CHAPTER 21
MALIGNANT MELANOMA, MELANOCYTIC NEVI
AND THEIR SIMULATORS（悪性黒色腫、色素性母斑と類似症）
I. Origin of Melanoma Cells and Biological Characteristics
A. Origin of Melanoma Cells（黒色腫細胞の起源）
1. Melanoma cells derive from malignant transformation of melanocytes.
2. Melanocytes originate embryologically from neural crest tissues.
3. Melanocytes are dendritic and are located in the basal layer of the epidermis.
4. Melanocytes possess a unique biological property, i.e., synthesis of melanin and melanosomes, which is responsible for unique brown black coloration of malignant melanoma.
B. Biological Characteristics（生物学的特性）
Melanoma cells are derived from 2 ways:
(1) de novo malignant transformation of normal epidermal melanocytes（正常表皮メラノサイトの局所悪性変化）, and
(2) malignant transformation of pre-existing nevus cells, i.e., nevo-melanocytic cells（既存の母斑細胞の癌化）.
These two cell types are located above the basement membrane of the epidermis of the skin and mucosa. It is generally accepted that 50% of melanoma occurs from de novo malignant transformation of normal epidermal melanocytes and the remaining 50% derives from malignant transformation of pre-existing nevus cells.
II. Growth Pattern, Clinical Subtypes and Histopathological Correlation
A. Growth Pattern
Two major growth patterns of melanoma cells:
1. Radial, lateral along epidermal surface
2. Vertical, invasive to dermis
B. Growth Pattern and Clinical Subtypes of Melanoma
Based upon these unique growth patterns of malignant
melanocytes, there are 4 major subtypes of malignant
melanoma. These are:
1. Lentigo maligna melanoma（悪性黒子型悪性黒色腫）- LMM
2. Superficial spreading melanoma（表在性拡大性悪性黒色腫） - SSM
3. Nodular melanoma（結節性悪性黒色腫）- NM
4. Acral lentiginous melanoma（末端黒子型悪性黒色腫）- ALM
LMN, SSM and ALM have both radical and vertical growth phases, whereas, nodular melanoma takes only vertical growth phase. Each subtype has unique clinical and histopathological features as well as distribution in the body which will be discussed in the following.
C. Lentigo Maligna Melanoma（悪性黒子型悪性黒色腫）
1. Least common form of melanoma in Caucasians; most common in Orientals
2. Almost exclusively limited to the markedly sun-exposed skin of face and neck, cheek being the most common
3. Long period of radial growth phase, 3-15 years
4. Flat lesion with various shades of tan, brown, black and occasional hypopigmentation (regression)
5. 3-6 cm in size: average age of onset being 65 years
6. Extensive variation in morphologic features of epidermal melanocytes in tan, brown and flat black lesions
D. Superficial Spreading Melanoma（表在性拡大性悪性黒色腫）
1. Most commonly diagnosed in 4th and 5th decades (average 44)
2. Most frequent histopathological and clinical variant of melanoma among Caucasians (70%)
3. Palpable lesion with various shades of brown, black, grey and red; definite angular notches or protrusions.
4. 2.5 cm in size, 1-7 years of radial growth phase
5. Most frequently involving trunk, back in men and lower legs in women
6. Most frequently associated with contiguous melanocytic nevi
E. Nodular Melanoma（結節性悪性黒色腫）
1. Next most prevalent subtype after SSM in Caucasians
2. Most common site: trunk in men and legs in women
3. Rapid evolution, 6 to 18 months on average
4. 1 to 2 cm in size: dark, blueberry-like nodule or raised plaque with quite uniform dark discoloration
5. Affecting all sites
6. Median age 53 years
7. Little tendency for intraepidermal growth
8. Invasion of dermis conjointly with any area of intraepidermal invasion
F. Acral Lentiginous Melanoma（末端黒子型悪性黒色腫）
1. Relatively infrequent among Caucasians (2-8%), but most common in dark-skinned people
2. Involves acral parts of body, sole being most common
3. Older individuals: 65 years
4. Similar clinical and histopathological appearance to SSM but much more aggressive
1. Macular, lateral growth component with irregular borders and variegation in coloration
2. Basilar proliferation of large melanocytes with elongated dendrites
All these 3 types of melanoma occurs on the trunk, face and limbs affecting primarily the sun?exposed areas. There is a remarkable difference for the distribution of melanoma on the lower legs between men and women, with the women showing a higher incidence of melanoma on the calves where the sunlight may reflect, through the asphalt because women wear skirts. In contrast, the melanoma incidence for men on lower legs are low because the sites are usually covered by pants.
H. Comparative Histologic Features of the Radial Growth Phases of Acral Lentiginous, Superficial Spreading, and Lentigo Maligna Types
|
|
ACRAL LENTIGINOUS MELANOMA |
LENTIGO MALIGNA MELANOMA |
SUPERFICIAL SPREADING MELANOMA |
|
Location of melanoma cells within the epidermis |
Basilar region |
Basilar region |
All epidermal layers |
|
Cytology of the individually disposed intraepidermal melanocytes |
Uniformly large with prominent, complex dendrites |
Pleomorphic - "normal" and bizarre melanocytes mixed. Dendrites inconspicuous |
Uniformly large epithelioid cells without prominent dendrites |
|
Histology of the intraepidermal nests of melanocytes |
Nests tend to bulge into dermis |
Nests may be ellipsoidal in outline with the long axis tending to parallel the epidermal surface |
Nests quite large frequently bridging the entire thickness of the epidermis |
|
Cytology of the melanocytes forming the intraepidermal nests |
Cells tend to be spindle shaped, may be epithelioid |
Cells are pleomorphic, some quite small, others large and bizarre |
Uniformly large epithelioid cells form the nests |
|
Invasion of the papillary dermis |
Present, but may require search to find it |
Essentially absent |
Easily demonstrated |
|
Solar changes in connective tissue |
Absent |
Present |
Variable |
|
Host response of lymphocytes and macrophages |
Present and prominent with extension into epidermis |
Minimal to absent |
Usually well developed |
Clark WC Jr et al, in Human Malignant Melanoma, Grane & Stratton
III. Unusual Forms of Melanoma
A. Subungual Melanoma（爪甲下黒色腫）
B. Amelanotic Melanoma（無色素性黒色腫）
C. Mucosal Melanomas（粘膜黒色腫）: mouth, eye, ear, nose, anorectum, vagina
D. Eye Melanoma (uveal or ciliochoroidal)
E. Leptomeningeal Melanoma（軟脳膜黒色腫）
F. Unknown Primary Melanoma
IV. Prognostic Factors for Cutaneous Melanoma
A. Clinical Variables
1. Age - worse prognosis with increasing age
2. Sex - women have better prognosis than men
3. Anatomic site - extremity more favorable prognosis
B. Histologic Variables of Primary Tumor
1. Tumor thickness - worse prognosis with increasing thickness
2. Levels of invasion - worse prognosis with deeper levels
3. Ulceration - worse prognosis with presence of ulceration
4. Regression - increased risk for metastasis in tumors < 1.0 mm with marked regression
The tumor invasion is divided into 5 levels and the tumor thickness is measured from the top of the granular layer to the bottom of the tumor. The tumor thickness as well as the level of invasion have a fairly good correspondence to the overall 5-year survival. If the tumor has a Level V invasion and tumor thickness of more than 3.0 mm, the patient will unfortunately die with a risk of more than 50% no matter what treatment is used on the patient.
In contrast, if the tumor is located with the papillary dermis, having < 0.75 mm in tumor thickness, you may be able to get a 5-year survival rate, i.e., more than 98-99% cure. If the tumor is confined to the epidermis, a 100% cure rate is obtained.
One should also be careful for the high risk thin melanoma which has a tumor thickness < 1.0 mm but has a regression. The regression of the primary melanoma does not mean a good prognosis but it shows a poorer prognosis. One has to be very careful to tell the patient requiring the prognosis even though the primary tumor shows less than 1.0 mm in tumor thickness. In our practice, we usually see at least 10% of melanoma metastasis from these thin melanoma group.
C. Anatomic Distribution of Mucosal Malignant Melanomas
|
Location |
No. |
% of all Melanomas |
|
Skin |
899 |
85.6 |
|
Eyes |
102 |
9.7 |
|
Central Nervous System |
2 |
0.2 |
|
Mucosal Primary Lesions |
47 |
4.5 |
| TOTAL | 1,050 | 100.1 |
CCABC = Cancer Control Agency of British Columbia
D. Anatomic Distribution of Mucosal Malignant Melanomas
|
Location
|
No.
|
% of all Melanomas
|
|
Head & Neck |
20 |
1.9 |
|
Vulva |
14 |
1.3 |
|
Vagina |
7 |
0.7 |
|
Anal Canal |
3 |
0.2 |
|
Female Urethra |
2 |
0.1 |
|
Esophagus |
1 |
0.1 |
|
TOTAL
|
47
|
4.5
|
CCABC = Cancer Control Agency of British Columbia
E. Risk Factors for the Development of Malignant Melanoma
1. Pigmentary Characteristics
a. Blue eyes
b. Blond, fair, or red hair
c. Fair or pale complexion
2. Response to Sun Exposure
a. Tendency to sunburn
b. Inability to tan (skin prototype I)
c. Freckling tendency
3. Upper socioeconomic status
F. 5-Year Survival of Cutaneous Melanoma
|
Level of Invasion |
Clark, et al |
McGovern et al |
Wanebo et al |
Balch et al |
Eldh et al |
|
I |
--- |
--- |
--- |
--- |
--- |
|
II |
72(36) |
82(51) |
100(29) |
85(36) |
100(67) |
|
III |
47(71) |
65(62) |
88(58) |
72(70) |
87(111) |
|
IV |
32(76) |
49(53) |
65(58) |
57(78) |
72(127) |
|
V |
12(25) |
29(17) |
16(6) |
28(28) |
35(19) |
G. Risk Factors for the Development of Malignant Melanoma
1. Family history of melanoma
2. Sex, reproductive, and hormonal status
3. Melanocytic nevi
a. Increased numbers of nevi
b. Atypical nevus characteristics
1) Increased nevus size
2) Irregular border
3) Variegated color
c. Nevi with architectural and cytological atypia (dysplastic nevi)
d. Congenital nevi
4. History of nonmelanoma skin cancer
V. Treatment of Melanoma
A. Principle
1. Primary cutaneous melanoma; surgical excision with/without skin graft
2. Regional metastasis; complete lymph node dissection. Hyperthermic regional limb perfusion
3. Distant metastasis:
a. surgery: skin, lung, brain and GI metastasis
b. radiation therapy: brain metastasis, pain of bone
c. chemotherapy: dacarbazine (DTIC) with/without combination of VCR, ACNU, BLM, and/or cisplatin
d. immunotherapy: IFN, TNF, IL-2, TILs with IL-2
e. gene therapy: ?
B. Margins of Surgical Resection for Clinical Stage I Melanoma
|
Tumor Thickness, mm |
Margins of Surgical Resection, cm |
|
in situ |
0.5 |
|
< 1.0 |
1 |
|
1.0 - 1.5 |
1.5 |
|
1.5 - 4.0 |
2 to 3 |
|
> 4.0 |
3 |
VI. Differential Diagnosis and Precursors of Melanoma
A. Possible Precursors of Human Melanoma and Differential Diagnosis
1. Common acquired nevomelanocytic nevus（通常型後天性色素細胞性母斑）
2. Acquired dysplastic melanocytic nevus（後天性異型色素細胞性母斑）
3. Congenital nevomelanocytic nevus（先天性色素細胞性母斑）
4. Halo nevomelanocytic nevus（白暈母斑）
5. Spitz's nevus（スピッツ母斑）or juvenile melanoma（若年性黒色腫）
6. Blue nevus（青色母斑）
7. Dermal melanocytosis（真皮メラノサイトーシス）
8. Lentigo simplex（単純黒子）, lentigo seniles（老人性色素斑） (solar lentigo)
9. Lentigo maligna （悪性黒子）
B. Common Acquired Nevomelanocytic Nevus
1. Appears after the first 6 to 12 months of life, enlarges with body growth and regresses in later life.
2. Darker skin is associated with fewer nevi (2-8 in American blacks vs 14-15 whites).
3. Prevalence of pigmented line on nail beds in race-related; 20-23% in Japanese, 96% in blacks older than 50 yrs and extremely rare in Whites.
4. Prevalence of nevi on conjunctivae and acral parts is race-related; 0.9% in whites and 4% in blacks.
5. Pigmented lesions on external genitalia are common in all races, 10-14%
C. Acquired Dysplastic Melanocytic Nevus（後天性異型色素細胞性母斑）
1. Dysplasia derives from Greek, dys ("bad") and plasis (molding), referring abnormal tissue development.
2. Fairly unique clinical features: flat surface relative to breadth, irregular and/or fuzzy outlines, irregular coloration, and "fried-egg" appearance.
3. Unique histopathological features: basilar proliferation of atypical nevomelanocytes, lentiginous or epithelioid-cell patterns of intraepidermal melanocytic proliferation, concentric eosinophilic fibrosis, neovascularization and dermal inflammatory response.
D. Familial Dysplastic Nevus Syndrome（家族性異型母斑症候群）
1. Laboratory evidence of increased sensitivity to UVR
2. Increased propensity to develop dysplastic nevi in sun-exposed areas
3. Autosomal dominant
4. High risk for melanoma development from moles: 80-100% and 56% by age 76 and 20?59 years, respectively
5. Not all family members have an equal risk of melanoma development; the more moles the higher the risk for melanoma
E. Comparison of Common Nevus and Dysplastic Nevus
1. Common Nevus（通常型母斑）
a. any site, sparing of "sun-protected" area
b. smooth, regular, well-demarcated outline
c. majority < 5 mm
d. orderly, symmetric distribution of no more than 2 colors
e. round or oval
f. dome shaped
2. Dysplastic nevus（異型母斑）
a. any site, but common in "horse collar" area
b. irregular, poorly demarcated outline
c. usually > 5 mm
d. disorderly, haphazard display of more than 2 colors
e. fried egg shaped
F. Congenital Nevomelanocytic Nevus
1. Apparent at birth, showing a number of variants; garment nevus, bathing trunk nevus, hairy nevus, giant nevus, verrucous nevus, divided nevus
2. Lifetime risk of melanoma development is high for giant nevus, at least 6.3%, and grave with sudden appearance of dermal or subcutaneous nodule.
3. Giant nevi of head/neck or posterior midline are associated with underlying cranial or spinal leptomeningeal melanocytosis; neurocutaneous melanosis having a poor prognosis (obstructive hydrocephalus)
G. Spitz's Nevus（スピッツ母斑）
1. Called also as juvenile melanoma because of histopathologically bizarre appearance
2. Benign acquired nevomelanocytic nevus
3. Solitary, asymptomatic, pink or red, hairless, firm dome-shaped telangiectatic papular nodule
4. Compound nevus with bizarre mononuclear and multinuclear giant cells, nuclear polymorphism but no atypical mitosis, cleft formation of junctional nest, widely dilated blood vessels
H. Blue Nevus（青色母斑）
1. Acquired or congenital blue, blue-grey, or blue-black papule, nodule, or plaque-like aggregate of aberrant dermal melanocytes actively producing melanin
2. Common blue nevus: benign and no malignancy
3. Cellular blue nevus: larger, more elevated and more aggressive locally than the common form and a variety of melanoma may develop
4. Ectopic accumulation of melanin-producing melanocytes in dermis during their migration from neural crest to site in skin
I. Lentigo（黒子）
1. Derive from Latin lens, "lentil", small brown spots
2. Lentigo simplex: melanocytic hyperplasia
3. Solar lentigo: brown spots caused by natural or artificial UVR and increased number of dendritic melanocytes without nesting
4. Lentigo maligna: intraepidermal in situ melanoma or melanocytic dysplasia
VII. Simulators of Malignant Melanoma
A. Melanotic Lesions
1. Simple lentigines（単純黒子）, and junctional and compound types of melanocytic nevi with features of simple lentigines
2. Solar lentigines（日光黒子）
3. Seborrheic keratoses（脂漏性角化症）
4. Dermatofibromas（皮膚線維腫）
5. Pigmented basal-cell carcinomas（色素性基底細胞癌）
B. Hemorrhagic Extravasations
Hemorrhage in the cornified layer of the epidermis, nail bed, or nail plate
1. Hemangiomas（血管腫）
2. Thrombosed capillary aneurysms（血栓性毛細血管性動脈瘤）
3. Kaposi's sarcoma（カポジ肉腫）
D. Adventitious Pigmentations, Particularly from Carbon
Tattoos - commercial and traumatic
E. Pigmentation Produced by Micro-Organisms
Tinea nigra（黒癬）
F. Pyogenic Granuloma（化膿性肉芽腫）
＜悪性黒色腫患者の5年生存率＞
|
Stage |
TNM |
thickness |
level |
5年生存率 |
|
I |
pT1 |
<0.75 or 0.75 mm |
II |
100% |
|
|
pT2 |
0.75<<1.5 or 1.5 mm |
III |
|
|
II |
pT3a |
1.5<<3.0 or 3.0 mm |
IV |
75% |
|
|
pT3b |
3.0<<4.0 or4.0 mm |
IV |
|
|
III |
pT4a |
4.0 mm< |
V |
50% |
|
|
pT4b |
satellite (s) |
2 cm以内の皮膚、皮下転移 |
|
|
|
N1 |
長径3 cm以下の所属リンパ節転移 |
|
|
|
|
N2a |
長径3 cmを越える所属リンパ節転移 |
|
|
|
|
N2b |
in-transit |
2 cmを越える皮膚、皮下転移 |
|
|
|
N2c |
N2a and N2b |
|
|
|
IV |
M1a |
(所属リンパ節を越えた皮膚、皮下、リンパ節転移) |
2年生存率 |
|
|
|
M1b |
(血行性転移) |
|
20%以下 |
＜母斑（ホクロ）とメラノーマの臨床的鑑別＞
A: asymmetry: 非対照性
B: Border irregular: 辺縁不規則
C: Color variegated:色調が多彩
D: Diameter: 直径
E: Elevation (Enlargement): 隆起（増大）