Patient

64 yo caucasian woman noted to have elevated LFTs on annual P.E. Felt well.

US Liver: 9 cm mass in right lobe of liverBiopsy: Melanoma, high mitotic rate

PMH: Melanoma in situ removed from scalp 14 years earlier

Patient

PMH: Htn, osteoporosisFamHx: Fa had prostate cancer; died of

other causes at age 89; mother died of natural causes at age 84. Two healthy children. No other malignancies in family

SH: Married. Choir director, pianist. Rare EtOH. Remote, brief tobacco use.

Patient

ROS: Mild fatigue, mild dyspnea with exertion, dry cough, 3# wt loss

PE: Normal vital signs. Normal funduscopic exam. No adenopathy. Normal lung exam. Normal abdominal exam. Normal skin exam.

Labs: Alk Phos 160; AST 64; ALT 46

Patient

CT chest: 3 nodules, largest 7 cm in right lung base

CT abdomen: 4 liver mets, largest 9 cm; bilateral adrenal mets, 7 cm

MRI brain: Normal

Melanoma

54,000 new cases in 2003; 7600 deathsIncidence risingLifetime risk 1 in 82 for women; 1 in 58

for menNinth most common cancer; second in

terms of loss of years of potential lifeAt presentation, 84% localized; 12%

regional; 4% distant metastatic disease

Risk Factors for Melanoma

Fair complexion with red/blonde hairLiving in Australia (3X US incidence)>5 nevi >5mm or >50 nevi over 2mmDysplastic nevus syndrome Intense, intermittent sun exposure (ages 10-19)Family history of melanoma- 1/3 have mutation

in p16 (INK4a =CDKN2A cyclin dependent kinase) on chromosome 9p21

UV Light & Melanoma

Intense intermittent exposure does not give time for melanocytes to synthesize melanin to protect them from UV-B irradiation & subsequent DNA mutations

Melanocytes contain antiapoptotic proteins that inhibit cell death after intense UV exposure

Genetic Basis of Hereditary Melanoma

CDKN2A gene on 9p21: p16 protein that prevents phosphorylation of RB protein which regulates transcription factors and cell division

Mutations in this tumor suppressor gene can lead to unregulated cell growth

Associated with increased risk of pancreatic caAssociation of this mutation with atypical moles

is unclearGenetic testing is commercially available

Other proto-oncogene links

Mutation in B-raf protooncogene in 65% of melanomas

This gene product is similar to the tyrosine kinase targeted by Gleevec which has been very successful in treating CML and GIST

Inhibitors of this gene are undergoing testing (BAY 43-9006)

Melanoma Staging

Stage 0: melanoma in situ (95% cure rate)Stage IA: <1 mm, level II-III, no ulceration (88% IB: <1mm, level IV-V or 1-2 mm, no ulcer(79%) IIA: 1-2mm with ulcer; 2-4mm, no ulcer (64%) IIC: >4mm, with ulcer (45%) IIIA: Microscopic node met (55%) IIIB: Micro2 or 3 regional nodes (37%) IIIC: Macroscopic dz in 2 or 3 nodes (20%) IV: Distant metastases (<5%)

Melanoma

Breslow: thickness of the melanoma, most useful prognostic factor

Clark’s: level of penetration- (I)confined to epidermis, (II) into papillary dermis, (IV) into reticular dermis, (IV) into subcutaneous fat

Melanoma

Prognostic factors for localized disease: Breslow’s thickness, ulceration, Clark’s level (only for <1mm), primary tumor site, gender

Ulceration: absence of an intact epidermis overlying the melanoma (microscopic)

Likelihood of regional nodal involvement rises with increasing tumor thickness

Treatment of Melanoma

In situ: Excision< 1mm deep, 1 cm excision margin1-2 mm deep, 1 to 2 cm margin>2 mm deep, 2 cm marginConsider sentinel node evaluation if >1mm

deep with Clark level IV or ulcerated; node dissection only if positive

Adjuvant Therapy in Melanoma

Most pts with in situ or early stage disease are cured by excision alone

For node negative patients with <4mm without ulceration or <1mm with ulceration, no proven benefit

Clinical trial or high dose interferon adjuvant therapy appropriate for >4mm without ulceration & >1mm with ulceration

Improved relapse free survival but no improvement in overall survival in these node negative patients

Adjuvant Therapy in Melanoma

For node positive patients whose disease has been resected: Adjuvant high dose interferon prolongs survival (37% 5yr RFS vs 26% with no Rx)

20 million U/m2 IV 5 d/wk x 4 wks then 10 million U/m2 SQ 3 d/wk x 48 wks

Follow up after excision

Stage 0: skin exams for life IA: exam q3 to 12 mos IB-III: history, physical exam (attn to regional

node area), skin exam q3-6 mos x 3 yrs, q4-12 mos x 2 years, then annually. CXR, LDH, CBC “amy be considered”. CTs and PET scans not recommended.

Lifetime risk for developing second melanoma: 5%

Treatment of Metastatic Disease

Solitary site: resect (often wait 8 to 12 wks to be sure there are not many subclinical sites)

Multiple sites: clinical trial vs systemic therapy (Dacarbazine or Temazolamide or IL-2 or combination chemoimmunotherapy [Dacarbazine + Vinblastine+ cisPlatin + IL2 + Interferon)

Treatment of Metastatic Disease

BiochemotherapyCisplatinum 20mg/m2 daily x 4dVinblastine 1.6 mg/m2 daily x 4dDTIC 800 mg/m2 day 1 onlyInterleukin-2 9 million U/m2/d x 4d CIVInterferon alpha: 5 million U/m2 SQ qd x 5Repeat q3 wks

Treatment of Metastatic Disease

Biochemotherapy21% Complete response43% partial responseHalf of the patients with CR remained in

remission >5 years.This complete response rate is ~3X greater

than with single agent chemo

Other drugs

Thalidomide: active in myeloma, gliomas, renal cell cancer

Antiangiogenesis and anti-inflammatory properties; inhibits TNF

When given with temozolomide, 25% respond

Vaccine therapy in melanoma

Rare spontaneous regression of metastatic melanoma suggests host immunity plays important role in control

CancerVax: whole cell vaccine from 3 melanoma cell lines helpful in initial trial

Melacine: immunizes with 3 peptides present in/on melanoma cells; studies ongoing

No vaccine has thus far improved survival in adjuvant or metastatic setting

Patient Follow Up

3 cycles of chemoimmunotherapyLung nodule decreased from 7 to 5 cmNo change in liver masses but LFTs normalizedAdrenal metastases decreased from 7 to 5 cmMesenteric adenopathy improvedThalidomide + Temozolamide planned for 8

weeks

Lessons

Even in situ lesions can spreadDon’t allow kids to get sunburnsLook at your patients skin (everywhere)

during annual examUnderstanding the molecular biology may

lead to better treatments