PERSPECTIVE, PATTERNS OF SPREAD, AND PATHOLOGY
The risk factors remain excessive sun exposure, change in a nevus, and family history of melanoma.
PERSPECTIVE
The origin of melanoma can be as de novo lesions versus arising from nevi. It is due to the melanocyte—an ectodermal junctional cell located between the epidermal basale stratum and dermal papillary zone.
There are validated genes for skin nevus that are mutated and deregulated, leading normal melanocytes to progress into melanomas. The RB pathway prevents cell from incorrectly entering into the cell cycle; loss of the RB gene leads to retinoblastomas and many solid cancers. Its deregulation in melanoma is also established.
Malignant melanoma has been rising in incidence, with approximately 50,000 new cases annually; the increase is at an alarming rate of 6% per year. Melanomas occur particularly in white, fair-skinned persons and are rare in blacks. Emphasis on early diagnosis has been able to lower mortality rates to 20%, or 10,000 deaths annually. The ABC rule of the New York University Melanoma Cooperative Group is presented with DEF modifications and alerts physicians when to be suspicious of a pigmented skin lesion:
• Asymmetry of the lesion
• Border irregularity (or indistinctiveness)
• Color variation
• Diameter >6 mm
• Existing melanocytic nevi with recent change in color, size, shape
• Finding a new pigmented lesion, especially in persons >40 years of age
PATTERNS OF SPREAD
The histopathology categorizes four major clinical subtypes with their shared patterns of spread (Table 51.1; Fig. 51.1). They are lentigo malignant melanoma, superficial spreading melanoma, nodular melanoma, and acral lentiginous melanoma.
The lentigo variety is associated with sun exposure, whereas the others are characterized by an initial lesion with indolent enlargement of a primarily flat area with radial horizontal growth, followed by a vertical growth phase that signals aggressiveness and increases likelihood of nodal and hematogenous spread.
Clinically and histopathologically, there are four subtypes:*
Superficial spreading melanoma. Superficial spreading melanoma comprises about 70% of malignant melanoma lesions in whites, and most develop in a precursor nevus. The radial growth phase is characterized by an inflammatory response, which results in epidermal hyperplasia, slight elevation, and color variegation with a rose-pink component to the tan-to-brown lesion. Radial growth may progress over 1 to 12 years and is characterized by a 5% metastatic potential. Vertical growth phase proceeds much more rapidly, with the formation of a nodule with red, white, and blue coloration and 35% to 85% metastatic potential, depending upon depth. Superficial spreading melanomas occur most frequently on the back in males and the lower extremity in females.
Nodular melanoma. Nodular melanoma constitutes about 12% to 30% of malignant melanomas and is the most malignant form. The male:female incidence ratio is 2:1, and the median age of occurrence is 50 years. This lesion has only a vertical growth phase and evolves relatively quickly over several months to a year. Nodular melanoma usually develops on trunk or head and neck sites and arises de novo without a precursor lesion. There is a characteristic blue-black coloration, and lesions often ulcerate or bleed.
Lentigo maligna melanoma. Lentigo maligna melanoma comprises 4% to 15% of all malignant melanoma lesions and is the most benign in behavior. These lesions are seen most often on sun-exposed skin of the head and neck and dorsum of the hands. More common in women than in men, lentigo maligna melanoma has a median age of incidence of 70 years. In the radial growth phase, the lesions are flat and variegated with tan-to-brown coloration. There is very slow radial growth, and then the lesions become elevated with the onset of the vertical phase.
Acral lentiginous melanoma. Acral lentiginous melanoma represents 2% to 8% of all malignant melanomas but 35% to 90% of all malignant melanomas occurring in blacks, Asians, and Hispanics; it occurs on the palms and soles and in subungual regions. Lesions are characterized by a flat radial phase that may last for several years, followed by a more rapid vertical phase. Acral lentiginous melanoma is most common in the sixth decade, and metastases are common.
*Rubin P, Williams JP. Clinical Oncology: A Multi- Disciplinary Approach for Physicians & Students, 8th edition. Philadelphia, W.B. Saunders. 2001.p 260.
Figure 51.1 | A. Patterns of spread. The spread pattern of melanoma is both horizontal and vertical and is color coded for stage: Tis, yellow; T1, green; T2, blue; T3, purple; and T4, red. The concept of visualizing patterns of spread to appreciate the surrounding anatomy is well demonstrated by the six-directional pattern (SIMLAP, Table 51.1).
Figure 51.1 | B. Superficial spreading melanoma (SSM) with all the classic features of the ABCD mnemonic. C. A nodule of vertical growth phase melanoma arising from a radial growth phase pigmented macule on the right cheek.
Radial Growth Phase
In the radial growth phase (Fig. 51.1D), cells grow in the epidermis and are present in the dermis. They grow in all directions: outward, peripherally, and downward. The net direction of growth is peripheral—along the radii of an imperfect circle. Growth, as manifested by mitotic activity, is largely in the epidermis. No cells in the dermis seem to have a growth preference over others. The nest depicted here is shown as it evolves into the vertical growth phase. The anatomic landmarks of the levels of invasion are shown. Level III is not simply the occasional impingement of a tumor cell against the reticular dermis but indicates a collection of cells that fills and widens the papillary dermis and broadly abuts the reticular dermis. Level III invasion is usually a manifestation of the vertical growth phase. Level IV invasion should be designated only when tumor cells clearly permeate between otherwise unaltered collagen bundles of the reticular dermis.
Vertical Growth Phase
The evolved vertical growth phase (Fig. 51.1E) in malignant melanoma of the superficial spreading type is shown, with an indication of how thickness is measured. In this illustration, the vertical growth phase has extended into the reticular dermis. Small nodules of tumor cells that clearly have a growth preference over other tumor cells may be a manifestation of the vertical growth phase. Thickness measurements (arrows) are taken from the outermost granular layer across the tumor in its thickest part.
There are numerous modifications in some of the criteria such as mitotic rate, metastatic volume, elevated serum LDH, and level of invasion, which has been abandoned for staging. Thickness of the melanoma and ulceration are the same key criteria for staging.
Figure 51.1 | D. Radial growth phase.
Figure 51.1 | E. Verticle growth phase.
HISTOGENESIS AND HISTOPATHOLOGY
Histogenesis
The melanocyte is a junctional cell usually located at the interface between the dermis and the epidermis. The integumentary system encompasses the entire skin surface, including its folds, openings, adnexae, derivatives, and appendages. In humans, it is the largest organ, and its derivatives include nails, hair, and sweat and sebaceous glands. The skin consists of two layers—the epidermis and the dermis (Fig. 51.2). The superficial epidermis is nonvascular and consists of a stratified squamous epithelium with distinct cell types and layers referred to as strata. The dermis is the vascular zone, and the epidermis is avascular. The majority of the dermis is a dense, irregular connective tissue, and below this is the hypodermis or subcutaneous tissue, which is mainly a mixture of connective tissue and fat that forms the fascial layers. The epidermis can be thick or thin in different regions of the body. Thick skin is largely keratinized and devoid of hair and glands, whereas thin skin contains hair and sweat and sebaceous glands and tends to be the sites for malignancy.
The dermis consists of a papillary and a reticular layer. The papillary layer is at the junction of epidermis and dermis and is irregular owing to projections of dermal papillae that interdigitate with epidermal ridges. This layer is loose connective tissue, which has capillary loops, fibroblasts, and macrophages. The reticular layer is thicker and denser; it has connective tissue without distinct boundaries. The hypodermis blends inferiorly and contains superficial fascia and fat tissues. This layer contains Pacinian corpuscles; Meissner's corpuscles are at the dermal papillary level. Both provide sensory receptors for skin. The skin appendages lie in the reticular layer, extend into the hypodermis, and include hair follicles, merocrine sweat glands, and apocrine sebaceous glands (Fig. 51.2A).
The layers that constitute the epidermis have germinal stem cells, stratum basale. The next layer is the stratum spinosum, which is four or five cells thick. The stratum granulosum is filled with granules of keratohyalin. When the cell loses its nucleus, it becomes the stratum lucidum. Finally, the piling of cells in the stratum corneum consists of flat, dead cells that provide the thickness to skin and account for desquamation.
Melanocytes are the key cell in determining skin color and are of neural crest origin, that is, dendrite cells. One melanocyte may supply more than 30 keratinocytes with dendrites and melanin granules via spider-like extensions. Melanosomes are the pigment granules in distinctive organelles synthesized on small filaments. Melanomas reflect visible light, resulting in different skin colors (Fig. 51.2B).
Figure 51.2 | Orientation of integumentary system. The melanocyte interacts with several cells of the stratum basale and the stratum spinosum. A. Epidermis showing Clark levels. I. Epidermis. II. Dermis papillary. III. Reticular dermis. IV. Hypodermis or subcutaneous layer. B. A melanocyte supplies more than 30 keratinocytes with melanin granules by way of complex dendritic cytoplasmic extensions. Melanin granules are transferred to keratinocytes and come to lie in a supranuclear cap, a site indicating their protective function. Pigment granules are actually formed in the melanocytes within distinctive organelles—the melanosomes. Pigment is synthesized on small filaments within this organelle (inset).
Histopathology
The melanoma develops and extends either in a horizontal or a vertical growth phase as illustrated previously (Fig. 51.2D, E).
The various histologic types of melanoma are listed in Table 51.2.
The dysplastic melanocyte may grow to become continuous streams bridging from rete to rete. Large atypical nuclei portend neoplasia.
• The superficial spreading type (in a radial growth phase), occurring at the dermal–epidermal junction (Fig. 51.3A).
• The superficial spreading types (in a vertical phase) (Fig. 51.3B).
• The lower half of the reticular layer.
• The nodular type, in which the invasive component extends into the dermis (Fig. 51.3C).
• The acral lentiginous type (Fig. 51.3D).
Figure 51.3 | A. Compound nevus with melanocytic dysplasia. On the right, a compound nevus is apparent with both intraepidermal and dermal components. To the left, within the epidermis are single atypical melanocytes within the basal unit, as well as incipient lamellar fibroplasia. Dermal melanocytes are present below. B. Malignant melanoma, superficial spreading type, vertical growth phase. Vertical growth is manifested by the distinct spheroid tumor nodule to the right. A focus of melanocytes clearly has a growth advantage (larger size) over other nests in the radial growth phase (left). The nodule distorts the papillary dermal–reticular dermal junction and therefore is level III. C. Malignant melanoma, nodular type. Intraepidermal growth is essentially absent. There is no radial growth lateral to the nodule. This tumor expands the papillary dermis and distorts the reticular dermal junction; it is therefore level III. D. Malignant melanoma, acral lentiginous type, vertical growth phase. On the left is confluent growth of atypical dermal melanocytes filling and expanding the papillary dermis.
TNM STAGING CRITERIA
TNM STAGING CRITERIA
The origin of melanoma can be as de novo lesions versus arising from nevi. It is due to the melanocyte, an ectodermal junctional cell located between the epidermal basale stratum and the dermal papillary zone. A completely revised melanoma staging system is described in the seventh edition of the AJCC Cancer Staging Manual, based on a major data analyses of numerous prognostic factors derived from a 17,000-patient database from 13 centers. The major differences between the new version and the previous criteria are given later in Table 51.4.
The biologic aggressiveness is noted in the change of only 1 mm in size, which singles this malignancy out. Rather than measuring the cancer in centimeters, the stage and/or substage in melanomas advances by 1 mm. The T categories of melanoma are currently defined in whole integers: T1, 1 mm; T2, 2 mm; and T3, 4 mm. Subcategories such as ulceration or loss of overlying epidermis, assessed by histopathology, advances the stage. Regional nodes (N) are defined by radioisotope injection at the site and dissection of the radioactive sentinel node. The number of nodes involved defines the N category. Stage grouping has many gradations of both primary and nodes. Collectively the current staging system is subcategorized into 20 subgroupings. The scientific survival data analysis is exemplary and perhaps one of the most thorough in the Manual to justify the new subgroups.
SUMMARY OF CHANGES SEVENTH EDITION AJCC
• Mitotic rate (histologically defined as mitoses/mm2, not mitoses/10 HPF) is an important primary tumor prognostic factor. A mitotic rate equal to or greater than 1/mm2 denotes a melanoma at higher risk for metastases. It should now be used as one defined criteria of T1b melanomas. (Fig. 51.4; Table 51.1B)
• Melanoma thickness and tumor ulceration continue to be used in defining strata in the T category. For T1 melanomas, in addition to tumor ulceration, mitotic rate replaces level of invasion as a primary criterion for defining the subcategory of T1b.
• The presence of nodal micrometastases can be defined using either H&E or immunohistochemical staining (previously, only the H&E could be used).
• There is no lower threshold of tumor burden defining the presence of regional nodal metastasis. Specifically, nodal tumor deposits less than 0.2 mm in diameter (previously used as the threshold for defining nodal metastasis) are included in the staging of nodal disease as a result of the consensus that smaller volumes of metastatic tumor are still clinically significant. A lower threshold of clinically insignificant nodal metastases has not been defined on evidence.
• The site of distant metastases [nonvisceral (i.e., skin/soft tissue/distant nodal) vs. lung vs. all other visceral metastatic sites] continues to represent the primary component of categorizing the M category.
• Survival estimates for patients with intralymphatic regional metastases (i.e., satellites and in transit metastasis) are somewhat better than for the remaining cohort of Stage IIIB patients. Nevertheless, Stage IIIB still represents the closest statistical fit for this group, so the current staging definition for intralymphatic regional metastasis has been retained.
• The prognostic significance of microsatellites has been established less broadly. The Melanoma Task Force recommended that this uncommon feature be retained in the N2c category, largely because the published literature is insufficient to substantiate revision of the definitions used in the Sixth Edition Staging Manual.
• The staging definitions of metastatic melanoma from an unknown primary site was clarified, such that isolated metastases arising in lymph nodes, skin, and subcutaneous tissues are to be categorized as Stage III rather than Stage IV.
• The definitions of tumor ulceration, mitotic rate, and microsatellites were clarified.
• Lymphoscintigraphy followed by lymphatic mapping and sentinel lymph node biopsy (sentinel lymphadenectomy) remain important components of melanoma staging and should be used (or discussed with the patient) in defining occult Stage III disease among patients who present with clinical Stage IB or II melanoma.
IMPORTANT DETAILS FOR STAGING
• Tumor thickness is the strongest prognostic factor and is measured from the most superficial aspect of stratum granulosum to the deepest margin in the dermis.
• Dermal mitotic rate predicts poorer survival with increase in mitotic activity, and it is recommended to find “hot spots” with the most mitotic cells and view areas equal to 1 mm2. Lower rates are expressed as mitoses/mm2.
• Ulceration is associated with poorer survival and upstages melanomas of the same thickness for T stage a to b.
• Lymphocytic response refers to tumor infiltrating lymphocytes (TILs) and improves prognosis if present “location” head and neck are worse than trunk, with extremities being best.
• “Lymphatic spread” satellite lesions are “in-transit” metastases and portend a poor prognosis; however, microsatellites are less reliable predictors. Immunohistochemical staining (IHS) is now advised.
• “Node metastases” are ominous and decrease survival. These are determined in sentinel nodes. N1, one node; N2, two or three nodes; N3, four or more nodes and update T lesions to stage III.
SKIN INTEGUMENTARY SYSTEM–MELANOMA
Figure 51.4 | TNM staging diagram arranged vertically with T definitions on the left and stage groupings on the right. Melanoma with regard to size is one of the most virulent malignancies and spreads insidiously into lymph nodes. Ulcerations of a primary lesion (symbolically without [open dot with minus sign above] or with [solid dot with plus sign above]) and in-transit metastases [cluster of points] are ominous signs prognostically. Occult lymph nodes are microscopically positive ones. Color bars are coded for stage: stage 0, yellow; I, green; II, blue; IIIA, purple; IIIB/C, red; and IV, metastatic disease to viscera and nodes, black.
T-ONCOANATOMY, N-ONCOANATOMY, AND M-ONCOANATOMY
T-ONCOANATOMY
The skin can be divided into its surface sectors and the lymph node region that drains a sector. The incidence of melanoma, according to body sectors, with emphasis on gender related differences is presented in Fig. 51.5A. This can be age related distribution of melanoma peaks between 25 and 70 years. 66% of all patients are between 25 and 64 years. Only 22% of cases are less than 40 years of age (Fig. 51.5B).
• The head and neck includes the face and scalp. It is the face and scalp that demand careful attention clinically because of the complex functions, cosmesis, and special senses that all need to be preserved. The lymph node drainage of the integumentary surface differs from the upper aerorespiratory and digestive passages. The first station or echelon draining the skin of the face and scalp is a ring of superficial nodes: submental, submaxillary, facial, preauricular, parotid, mastoid, and occipital.
• Anterior chest wall from the clavicles to the navel in males tends to be hirsute. Lesions on the anterior thoracic wall skin drain to the anterior axillary nodes.
• Posterior chest wall to the same level tends to be less hirsute, is exposed more often to the sun, and is subject to forming cancers. The regional nodes are along the posterior wall of the axilla, although all axillary nodes are at risk.
• The upper extremity is an infrequent sector involved with skin cancer but can be a site for burn and chronic inflammation. It is notorious for radiation-induced cancer in dentists who finger-held dental films during their practice. Serial resections occur with loss of fingers, then the hand, and then the forearm. Involvement of epitrochlear node, then axillary nodes, invariably leads to the patient's death from pulmonary metastases.
• The anterior abdominal wall draws into the femoral and inguinal nodes, but this sector of skin is rarely involved with skin cancers.
• The posterior abdominal wall or skin of the lower back is an infrequent site of malignancy and drains to femoral and inguinal nodes.
• The lower extremity is not a common site for skin cancers. Burns or chronic inflammation may cause lesions to evolve from hyperplasia to dysplasia and on to neoplasia. Popliteal nodes drain the foot and leg and ultimately drain into superficial femoral lymph nodes, which also drain the thigh.
Figure 51.5A | Incidence of melanoma in Virginia, 1970 to 1996, by gender. (From Virginia Cancer Registry, 1999.)
Gender differences according to body locations differ for men and women. Males tend to have more lesions on the trunk and then the head and neck loci than do women. Females have more lesions on the lower and upper limbs than do men (Fig. 51.5A).
The vast majority of melanomas (66%) occur between 25 and 65 years of age, with a median age of 53 years, and peak between 65 and 70 years (Fig. 51.5B).
N-ONCOANATOMY
N-oncoanatomy of the skin surfaces emphasizes the anterior location for most if not all lymph node stations (see Fig. 51.6A, B, C).
• The concept of the sentinel lymph node began by injecting vital blue dye intradermally and then adding lymphoscintigraphy with 99mTc, draining lymph nodes were trapped and dissected. This is proved detection of sentinel nodes to 99% vs 83% for dye alone (Fig. 51.6C).
• The face and scalp drain into the superficial ring of nodes at the junction of the mandible and neck: submental, submandibular, preauricular, mastoid, and occipital nodes. Once involved, the rest of the deep lymph nodes in the neck along the carotid sheath and internal jugular vein are at risk.
• The axillary nodes are the recipient of lymphatics of the upper extremity and upper half body, both anterior and posterior skin surfaces.
• The femoral and inguinal nodes drain the lower extremity and the lower half of the body, both the anterior and posterior skin surfaces. The only exceptions are the popliteal lymph nodes that are posterior to knee joint, which drain the foot and leg.
M-ONCOANATOMY
There is a rich network of venous channels beneath all skin surfaces that allows for venous hematogenous spread once the dermal and hypodermal layers are penetrated by invading cancers. These venous collateral channels and plexus are rich and appear once obstruction occurs. (Fig. 51.6A, B).
Figure 51.5B | Age related incidence of melanoma in Virginia, USA, 1970–1999. (From Virginia Cancer Registry, 1999.)
Figure 51.6 | A. Overview of superficial and deep lymphatics. B. Lymphatic capillaries, vessels, and nodes. Black arrows indicate the flow (leaking of interstitial fluid out of blood vessels and absorption) into the lymphatic capillaries. C. Schematic of the method to identify using lymphoscintigraphy with Tc99m. The draining sentinel node using a handheld gamma camera.
STAGING WORKUP
RULES OF CLASSIFICATION AND STAGING
The clinical and pathologic classifications are identified. Clinical staging is based on physical examination, inspection, and palpation of primary sites and draining regional nodes. Imaging with regular radiographs is adequate and includes skull films, facial bones, and mandible for deeply invading or fixed tumors beyond T1 in size. Computed tomography may be desirable for deeper invasion. Because of the high proclivity to metastasize, all advanced-stage melanoma must be thoroughly assessed with enhanced computed tomography and magnetic resonance imaging, especially if symptomatic (Table 51.3A).
It is important to compare the changes in the sixth versus the seventh edition of the AJCC Manual for accuracy in staging (Table 51.1B).
Pathologic Staging
Complete resection of the entire site is often performed with wide margins and the need to determine if there is any residuum. Skin grafting may be required to close the defect. Orientation of the section is critical to be sure the microsection is at a right angle to the skin surface. Any obliquity may increase the size of the melanoma depth of invasion. Ulceration advances the stage and must be determined on histopathology.
Sentinel lymph node biopsy is recommended for all T stages: T1b, T2, T3, and T4.
• Clinical assessment of regional lymph nodes is done after excision of the primary tumor.
• Complete staging of regional lymph nodes is done after surgical resection of the nodes.
PROGNOSIS AND CANCER SURVIVAL
PROGNOSIS
The limited number of prognostic factors are listed in Table 51.4.
Cox regression analysis of prognostic factors in 10,233 patients with localized cutaneous melanoma (stage I and II) is given in Table 51.5.
CANCER STATISTICS AND SURVIVAL
Without exception, the cancer facts, findings, and statistics have been meticulously compiled (Fig. 51.7). The analysis of data on melanoma in the sixth edition of the AJCC Manual is very detailed and supports splitting four stages into 20 subgroupings as to outcomes. There are 63,130 new cases annually, 8,700 of whom will die. The 5-year survival rates of pathologically staged patients by Balch et al. demonstrate that ulceration and nodal involvement decrease survival. The differences in 15-year survival by stage are shown for localized stages IA and IB (>50%) versus stage III (30%) for nodal involvement and 10% survival at 5 years for stage IV metastasis based on the AJCC database of 17,000 patients with complete clinical and pathologic data.
Tumor Thickness as sole predictor of ten year survival after definitive therapy of primary melanoma Table 51.6. According to the recent American Cancer Society Figures and Facts 2010, the five year survival, according to stage, is:
• All stage 91%
• Localized 98%
• Regional 62%
• Metastatic 32%
Figure 51.7 | Survival curves based on melanoma staging according to AJCC melanoma staging database. (Data from Edge SB, Byrd DR, Compton CC, et al., AJCC Cancer Staging Manual, 7th edition, New York, Springer, 2010, p. 329, Table 31.3.)
