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cutaneous melanoma

Classification: - melanoma in situ - acral lentiginous melanoma - balloon cell melanoma - desmoplastic melanoma - epithelioid cell melanoma - lentigo maligna melanoma - mucous membrane melanoma - nodular melanoma - superficial spreading melanoma - blue nevus, malignant - malignant melanoma in giant pigmented nevus * classification by histology Etiology: 1) 1/3 of melanomas arise from a pre-existing nevus 2) precursors of cutaneous melanoma - congenital melanocytic nevus - dysplastic (Clark's) melanocytic nevus - lentigo maligna 3) risk factors: - > 50 nevi >= 2 mm in diameter - family history of malignant melanoma - blond or red hair - freckles on upper back - 3 or more blistering sunburns before age 20 - only early sun exposure associated with increased risk [32] - 3 or more years of outdoor summer job - actinic keratosis - history of endometriosis (RR = 1.6) [11] - history of uterine fibromas (RR = 1.3) [11] - alcohol consumption - especially white wine & hard liquor [26] - airline pilots & cabin crew members wirh 2-fold increased risk & 42% increased mortality from melanoma [33] - high citrus fruit consumption [38] - RR=1.36 for orange juice & grapefruit only [38]* * association possibly due to psoralen in citrus fruits; psoralen has photocarcinogenic properties in animals [38] Epidemiology: 1) common - superficial spreading melanoma - nodular melanoma - lentigo maligna melanoma 2) less common - acral lentiginous melanoma - mucous membrane melanoma - melanoma arising from congenital melanocytic nevus - melanoma arising from dysplastic melanocytic nevus 3) rare - desmoplastic melanoma 4) incidence of melanoma 2.4 fold in US from 1986-2001, 18/100,000, parallels increase in skin biopsies [9] 5) 5% of all skin cancers 6) 3-6% of patients with melanoma will develop a 2nd primary melanoma 7) in USA, lifetime probability of developing melanoma - 2.8% men - incidence has increased 20-fold since 1950 in men > 70 years of age - associated mortality has increased 3-fold [29] - 1.8% women [18] 8) incidence of invasive melanoma increasing in U.S. - 22.2 (2009) vs 23.6 (2016) per 100,000 population - melanoma mortality 2.8 (2009) vs 3.1 (2016) per 100,000 9) In Australia which has the highest rate of skin cancer in the world, melanoma was 4th most common cause of cancer in men & 3rd most common cause of cancer in women in 2001 [8] 10) bulky melanomas occur most often on sun-damaged head & neck of older men [29] 11) ulcerated melanomas more common in older men & associated with increased mortality [31] Pathology: 1) excisional skin biopsy is diagnostic test of choice [3] 2) essential components of a melanoma pathology report are: a) thickness - depth of lesion (Breslow depth) is most important prognostic factor [3] - depth of deep margin in cutaneous melanoma (Loinc) - lymph node involvement uncommon if depth < 1 mm [3] b) ulceration c) dermal mitotic rate (mitoses/mm2) - mitotic count > 1.0/mm2 upstages to Stage Ib d) peripheral & deep margins e) Clark level f) microsatellitosis - upstages to Stage IIIb (even if thin) 3) metastases a) lymph nodes (58%) b) liver (63%) c) lung (60%) d) bone (48%) e) brain (48%) f) skin (44%) g) adrenal (48%) h) kidney (27%) Genetics: 1) familial melanoma has been mapped to chromosome 9p 2) point mutations in BRAF gene in 66% if patients [6] a) these are somatic (acquired mutations) b) V599E found in 80% of BRAF point mutations c) V600E: BRAF & MEK inhibitors approved to treat BRAF V600E 3) expression of BAMBI, GPNMB, LLGL1 may be diminished or absent 4) other implicated genes KAAG1, JARID1B, MIA3, SH3PXD2A, SPANXC, SPANXD, SPANXE, CSAG1, CSAG2, FMR1NB, BAGE1, BAGE2, BAGE3, BAGE4, BAGE5, RASEF, PHF19, ARMS, CDK4, GINS4, NOX5, c-MYC, TP73, C9orf14, CDKN2A, VDR, XRCC3, MCAM Clinical manifestations: - classic clinical features (ABCDE) - A: Asymmetry - B: irregular Border - C: irregular Color - D: expanding Diameter (> 6 mm) - E: Evolution (lateral expansion or vertical growth) - pigmented lesions of different form depending upon type, i.e. superficial-spreading melanoma, nodular melanoma - amelanoytic melanomas occur & resemble basal cell carcinoma - in dark-skinned patients, melanomas may occur in non sun exposed areas, including palms, soles, mucous membranes - the back is the most common site in men, the legs in women [3] * images [47,48] Laboratory: 1) excisional skin biopsy is diagnostic test of choice [3] a) complete removal with 1-3 mm margins [17]; 1-2 mm margins [69] - 1 cm margins unnecessary for initial biopsy [68] - initial biopsy of entire lesion (no margins specified) [68] b) partial sampling is acceptable for facial lesions, large pigmented lesions [17] c) sentinal lymph node biopsy for lesions > 1 mm thick 2) do not shave, freeze, laser or otherwise destroy a pigmented lesion suspicious for melanoma - lentigo maligna not suspicious for melanoma is exception [3] 3) routine lab tests not helpful [3] 4) BRAF V600E mutation all patients with metastatic melanoma [3,39,44] - 50-70% positive [3] 5) Loincs for pathology specimens - surgical margin tumor involvement in cutaneous melanoma - depth of deep margin in cutaneous melanoma - growth phase in cutaneous melanoma - tumor invasion in cutaneous melanoma - location within lymph node in cutaneous melanoma 6) see ARUP consult [20] Radiology: - imaging studies (CT, MRI, PET scan) after surgical resection have low yield & fairly high rate of false-positives [3] Differential diagnosis: 1) melanocytic nevus a) blue nevus b) compound nevus c) junctional nevus 2) hemangioma 3) lentigo a) juvenile lentigo b) solar lentigo 4) basal cell carcinoma (pigmented or not) 5) pigmented dermatofibroma 6) seborrheic keratosis 7) subungual hematoma 8) tattoo (medical or medicinal) 9) malignant melanoma (distinguishing features)* a) asymmetry b) border irregularity c) color variegation d) diameter > 6 mm e) enlargement & elevation of lesion * pruritus in a pigmented lesion may suggest melanoma Staging: AJCC/TNM classification/staging [7] primary tumor [T] TX: primary tumor cannot be assessed. T0: no evidence of primary tumor. Tis: melanoma in situ T1: melanoma ~1 mm thickness with or without ulceration. T1a: melanoma ~1 mm thickness, level II or III, no ulceration. T1b: melanoma ~1 mm thickness, level IV or V or with ulceration. T2: melanoma 1.01 - 2 mm thickness with or without ulceration. T2a: melanoma 1.01 - 2 mm thickness, no ulceration. T2b: melanoma 1.01 - 2 mm thickness, with ulceration. T3: melanoma 2.01 - 4 mm thickness with or without ulceration. T3a: melanoma 2.01 - 4 mm thickness, no ulceration. T3b: melanoma 2.01 - 4 mm thickness, with ulceration. T4: melanoma > 4mm in thickness with or without ulceration. T4a: melanoma > 4mm in thickness, no ulceration. T4b: melanoma > 4mm in thickness with ulceration. regional lymph nodes [N] NX: regional lymph nodes cannot be assessed. N0: no regional lymph node metastases. N1: metastasis in one lymph node. N1a: clinically occult (microscopic) metastasis. N1b: clinically apparent (macroscopic) metastasis. N2: metastases in 2 - 3 regional lymph nodes or intralymphatic regional metastasis without nodal metastasis. N2a: clinically occult (microscopic) metastasis. N2b: clinically apparent (macroscopic) metastasis. N2c: satellite or in-transit metastasis without nodal metastasis. N3: metastasis in 4 or more regional nodes or matted metastatic nodes or in-transit metastasis or satellite(s) with metastasis in regional node(s). distant metastasis [M] MX: distant metastasis cannot be assessed. M0: no distant metastasis. M1: distant metastasis. M1a: metastasis to skin, subcutaneous tissues or distant lymph nodes. M1b: metastasis to lung. M1c: metastasis to all other visceral sites or distant metastasis at any site associated with elevated serum LDH clinical & pathologic stage grouping 80% of newly diagnosed cutaneous melanomas are stage 1 [14] stage T N M comment stage 0: Tis N0 M0 (clinical & pathologic) stage IA: T1a N0 M0 (clinical & pathologic) stage IB: T1b N0 M0 (clinical & pathologic) - T2a N0 M0 (clinical & pathologic) stage IIA: T2b N0 M0 (clinical & pathologic) - T3a N0 M0 (clinical & pathologic) stage IIB: T3b N0 M0 (clinical & pathologic) - T4a N0 M0 (clinical & pathologic) stage IIC: T4b N0 M0 (clinical & pathologic) stage III: any T any N M0 (clinical) stage IIIA: T1 - 4a N1a M0 (pathologic) - T1 - 4a N2a M0 (pathologic) stage IIIB: T1 - 4b N1a M0 (pathologic) - T1 - 4b N2a M0 (pathologic) - T1 - 4a N1b M0 (pathologic) - T1 - 4a N2b M0 (pathologic) - T1 - 4a/b N2c M0 (pathologic) stage IIIC: T1 - 4b N1b M0 (pathologic) - T1 - 4b N2b M0 (pathologic) - any T N3 M0 (pathologic) stage IV: any T any N M0 (clinical & pathologic) Complications: - metastases (see Pathology: above) Management: 1) excision (surgery) is the primary treatment - biopsy & excision by dermatologists associated with the lowest likelihood of delay [37] - Mohs micrographic surgery for T1a-T2a may be an option [61] 2) depth of lesion is most important prognostic factor (< 0.8 mm low risk) 3) other independent predictors of survival include: a) women have better prognosis than men b) age > 60 years is associated with poorer prognosis c) truncal lesions are associated with poor prognosis than lesions on extremities 4) 95% can be surgically removed when < 0.76 mm in depth 5) lesions > 4 mm are associated with a 40% surgical cure rate 6) surgical margins determined by lesion depth/thickness (lesion thickness: surgical margin) - in situ: 0.5-1 cm - < 1 mm: 1 cm - 1.0-2.0 mm: 1-2 cm - > 2.0 mm: 2 cm - surgical margins have become narrower over time [9,17] - maximum margin at 2 cm [17] 7) consider sentinal lymph node biopsy for melanomas > 0.8-1 mm thick [3,17,30,43] - indicted for melanomas > 1 mm thick [3] 8) spread to regional lymph nodes (stage III) a) lymph node dissection [3] b) decreases 5 year survival to < 30% c) therapeutic lymph node dissection indicated d) interferon alpha-2b improves survival 9) interferon therapy a) melanoma > 4 mm thick or b) lymph node positive melanoma c) pegylated interferon alfa-2b maginally effective for stage 3 melanoma [40] 10) talimogene laherparepvec (Imlygic) - FDA-approved for non-resectable melanoma - does not improve survival 11) distant metastases a) metastases renders melanoma incurable - resection is still indicated if primary tumor is resectable & metastases are limited [3] - surgical resection of isolated brain metastasis [3] - postoperative radiosurgery to tumor bed [3] b) combination of BRAF inhibitor plus MEK inhibitor (BRAF V600 mutation-positive) for metastatic melanoma - dabrafenib (Tafinalar) or vemurafenib [39] plus trametinib (Mekinist) or cobimetinib [34] - useful for patients with poor performance status &/or advanced disease [3] - vemurafenib induces clinical responses in > 1/2 of patients with previously treated BRAF V600 mutation-positive metastatic melanoma [44] c) ipilimumab (Yervoy) a checkpoint inhibitor (CTLA4 inhibitor) 1] FDA-approved to treat metastatic melanoma 2] improves survival 10 vs 6.5 months [24], not curative 3] ipilimumab apparently decreases Bacteroidales species in stool [46] d) tremelimumab in phase 3 trials e) prior to approval of ipilimumab 1] treatment did not prolong life, even if detected early when patient asymptomatic 2] chemotherapy was not indicated 3] workup for metastases was not indicated 4] 5 year survival < 5% f) pembrolizumab (PD-1 inhibitor) superior to ipilimumab [36] - 6 month survival 47% vs 25% [36] - treatment of cutaneous melanoma BRAF V600 mutation positive (NICE, NGC) - adjuvant chemotherapy after surgical resection of stage 3 cutaneous melanoma [53] - lenvatinib plus pembrolizumab [63] - pembrolizumab for patients with brain metastases [56] g) nivolumab (PD-1 inhibitor) + ipilimumab (CTLA4 inhibitor) superior to ipilimumab alone [36] - objective response rates of 61%, versus 11% [36] - > 50% response rates in brain metastases [54] - 53% response rate [62] - standard of care for immunotherapy in most patients [62] h) investigational 1] IL-2 plus gp100:209-217(210 M) peptide vaccine [16] 2] anti-PDCD1 &/or anti-CD274 antibody may induce tumor regression & prolonged stabilization in patients with advanced cutaneous melanoma, renal cell carcinoma, or non-small-cell lung cancer [19] 3] RNA vaccine elicits response in 17 of 42 patients with late-stage melanoma [59] 4] non-responders to immunotherapy may respond after fecal transplantation from patients who had responded to that immunotherapy. [60] 5] positive association between a Mediterranean diet & response to treatment with immune checkpoint inhibitors [67] 12) prognosis: survival by stage [18,42] a) localized: 98% b) regional: 61% c) distant: 15% d) checkpoint inhibitors have improved melanoma mortality rates [64] 13) follow-up [41] a) observation alone is an acceptable option for asymptomatic patients with surgically resected cutaneous melanoma [3] - annual skin examinations for life - monthly self examination [3] - low risk cutaneous melanoma (< 0.8 mm thickness) may be followed by physical examination & dermatologic evaluation every 6 months [3] b) imaging studies have low yield with fairly high false-positives [3] 14) prevention: - suncreen has not been shown to provide protection [3] - daily sunscreen uses reduces risk 50-75% [15] - aspirin may reduce risk of melanoma in postmenopausal white women [22] - vitamin D supplementation may reduce risk of cutaneous melanoma [66] - a diagnosis of melanoma does not change long-term behavior regarding unsafe sun exposure [25] Comparative biology: - fecal transplantation from mice with anti-melanoma immunity augments responses to anti-PDL1 immunotherapy [45] - augmented response apparently conferred by Bifidobacterium - fecal transplantation into mice from patients treated with ipilimumab enhances responses of mice to anti-CTLA4 therapy [46] Notes: - classification of melanoma in situ & early-stage invasive melanoma can vary among pathologists [52] - 8% of biopsies are over-interpreted & 9% are under- interpreted by the initial pathologist [52]

Interactions

disease interactions

Related

chromosomal translocation t(12;22)(q13;q12) (MMSP) clinical features distinguishing atypical from benign nevi melanocytic nevus (mole)

Specific

acral lentiginous melanoma anal melanoma desmoplastic melanoma external ear melanoma eyelid melanoma face melanoma lentigo maligna melanoma lip melanoma lower extremity melanoma nodular melanoma scalp/neck melanoma superficial spreading melanoma trunk melanoma upper extremity melanoma

General

melanoma skin cancer

References

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Databases & Images

OMIM correlations MORBIDMAP 123829 images related to cutaneous melanoma