);
most common sites included lung, subcutaneous tissue, brain, gastrointestinal (GI) tract, liver, and kidneys;
survival—patients with metastases of GI tract (primarily, small bowel), lungs, subcutaneous tissue, or
distant lymph nodes had median survival \>30 mo; surgery often contraindicated in patients with metastases inadrenal
gland, brain, or liver (multiple metastases common); complete resection required to achieve therapeutic
benefit
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| Factors predictive of positive outcome: early stage of disease; absence of nodal involvement; disease-free interval
(time between staging and metastasis) ≥36 mo; “low-risk” sites of metastasis (lung, GI tract, subcutaneous tissue)
or number of metastases
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| Other factors that may influence prognosis: tumor doubling time ≥60 days; ease of removal; serum lactate dehydrogenase
(LDH; high levels associated with poor outcome); S100- β proteins (higher levels possible negative predictor);
tumor-associated 90-kd glycoprotein antigen (TA90) immune complex (not yet verified); IL-13 and
platelet-derived growth factor (PDGF), but cytokines not specific to malignancies and levels vary
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| Reverse transcriptase PCR: sensitive method for identifying small volume of tumor cells (by amplifying melanoma-related
markers); attempts to correlate with serum levels of tyrosinase have had inconsistent results
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| Immunotherapies: IL-2—T-cell activating protein, given as bolus or continuous infusion, boosts immune response
to melanoma; response rate, 10% to 15%; lymphokine-activated killer (LAK) cells—harvested autologous
killer cells activated with IL-2; tumor-infiltrating lymphocytes (TILs)—T cells harvested from tumor, combined
with IL-2 or interferon; response rates—relatively low for patients with melanoma (although Food and Drug Administration
[FDA]-approved for advanced melanoma); high doses of IL-2 may cause capillary leak syndrome, necessitating
ICU care
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| Chemotherapy: DTIC has long history of use; combination therapy with IL-2 or interferon (known as biochemotherapy)
not shown to improve benefit
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Suggested Reading
Bovio S et al: Prevalence of adrenal incidentaloma in a contemporary computerized tomography series. J Endocrinol
Invest 29:298, 2006; Brunaud L et al: Observation or laparoscopic adrenalectomy for adrenal incidentaloma?
A surgical decision analysis. Med Sci Monit 12:CR355, 2006; Castillo OA et al: Laparoscopic
adrenalectomy for suspected metastasis of adrenal glands: our experience. Urology 69:637, 2007; Cohen PR et al:
The purse-string suture revisited: a useful technique for the closure of cutaneous surgical wounds. Int J Dermatol
46:341, 2007; Edwards-Dawn M et al: Mohs surgery for the treatment of melanoma in situ: a review. Dermatol
Surg 33:395, 2007; Kebebew E et al: Extent of disease at presentation and outcome for adrenocortical carcinoma:
have we made progress? World J Surg 30:872, 2006; Libe R et al: Adrenocortical cancer: pathophysiology and
clinical management. Endocr Relat Cancer 14:13, 2007; MacNeil S: Progress and opportunities for tissue-engineered
skin. Nature 445:874; Mathieu D et al: Gamma knife radiosurgery in the management of malignant melanoma
brain metastases. Neurosurgery 60:471, 2007; Meyer A, Behrend M: Indications and results of surgery for
incidentally found adrenal tumors. Urol Int 77:173, 2006; Mocellin S et al: Sentinel lymph node molecular ultrastaging
in patients with melanoma: a systematic review and meta-analysis of prognosis. J Clin Oncol 25:1588, 2007;
Samlowski WE et al: Multimodality treatment of melanoma brain metastases incorporating sterotactic radiosurgery
(SRS). Cancer 109:1855, 2007; Steels E et al: Long-term benefit of combined radiofrequency ablation and
surgery in a patient with AJCC stage IV metastatic melanoma. Clin Exp Dermatol 32:100, 2007; Taylor RC et al:
Tumor-infiltrating lymphocytes predict sentinel lymph node positivity in patients with cutaneous melanoma. J Clin
Oncol 25:869, 2007; Toniato A et al: Laparoscopic adrenalectomy for pheochromocytoma: is it really more difficult?
A surgical decision analysis. Surg Endosc [epub ahead of print], 2007.
Educational Objectives
| The goal of this program is to improve the management of melanoma and adrenal incidentaloma. After hearing and
assimilating this program, the clinician will be better able to:
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| 1. Describe anatomic classification and microstaging systems for melanoma.
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| 2. Determine appropriate excisional margins for melanoma lesions.
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| 3. Identify patients for whom sentinel lymph node biopsy or therapeutic lymph node resection is appropriate.
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| 4. Identify patients likely to benefit from surgical management of adrenal incidentalomas and discuss the recommendations
for open and laparoscopic approaches.
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| 5. Compare the surgical and nonsurgical options for treating patients with melanoma.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose
relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any
identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary
business or commercial interest. For this program, the following has been disclosed: Dr. Essner is on the advisory
board of Schering-Plough.
Acknowledgements
Drs. Cole and Farley were recorded at 35th Annual Postgraduate Course in Surgery, sponsored by the Medical University
of South Carolina, Department of Surgery, and held April 27-29, 2006, in Charleston, SC; Dr. Essner was recorded
at Current Concepts in General Surgery and Trauma Update, sponsored by the University of New Mexico
Health Sciences Center, Department of Surgery and Office of Continuing Medical Education, and held September 6-
8, 2006, in Albuquerque, NM. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation
in the production of this program.
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